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Cancers, Volume 3, Issue 1 (March 2011), Pages 1-1479

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Research

Jump to: Review, Other

Open AccessArticle Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer
Cancers 2011, 3(1), 61-78; doi:10.3390/cancers3010061
Received: 11 November 2010 / Revised: 20 December 2010 / Accepted: 27 December 2010 / Published: 28 December 2010
Cited by 21 | PDF Full-text (1187 KB) | HTML Full-text | XML Full-text
Abstract
The triblock copolymer is composed of two identical hydrophilic segments: Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε‑caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG‑COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer [...] Read more.
The triblock copolymer is composed of two identical hydrophilic segments: Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε‑caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG‑COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer Therapeutics)
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Open AccessArticle Detection of up to 65% of Precancerous Lesions of the Human Colon and Rectum by Mutation Analysis of APC, K-Ras, B-Raf and CTNNB1
Cancers 2011, 3(1), 91-105; doi:10.3390/cancers3010091
Received: 24 October 2010 / Revised: 7 December 2010 / Accepted: 20 December 2010 / Published: 29 December 2010
Cited by 1 | PDF Full-text (268 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signaling pathways was used to analyze 20 colorectal serrated lesions and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned potentially precancerous [...] Read more.
In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signaling pathways was used to analyze 20 colorectal serrated lesions and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned potentially precancerous lesions carrying at least one of the four above-mentioned genes in a mutated form. CTNNB1 and B-Raf were screened by PCR-single-strand conformation polymorphism analysis, K-Ras by restriction fragment length polymorphism analysis and the APC gene mutation cluster region (codons 1243–1567) by direct DNA sequencing. APC mutations were only detected in 10% of the serrated lesions but in 34% of the adenomas. Twenty percent of the serrated lesions and 14% of the adenomas carried a mutated K-Ras. B-Raf was found to be mutated in 50% of the serrated lesions and in 22% of the adenomas. CTNNB1 was altered in 12% of the adenomas, but not in serrated lesions. By using the above gene marker panel it could be shown that 65% of the serrated lesions and 61% of the adenomas carried at least one of the four genes in a mutated form. Based on its excellent performance in detecting mutations in sporadic preneoplastic (in this study) and neoplastic lesions (in a previous study) of the human colon and rectum, this primer combination might also be suited to efficiently and non-invasively detect genetic alterations in stool DNA of patients with early colorectal cancer. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
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Open AccessArticle Dependence of Relative Expression of NTR1 and EGFR on Cell Density and Extracellular pH in Human Pancreatic Cancer Cell Lines
Cancers 2011, 3(1), 182-197; doi:10.3390/cancers3010182
Received: 1 December 2010 / Revised: 24 December 2010 / Accepted: 27 December 2010 / Published: 4 January 2011
Cited by 4 | PDF Full-text (581 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic adenocarcinoma is a devastating disease characterized by early dissemination and poor prognosis. These solid tumors express receptors for neuropeptides like neurotensin (NT) or epidermal growth factor (EGF) and exhibit acidic regions when grown beyond a certain size. We previously demonstrated increases [...] Read more.
Pancreatic adenocarcinoma is a devastating disease characterized by early dissemination and poor prognosis. These solid tumors express receptors for neuropeptides like neurotensin (NT) or epidermal growth factor (EGF) and exhibit acidic regions when grown beyond a certain size. We previously demonstrated increases in intracellular Ca2+ levels, intracellular pH and interleukin-8 (IL-8) secretion in BxPC-3 and PANC-1 pancreatic cancer cells in response to a stable NT analog. The present study aimed at investigation of the dependence of the relative expression of NT receptor 1 (NTR1) and EGFR in BxPC-3 and MIA PaCa-2 cells on cell density and extracellular pH (pHe). MTT assays revealed the NTR1 inhibitor SR 142948-sensitive Lys8-ψ-Lys9NT (8–13)-induced proliferation in BxPC-3 and PANC-1 cells. Confluent cultures of BxPC3 and HT-29 lines exhibited highest expression of NTR1 and lowest of EGFR and expression of NTR1 was maximal at slightly acidic pHe. IL-8 production was stimulated by Lys8-ψ-Lys9NT (8–13) and even enhanced at both acidic and alkaline pHe in BxPC-3 and PANC-1 cells. In conclusion, our in vitro study suggests that one contributing factor to the minor responses obtained with EGFR-directed therapy may be downregulation of this receptor in tumor cell aggregates, possibly resulting in acquisition of a more aggressive phenotype via other growth factor receptors like NTR1. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessArticle Anti-Neuroblastoma Activity of Gold Nanorods Bound with GD2 Monoclonal Antibody under Near-Infrared Laser Irradiation
Cancers 2011, 3(1), 227-240; doi:10.3390/cancers3010227
Received: 7 December 2010 / Revised: 26 December 2010 / Accepted: 4 January 2011 / Published: 6 January 2011
Cited by 7 | PDF Full-text (539 KB) | HTML Full-text | XML Full-text
Abstract
High-risk neuroblastoma is one of the most common deaths in pediatric oncology. Current treatment of this disease involves a coordinated sequence of chemotherapy, surgery, and radiation. Further advances in therapy will require the targeting of tumor cells in a more selective and [...] Read more.
High-risk neuroblastoma is one of the most common deaths in pediatric oncology. Current treatment of this disease involves a coordinated sequence of chemotherapy, surgery, and radiation. Further advances in therapy will require the targeting of tumor cells in a more selective and efficient way so that survival can be improved without substantially increasing toxicity. To achieve tumor-selective delivery, disialoganglioside (GD2) expressed by almost all neuroblastoma tumors represents a potential molecular target that can be exploited for tumor-selective delivery. In this study, GD2 monoclonal antibody (anti-GD2) was conjugated to gold nanorods (GNRs) which are one of anisotropic nanomaterials that can absorb near-infrared (NIR) laser light and convert it to energy for photothermolysis of tumor cells. Thiolated chitosan, due to its biocompatibility, was used to replace cetyltrimethylammonium bromide (CTAB) originally used in the synthesis of gold nanorods. In order to specifically target GD2 overexpressed on the surface of neuroblastoma stNB-V1 cells, anti-GD2 was conjugated to chitosan modified GNRs (CGNRs). To examine the fate of CGNRs conjugated with anti-GD2 after incubation with neuroblastoma cells, rhadoamine B was labeled on CGNRs functionalized with anti-GD2. Our results illustrated that anti-GD2-conjugated CGNRs were extensively endocytosed by GD2+ stNB-V1 neuroblastoma cells via antibody-mediated endocytosis. In addition, we showed that anti-GD2 bound CGNRs were not internalized by GD2 SH-SY5Y neuroblastoma cells. After anti-GD2-linked CGNRs were incubated with neuroblatoma cells for six hours, the treated cells were further irradiated with 808 nm NIR laser. Post-NIR laser exposure, when examined by calcein-AM dye, stNB-V1 cells all underwent necrosis, while non-GD2 expressing SH-SY5Y cells all remained viable. Based on the in vitro study, CGNRs bound with anti-GD2 has the potential to be utilized as a therapeutic thermal coupling agent that generates heat sufficient to selectively kill neuroblastoma cells under NIR laser light exposure. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer Therapeutics)
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Open AccessArticle Ras Isoprenylation and pAkt Inhibition by Zoledronic Acid and Fluvastatin Enhances Paclitaxel Activity in T24 Bladder Cancer Cells
Cancers 2011, 3(1), 662-674; doi:10.3390/cancers3010662
Received: 29 December 2010 / Revised: 30 January 2011 / Accepted: 9 February 2011 / Published: 14 February 2011
Cited by 4 | PDF Full-text (328 KB) | HTML Full-text | XML Full-text
Abstract
Background: Bisphosphonates interfere with the mevalonate pathway and inhibit the prenylation of small GTP-binding proteins such as ras and rap. We hypothesized that zoledronic acid would synergistically inhibit T24 bladder cancer cell growth in combination with fluvastatin and paclitaxel. Methods: [...] Read more.
Background: Bisphosphonates interfere with the mevalonate pathway and inhibit the prenylation of small GTP-binding proteins such as ras and rap. We hypothesized that zoledronic acid would synergistically inhibit T24 bladder cancer cell growth in combination with fluvastatin and paclitaxel. Methods: Increasing doses of fluvastatin, zoledronic acid, and paclitaxel were investigated as single agents and in combination, and synergistic interactions were evaluated by the Chou-Talalay method. Western blots were used to assess effects on signal transduction pathways. Results: Growth of T24 was significantly inhibited with IC50 values of 2.67 ± 0.61 mM for fluvastatin and 5.35 ± 1.35 mM for zoledronic acid after 72 hours treatment. Geranylgeranyl pyrophosphate and farnesyl pyrophosphate was able to block, in part, this inhibitory activity. The combinations of zoledronic acid and paclitaxel, zoledronic acid and fluvastatin, and fluvastatin and paclitaxel were all synergistic. Both fluvastatin and zoledronic acid inhibited Ras and Rap prenylation, and the phosphorylation of ERK1/2 and AKT. The degree of inhibition of phosphorylation of these key signaling transduction pathways appears to closely correlate with their synergistic interactions. Conclusions: Zoledronic acid enhances fluvastatin and paclitaxel activity against T24 in a synergistic manner and this is mediated largely by inhibition of both the Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways via isoprenylation inhibition. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
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Open AccessArticle A Methodological Framework for Evaluating the Evidence for Complementary and Alternative Medicine (CAM) for Cancer
Cancers 2011, 3(1), 773-788; doi:10.3390/cancers3010773
Received: 24 January 2011 / Revised: 5 February 2011 / Accepted: 21 February 2011 / Published: 23 February 2011
Cited by 1 | PDF Full-text (164 KB) | HTML Full-text | XML Full-text
Abstract
In spite of lacking evidence for effects on cancer progression itself, an increasing number of cancer patients use various types of complementary and alternative medicine (CAM). There is disagreement between CAM practitioners, researchers and clinical oncologists, as to how evidence concerning effects [...] Read more.
In spite of lacking evidence for effects on cancer progression itself, an increasing number of cancer patients use various types of complementary and alternative medicine (CAM). There is disagreement between CAM practitioners, researchers and clinical oncologists, as to how evidence concerning effects of CAM can and should be produced, and how the existing evidence should be interpreted. This represents a considerable challenge for oncologists; both in terms of patient needs for an informed dialogue regarding CAM, and because some types of CAM may interact with standard treatments. There is a need for insight into which kinds of CAM may work, for whom they work, what the possible effects and side-effects are, and in what ways such effects may come about. The present article presents a framework for evaluating effects of CAM by suggesting a taxonomy of different levels of evidence related to different types of research questions and discussing the relevance of different research methodologies for different types of effects. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessArticle Mastic Oil Inhibits the Metastatic Phenotype of Mouse Lung Adenocarcinoma Cells
Cancers 2011, 3(1), 789-801; doi:10.3390/cancers3010789
Received: 30 December 2010 / Revised: 9 February 2011 / Accepted: 15 February 2011 / Published: 23 February 2011
Cited by 5 | PDF Full-text (420 KB) | HTML Full-text | XML Full-text
Abstract
Mastic oil from Pistacia lentiscus variation chia, a natural combination of bioactive terpenes, has been shown to exert anti-tumor growth effects against a broad spectrum of cancers including mouse Lewis lung adenocarcinomas (LLC). However, no studies have addressed its anti-metastatic actions. [...] Read more.
Mastic oil from Pistacia lentiscus variation chia, a natural combination of bioactive terpenes, has been shown to exert anti-tumor growth effects against a broad spectrum of cancers including mouse Lewis lung adenocarcinomas (LLC). However, no studies have addressed its anti-metastatic actions. In this study, we showed that treatment of LLC cells with mastic oil within a range of non-toxic concentrations (0.01–0.04% v/v): (a) abrogated their Matrigel invasion and migration capabilities in transwell assays; (b) reduced the levels of secreted MMP-2; (c) restricted phorbol ester-induced actin remodeling and (d) limited the length of neo-vessel networks in tumor microenvironment in the model of chick embryo chorioallantoic membrane. Moreover, exposure of LLC and endothelial cells to mastic oil impaired their adhesive interactions in a co-culture assay and reduced the expression of key adhesion molecules by endothelial cells upon their stimulation with tumor necrosis factor-alpha. Overall, this study provides novel evidence supporting a multipotent role for mastic oil in prevention of crucial processes related to cancer metastasis. Full article
(This article belongs to the Special Issue Lung Cancer)
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Open AccessArticle Plasmonic Nanobubbles as Tunable Cellular Probes for Cancer Theranostics
Cancers 2011, 3(1), 802-840; doi:10.3390/cancers3010802
Received: 19 January 2011 / Revised: 12 February 2011 / Accepted: 17 February 2011 / Published: 23 February 2011
Cited by 26 | PDF Full-text (1984 KB) | HTML Full-text | XML Full-text
Abstract
This review is focused on a novel cellular probe, the plasmonic nanobubble (PNB), which has the dynamically tunable and multiple functions of imaging, diagnosis, delivery, therapy and, ultimately, theranostics. The concept of theranostics was recently introduced in order to unite the clinically [...] Read more.
This review is focused on a novel cellular probe, the plasmonic nanobubble (PNB), which has the dynamically tunable and multiple functions of imaging, diagnosis, delivery, therapy and, ultimately, theranostics. The concept of theranostics was recently introduced in order to unite the clinically important stages of treatment, namely diagnosis, therapy and therapy guidance, into one single, rapid and highly accurate procedure. Cell level theranostics will have far-reaching implications for the treatment of cancer and other diseases at their earliest stages. PNBs were developed to support cell level theranostics as a new generation of on-demand tunable cellular probes. A PNB is a transient vapor nanobubble that is generated within nanoseconds around an overheated plasmonic nanoparticle with a short laser pulse. In the short term, we expect that PNB technology will be rapidly adaptable to clinical medicine, where the single cell resolution it provides will be critical for diagnosing incipient or residual disease and eliminating cancer cells, while leaving healthy cells intact. This review discusses mechanisms of plasmonic nanobubbles and their biomedical applications with the focus on cancer cell theranostics. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer Therapeutics)
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Open AccessArticle The Prognostic Impact of p53 Expression on Sporadic Colorectal Cancer Is Dependent on p21 Status
Cancers 2011, 3(1), 1274-1284; doi:10.3390/cancers3011274
Received: 19 January 2011 / Revised: 28 February 2011 / Accepted: 4 March 2011 / Published: 11 March 2011
Cited by 1 | PDF Full-text (238 KB) | HTML Full-text | XML Full-text
Abstract
The prognostic value of p53 and p21 expression in colorectal cancer is still under debate. We hypothesize that the prognostic impact of p53 expression is dependent on p21 status. The expression of p53 and p21 was immunohistochemically investigated in a prospective cohort of 116 patients with UICC stage II and III sporadic colorectal cancer. The results were correlated with overall and recurrence-free survival. The mean observation period was 51.8 ± 2.5 months. Expression of p53 was observed in 72 tumors (63%). Overall survival was significantly better in patients with p53-positive carcinomas than in those without p53 expression (p = 0.048). No differences were found in recurrence-free survival (p = 0.161). The p53+/p21− combination was seen in 68% (n = 49), the p53+/p21+ combination in 32% (n = 23). Patients with p53+/p21− carcinomas had significantly better overall and recurrence-free survival than those with p53+/p21+ (p < 0.0001 resp. p = 0.003). Our data suggest that the prognostic impact of p53 expression on sporadic colorectal cancer is dependent on p21 status. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessArticle The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis
Cancers 2011, 3(1), 1329-1350; doi:10.3390/cancers3011329
Received: 5 February 2011 / Revised: 15 February 2011 / Accepted: 10 March 2011 / Published: 15 March 2011
Cited by 3 | PDF Full-text (1399 KB) | HTML Full-text | XML Full-text
Abstract
Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding [...] Read more.
Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessArticle Overexpression of CYP3A4 in a COLO 205 Colon Cancer Stem Cell Model in vitro
Cancers 2011, 3(1), 1467-1479; doi:10.3390/cancers3011467
Received: 30 January 2011 / Revised: 9 February 2011 / Accepted: 9 February 2011 / Published: 22 March 2011
Cited by 5 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
Cancer stem cells (CSCs) seem to constitute a subpopulation of tumor cells that escape from chemotherapy and cause recurrent disease. Low proliferation rates, protection in a stem cell niche and overexpression of drug resistance proteins are considered to confer chemoresistance. We established [...] Read more.
Cancer stem cells (CSCs) seem to constitute a subpopulation of tumor cells that escape from chemotherapy and cause recurrent disease. Low proliferation rates, protection in a stem cell niche and overexpression of drug resistance proteins are considered to confer chemoresistance. We established an in vitro colon CSC-like model using the COLO 205 cell line, which revealed transiently increased expression of CD133 when transferred to serum-free stem cell culture medium. Assessment of global gene expression of COLO 205 cells under these conditions identified a set of upregulated genes including cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase 1A1 (ALDH1A1), as confirmed by real-time qPCR. ALDH1A1 is a CSC marker for certain tumor entities and confers resistance to cyclophosphamide. CYP3A4 is expressed in liver and colon and its overexpression seems particularly relevant in colon cancer, since it inactivates irinotecan and other xenobiotics, such as taxols and vinca alkaloids. In conclusion, this COLO 205 model provides evidence for CD133 induction concomitant with overexpression of CYP3A4, which, together with ATP-binding cassette, subfamily G, member 2 (ABCG2) and others, may have a role in chemoresistant colon CSCs and a negative impact on disease-free survival in colon cancer patients. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Review

Jump to: Research, Other

Open AccessReview The Role of Apoptosis in the Pathology of Pancreatic Cancer
Cancers 2011, 3(1), 1-16; doi:10.3390/cancers3010001
Received: 11 November 2010 / Revised: 14 December 2010 / Accepted: 21 December 2010 / Published: 23 December 2010
Cited by 10 | PDF Full-text (494 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer is a disease with high resistance to most common therapies and therefore has a poor prognosis, which is partly due to a lack of reaction to apoptotic stimuli. Signal transduction of such stimuli includes a death receptor-mediated extrinsic pathway as [...] Read more.
Pancreatic cancer is a disease with high resistance to most common therapies and therefore has a poor prognosis, which is partly due to a lack of reaction to apoptotic stimuli. Signal transduction of such stimuli includes a death receptor-mediated extrinsic pathway as well as an intrinsic pathway linked to the mitochondria. Defects in apoptotic pathways and the deregulation of apoptotic proteins, such as Survivin, Bcl-2, Bcl-xL and Mcl-1, play decisive roles in the development of pancreatic cancer. Investigation of the molecular mechanism allowing tumors to resist apoptotic cell death would lead to an improved understanding of the physiology and the development of new molecular strategies in pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Clinically Relevant Anticancer Polymer Paclitaxel Therapeutics
Cancers 2011, 3(1), 17-42; doi:10.3390/cancers3010017
Received: 12 November 2010 / Revised: 10 December 2010 / Accepted: 22 December 2010 / Published: 23 December 2010
Cited by 13 | PDF Full-text (692 KB) | HTML Full-text | XML Full-text
Abstract
The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled [...] Read more.
The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(L-g-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer Therapeutics)
Open AccessReview Pain Management in Pancreatic Cancer
Cancers 2011, 3(1), 43-60; doi:10.3390/cancers3010043
Received: 1 November 2010 / Revised: 25 November 2010 / Accepted: 20 December 2010 / Published: 24 December 2010
Cited by 4 | PDF Full-text (180 KB) | HTML Full-text | XML Full-text
Abstract
A majority of pancreatic cancer patients present with pain at the time of diagnosis. Pain management can be challenging in light of the aggressive nature of this cancer. Apart from conventional pharmacotherapy, timely treatment with neurolytic celiac plexus block (NCPB) has been [...] Read more.
A majority of pancreatic cancer patients present with pain at the time of diagnosis. Pain management can be challenging in light of the aggressive nature of this cancer. Apart from conventional pharmacotherapy, timely treatment with neurolytic celiac plexus block (NCPB) has been shown to be of benefit. NCPB has demonstrated efficacious pain control in high quality studies with analgesic effects lasting one to two months. NCPB has also shown to decrease the requirements of narcotics, and thus decrease opioid related side effects. Another option for the control of moderate to severe pain is intrathecal therapy (IT). Delivery of analgesic medications intrathecally allows for lower dosages of medications and thus reduced toxicity. Both of the above mentioned interventional procedures have been shown to have low complication rates, and be safe and effective. Ultimately, comprehensive pancreatic cancer pain management necessitates understanding of pain mechanisms and delivery of sequential validated therapeutic interventions within a multidisciplinary patient care model. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Screening Technologies for Target Identification in Pancreatic Cancer
Cancers 2011, 3(1), 79-90; doi:10.3390/cancers3010079
Received: 23 November 2010 / Revised: 21 December 2010 / Accepted: 23 December 2010 / Published: 29 December 2010
Cited by 1 | PDF Full-text (306 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer exhibits an extraordinarily high level of resistance to almost any kind of systemic therapy evaluated in clinical trials so far. Therefore, the identification of novel therapeutic targets is urgently required. High-throughput screens have emerged as an important tool to identify [...] Read more.
Pancreatic cancer exhibits an extraordinarily high level of resistance to almost any kind of systemic therapy evaluated in clinical trials so far. Therefore, the identification of novel therapeutic targets is urgently required. High-throughput screens have emerged as an important tool to identify putative targets for diagnosis and therapy in an unbiased manner. More than a decade ago, microarray technology was introduced to identify differentially expressed genes in pancreatic cancer as compared to normal pancreas, chronic pancreatitis and other cancer types located in close proximity to the pancreas. In addition, proteomic screens have facilitated the identification of differentially secreted proteins in body fluids of pancreatic cancer patients, serving as possible biomarkers. Recently, RNA interference-based loss-of-function screens have been used to identify functionally relevant genes, whose knock-down has impact on pancreatic cancer cell viability, thereby representing potential new targets for therapeutic intervention. This review summarizes recent results of transcriptional, proteomic and functional screens in pancreatic cancer and discusses potentials and limitations of the respective technologies as well as their impact on future therapeutic developments. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Membrane Drug Transporters and Chemoresistance in Human Pancreatic Carcinoma
Cancers 2011, 3(1), 106-125; doi:10.3390/cancers3010106
Received: 1 December 2010 / Revised: 10 December 2010 / Accepted: 24 December 2010 / Published: 30 December 2010
Cited by 6 | PDF Full-text (654 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental [...] Read more.
Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental chemotherapy underlining the role of cellular transporters in drug resistance. Such contribution to the chemoresistant phenotype of tumor cells or tissues can be conferred both by uptake and export transporters, as demonstrated by in vivo and in vitro data. Our studies used human pancreatic carcinoma cells, cells stably transfected with human transporter cDNAs, or cells in which a specific transporter was knocked down by RNA interference. We have previously shown that 5-fluorouracil treatment affects the expression profile of relevant cellular transporters including multidrug resistance proteins (MRPs), and that MRP5 (ABCC5) influences chemoresistance of these tumor cells. Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations. In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance. These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Decoding Melanoma Metastasis
Cancers 2011, 3(1), 126-163; doi:10.3390/cancers3010126
Received: 1 December 2010 / Revised: 22 December 2010 / Accepted: 23 December 2010 / Published: 30 December 2010
Cited by 13 | PDF Full-text (1088 KB) | HTML Full-text | XML Full-text
Abstract
Metastasis accounts for the vast majority of morbidity and mortality associated with melanoma. Evidence suggests melanoma has a predilection for metastasis to particular organs. Experimental analyses have begun to shed light on the mechanisms regulating melanoma metastasis and organ specificity, but these [...] Read more.
Metastasis accounts for the vast majority of morbidity and mortality associated with melanoma. Evidence suggests melanoma has a predilection for metastasis to particular organs. Experimental analyses have begun to shed light on the mechanisms regulating melanoma metastasis and organ specificity, but these analyses are complicated by observations of metastatic dormancy and dissemination of melanocytes that are not yet fully malignant. Additionally, tumor extrinsic factors in the microenvironment, both at the site of the primary tumor and the site of metastasis, play important roles in mediating the metastatic process. As metastasis research moves forward, paradigms explaining melanoma metastasis as a step-wise process must also reflect the temporal complexity and heterogeneity in progression of this disease. Genetic drivers of melanoma as well as extrinsic regulators of disease spread, particularly those that mediate metastasis to specific organs, must also be incorporated into newer models of melanoma metastasis. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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Open AccessReview Assessment of Serosal Invasion and Criteria for the Classification of Pathological (p) T4 Staging in Colorectal Carcinoma: Confusions, Controversies and Criticisms
Cancers 2011, 3(1), 164-181; doi:10.3390/cancers3010164
Received: 28 October 2010 / Revised: 27 December 2010 / Accepted: 29 December 2010 / Published: 4 January 2011
Cited by 9 | PDF Full-text (776 KB) | HTML Full-text | XML Full-text
Abstract
Transmural spread by colorectal carcinoma can result in tumor invasion of the serosal surface and, hence, more likely dissemination within the peritoneal cavity and potentially to additional metastatic sites. The adverse prognostic significance of serosal invasion is widely accepted and its presence [...] Read more.
Transmural spread by colorectal carcinoma can result in tumor invasion of the serosal surface and, hence, more likely dissemination within the peritoneal cavity and potentially to additional metastatic sites. The adverse prognostic significance of serosal invasion is widely accepted and its presence may be considered an indication for chemotherapy in patients with node negative disease. However, controversy persists regarding the most appropriate criteria for diagnosis and there are also practical difficulties associated with histological assessment in some cases. Therefore, serosal invasion may be under-diagnosed in a significant proportion of tumors, potentially leading to sub-optimal treatment of high-risk patients. The examination of multiple microscopic sections combined with ancillary studies such as cytology preparations, elastin stains, and immunohistochemistry may prove beneficial in selected problematic cases, but these are not used routinely. The relative prognostic significance of serosal invasion and of direct tumor spread to other organs, both of which are incorporated within the pT4 category of the AJCC/UICC TNM staging system, remains unclear. Further studies are required to demonstrate whether recent adjustments to the TNM staging of pT4 tumors are appropriate. Full article
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Open AccessReview Nuclear Receptor Small Heterodimer Partner in Apoptosis Signaling and Liver Cancer
Cancers 2011, 3(1), 198-212; doi:10.3390/cancers3010198
Received: 30 November 2010 / Revised: 30 December 2010 / Accepted: 4 January 2011 / Published: 5 January 2011
Cited by 6 | PDF Full-text (258 KB) | HTML Full-text | XML Full-text
Abstract
Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical [...] Read more.
Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction with multiple nuclear receptors and transcriptional factors. SHP is a critical transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology. Recently, we and others have demonstrated that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer. In this review, we summarize recent major findings regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer. Future study will be focused on identifying SHP associated novel pro-oncogenes and anti-oncogenes in liver cancer progression and applying the knowledge gained on SHP in liver cancer prevention, diagnosis and treatment. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Vitamin D and Pancreatic Cancer—An Update
Cancers 2011, 3(1), 213-226; doi:10.3390/cancers3010213
Received: 7 December 2010 / Revised: 30 December 2010 / Accepted: 31 December 2010 / Published: 6 January 2011
Cited by 4 | PDF Full-text (345 KB) | HTML Full-text | XML Full-text
Abstract
The non-classical actions of vitamin D, namely anti-proliferation, pro-differentiation, immune function modulation, and anti-inflammation, have received great attention during the past decade, in particular, the potential of vitamin D analogs alone or in combination with other anticancer agents for the treatment of [...] Read more.
The non-classical actions of vitamin D, namely anti-proliferation, pro-differentiation, immune function modulation, and anti-inflammation, have received great attention during the past decade, in particular, the potential of vitamin D analogs alone or in combination with other anticancer agents for the treatment of a variety of cancers. The association between vitamin D status and the higher incidence of many forms of cancer has suggested that vitamin D may play a role in the etiology of these types of cancer. Although it is still controversial whether this association exists for pancreatic cancer, biochemical evidence clearly indicates pancreatic cancer cells are responsive to the inhibitory effect of vitamin D and its analogs. In this review, we discuss briefly the origin and current therapy of pancreatic cancer, the history, source, metabolism and functions of vitamin D, the recent progress in the epidemiological studies of sunlight, and vitamin D status, and biochemical studies of vitamin D analogs in the prevention and treatment of pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Targeting Apoptosis Signaling in Pancreatic Cancer
Cancers 2011, 3(1), 241-251; doi:10.3390/cancers3010241
Received: 24 November 2010 / Revised: 5 January 2011 / Accepted: 6 January 2011 / Published: 11 January 2011
Cited by 5 | PDF Full-text (218 KB) | HTML Full-text | XML Full-text
Abstract
The ability to escape apoptosis or programmed cell death is a hallmark of human cancers, for example pancreatic cancer. This can promote tumorigenesis, since too little cell death by apoptosis disturbs tissue homeostasis. Additionally, defective apoptosis signaling is the underlying cause of [...] Read more.
The ability to escape apoptosis or programmed cell death is a hallmark of human cancers, for example pancreatic cancer. This can promote tumorigenesis, since too little cell death by apoptosis disturbs tissue homeostasis. Additionally, defective apoptosis signaling is the underlying cause of failure to respond to current treatment approaches, since therapy-mediated antitumor activity requires the intactness of apoptosis signaling pathways in cancer cells. Thus, the elucidation of defects in the regulation of apoptosis in pancreatic carcinoma can result in the identification of novel targets for therapeutic interference and for exploitation for cancer drug discovery. Full article
Open AccessReview Rational and Irrational Issues in Breast Cancer Screening
Cancers 2011, 3(1), 252-266; doi:10.3390/cancers3010252
Received: 15 December 2010 / Revised: 3 January 2011 / Accepted: 6 January 2011 / Published: 11 January 2011
Cited by 4 | PDF Full-text (141 KB) | HTML Full-text | XML Full-text
Abstract
Evidence on the efficacy of breast screening from randomized controlled trials conducted in the last decades of the 1900s is reviewed. For decades, controversy about their results has centered on the magnitude of benefit in terms of breast cancer mortality reduction that [...] Read more.
Evidence on the efficacy of breast screening from randomized controlled trials conducted in the last decades of the 1900s is reviewed. For decades, controversy about their results has centered on the magnitude of benefit in terms of breast cancer mortality reduction that can be achieved. However more recently, several expert bodies have estimated the benefits to be smaller than initially expected and concerns have been raised about screening consequences such as over-diagnosis and unnecessary treatment. Trials with substantial mortality reduction have been lauded and others with null effects have been critiqued. Critiques of the Canadian National Breast Screening Study are refuted. Extreme responses by screening advocates to the United States Preventive Services Task Force 2009 guidelines are described. The role vested interests play in determining health policy is clearly revealed in the response to the guidelines and should be more generally known. A general reluctance to explore unexpected results or to accept new paradigms is briefly discussed. Full article
Open AccessReview The Hemostasis Apparatus in Pancreatic Cancer and Its Importance beyond Thrombosis
Cancers 2011, 3(1), 267-284; doi:10.3390/cancers3010267
Received: 5 November 2010 / Revised: 5 December 2010 / Accepted: 10 January 2011 / Published: 11 January 2011
Cited by 2 | PDF Full-text (563 KB) | HTML Full-text | XML Full-text
Abstract
Laboratory evidence of aberrant coagulation is found in the majority of patients with advanced pancreatic cancer and a clinical consequence of this is the high incidence and prevalence of vascular thromboembolic events. Other sequelae are hypothesized to be the facilitation and acceleration [...] Read more.
Laboratory evidence of aberrant coagulation is found in the majority of patients with advanced pancreatic cancer and a clinical consequence of this is the high incidence and prevalence of vascular thromboembolic events. Other sequelae are hypothesized to be the facilitation and acceleration of mechanisms that define the malignant phenotype, such as invasion, trafficking and anchoring, establishing the metastatic niche and inducing angiogenesis. We review the in vitro and preclinical evidence that supports the role of the coagulation apparatus in the metastatic process of pancreatic cancer, with a particular emphasis on interaction of this pathway with clinically-targeted growth factor receptor pathways. Links between hemostasis, angiogenesis and epidermal growth factor pathways and their significance as therapeutic targets are considered. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Enteric Bacteria and Cancer Stem Cells
Cancers 2011, 3(1), 285-297; doi:10.3390/cancers3010285
Received: 17 November 2010 / Revised: 24 December 2010 / Accepted: 10 January 2011 / Published: 14 January 2011
Cited by 5 | PDF Full-text (459 KB) | HTML Full-text | XML Full-text
Abstract
Intestinal bacteria can contribute to cell proliferation and cancer development, particularly in chronic infectious diseases in which bacteria and/or bacterial components might interfere with cell function. The number of microbial cells within the gut lumen is estimated to be 100 trillion, which [...] Read more.
Intestinal bacteria can contribute to cell proliferation and cancer development, particularly in chronic infectious diseases in which bacteria and/or bacterial components might interfere with cell function. The number of microbial cells within the gut lumen is estimated to be 100 trillion, which is about 10-times larger than the number of eukaryotic cells in the human body. Because of the complexity of the gut flora, identifying the specific microbial agents related to human diseases remains challenging. Recent studies have demonstrated that the stemness of colon cancer cells is, in part, orchestrated by the microenvironment and is defined by high Wnt activity. In this review article, we will discuss recent progress with respect to intestinal stem cells, cancer stem cells, and the molecular mechanisms of enteric bacteria in the activation of the Wnt pathway. We will also discuss the roles of other pathways, including JAK-STAT, JNK, and Notch, in regulating stem cell niches during bacterial infections using Drosophila models. Insights gained from understanding how host-bacterial interaction during inflammation and cancer may serve as a paradigm for understanding the nature of self-renewal signals. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview Cancer Stem Cells and Pediatric Solid Tumors
Cancers 2011, 3(1), 298-318; doi:10.3390/cancers3010298
Received: 8 December 2011 / Revised: 11 January 2011 / Accepted: 13 January 2011 / Published: 14 January 2011
Cited by 19 | PDF Full-text (422 KB) | HTML Full-text | XML Full-text
Abstract
Recently, a subpopulation of cells, termed tumor-initiating cells or tumor stem cells (TSC), has been identified in many different types of solid tumors. These TSC, which are typically more resistant to chemotherapy and radiation compared to other tumor cells, have properties similar [...] Read more.
Recently, a subpopulation of cells, termed tumor-initiating cells or tumor stem cells (TSC), has been identified in many different types of solid tumors. These TSC, which are typically more resistant to chemotherapy and radiation compared to other tumor cells, have properties similar to normal stem cells including multipotency and the ability to self-renew, proliferate, and maintain the neoplastic clone. Much of the research on TSC has focused on adult cancers. With considerable differences in tumor biology between adult and pediatric cancers, there may be significant differences in the presence, function and behavior of TSC in pediatric malignancies. We discuss what is currently known about pediatric solid TSC with specific focus on TSC markers, tumor microenvironment, signaling pathways, therapeutic resistance and potential future therapies to target pediatric TSC. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview The Role of Colorectal Cancer Stem Cells in Metastatic Disease and Therapeutic Response
Cancers 2011, 3(1), 319-339; doi:10.3390/cancers3010319
Received: 1 December 2010 / Revised: 17 December 2010 / Accepted: 10 January 2011 / Published: 14 January 2011
Cited by 31 | PDF Full-text (333 KB) | HTML Full-text | XML Full-text
Abstract
Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with [...] Read more.
Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-renewal and pluripotency capabilities. These “cancer stem cells” (CSCs) present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. In this review, we will summarize the current understanding of intestinal stem cell biology and translate it to colorectal CSCs to provide a basis for understanding chemoresistance, cancer recurrence and metastasis. A more complete understanding of the biology of colorectal CSCs will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview Why Victory in the War on Cancer Remains Elusive: Biomedical Hypotheses and Mathematical Models
Cancers 2011, 3(1), 340-367; doi:10.3390/cancers3010340
Received: 3 December 2010 / Revised: 6 January 2011 / Accepted: 11 January 2011 / Published: 17 January 2011
Cited by 7 | PDF Full-text (249 KB) | HTML Full-text | XML Full-text
Abstract
We discuss philosophical, methodological, and biomedical grounds for the traditional paradigm of cancer and some of its critical flaws. We also review some potentially fruitful approaches to understanding cancer and its treatment. This includes the new paradigm of cancer that was developed [...] Read more.
We discuss philosophical, methodological, and biomedical grounds for the traditional paradigm of cancer and some of its critical flaws. We also review some potentially fruitful approaches to understanding cancer and its treatment. This includes the new paradigm of cancer that was developed over the last 15 years by Michael Retsky, Michael Baum, Romano Demicheli, Isaac Gukas, William Hrushesky and their colleagues on the basis of earlier pioneering work of Bernard Fisher and Judah Folkman. Next, we highlight the unique and pivotal role of mathematical modeling in testing biomedical hypotheses about the natural history of cancer and the effects of its treatment, elaborate on model selection criteria, and mention some methodological pitfalls. Finally, we describe a specific mathematical model of cancer progression that supports all the main postulates of the new paradigm of cancer when applied to the natural history of a particular breast cancer patient and fit to the observables. Full article
Open AccessReview Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems
Cancers 2011, 3(1), 368-395; doi:10.3390/cancers3010368
Received: 1 December 2010 / Revised: 5 January 2011 / Accepted: 13 January 2011 / Published: 18 January 2011
Cited by 7 | PDF Full-text (744 KB) | HTML Full-text | XML Full-text
Abstract
The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence [...] Read more.
The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications
Cancers 2011, 3(1), 396-407; doi:10.3390/cancers3010396
Received: 3 December 2010 / Revised: 27 December 2010 / Accepted: 14 January 2011 / Published: 20 January 2011
Cited by 5 | PDF Full-text (189 KB) | HTML Full-text | XML Full-text
Abstract
Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal- as well as midregion- and C-terminal peptides, which have [...] Read more.
Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal- as well as midregion- and C-terminal peptides, which have been shown to regulate various biological events, such as survival, proliferation and differentiation, in diverse cell model systems, both normal and pathological. A number of experimental data have demonstrated that PTHrP is also able to modulate tumor-relevant phenotypic expressions, thereby playing a role in early and advanced tumorigenesis, and in the response to treatment. In particular, interest has mainly been focused on the effects of PTHrP on cell proliferation/apoptosis, migration and invasion, which are the main roles involved in cancer development in vivo. The objective of this review is to discuss collectively the literature data on the molecular and biochemical basis of the mechanisms underlying the different, and sometimes opposite, effects exerted by PTHrP on various neoplastic cytotypes, with some final comments on both present and potential utilization of PTHrP as a target for anti-cancer therapy. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Cancer Stem Cells in Head and Neck Cancer
Cancers 2011, 3(1), 415-427; doi:10.3390/cancers3010415
Received: 2 December 2010 / Revised: 24 December 2010 / Accepted: 14 January 2011 / Published: 20 January 2011
Cited by 6 | PDF Full-text (199 KB) | HTML Full-text | XML Full-text
Abstract
Head and neck cancer (HNC) is the sixth most common malignancy world-wide, however the survival rate has not improved for the past 20 years. In recent years, the cancer stem cell (CSC) hypothesis has gained ground in several malignancies and there is [...] Read more.
Head and neck cancer (HNC) is the sixth most common malignancy world-wide, however the survival rate has not improved for the past 20 years. In recent years, the cancer stem cell (CSC) hypothesis has gained ground in several malignancies and there is mounting evidence suggesting CSCs mediate tumor resistance to chemotherapy and radiation therapy. However, the CSC theory is also challenged at least in certain types of cancer. Here we review the progress of CSC studies in HNC, which suggest that HNC conforms to the CSC model. The identified CSC markers and their tumor initiation properties provide a framework for the development of novel therapeutic strategies for HNC. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview Progress in Nanotechnology Based Approaches to Enhance the Potential of Chemopreventive Agents
Cancers 2011, 3(1), 428-445; doi:10.3390/cancers3010428
Received: 14 December 2010 / Revised: 4 January 2011 / Accepted: 12 January 2011 / Published: 21 January 2011
Cited by 22 | PDF Full-text (291 KB) | HTML Full-text | XML Full-text
Abstract
Cancer chemoprevention is defined as the use of natural agents to suppress, reverse or prevent the carcinogenic process from turning into aggressive cancer. Over the last two decades, multiple natural dietary compounds with diverse chemical structures such flavonoids, tannins, curcumins and polyphenols [...] Read more.
Cancer chemoprevention is defined as the use of natural agents to suppress, reverse or prevent the carcinogenic process from turning into aggressive cancer. Over the last two decades, multiple natural dietary compounds with diverse chemical structures such flavonoids, tannins, curcumins and polyphenols have been proposed as chemopreventive agents. These agents have proven excellent anticancer potential in the laboratory setting, however, the observed effects in vitro do not translate in clinic where they fail to live up to their expectations. Among the various reasons for this discrepancy include inefficient systemic delivery and robust bioavailability. To overcome this barrier, researchers have focused towards coupling these agents with nano based encapsulation technology that in principle will enhance bioavailability and ultimately benefit clinical outcome. The last decade has witnessed rapid advancement in the development of nanochemopreventive technology with emergence of many nano encapsulated formulations of different dietary anticancer agents. This review summarizes the most up-to-date knowledge on the studies performed in nanochemoprevention, their proposed use in the clinic and future directions in which this field is heading. As the knowledge of the dynamics of nano encapsulation evolves, it is expected that researchers will bring forward newer and far more superior nanochemopreventive agents that may become standard drugs for different cancers. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer Therapeutics)
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Open AccessReview Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies
Cancers 2011, 3(1), 446-460; doi:10.3390/cancers3010446
Received: 17 December 2010 / Revised: 18 January 2011 / Accepted: 21 January 2011 / Published: 24 January 2011
Cited by 4 | PDF Full-text (381 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, [...] Read more.
Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Extra-Neural Metastases of Malignant Gliomas: Myth or Reality?
Cancers 2011, 3(1), 461-477; doi:10.3390/cancers3010461
Received: 31 December 2010 / Revised: 4 January 2011 / Accepted: 19 January 2011 / Published: 27 January 2011
Cited by 18 | PDF Full-text (769 KB) | HTML Full-text | XML Full-text
Abstract
Malignant gliomas account for approximately 60% of all primary brain tumors in adults. Prognosis for these patients has not significantly changed in recent years—despite debulking surgery, radiotherapy and cytotoxic chemotherapy—with a median survival of 9–12 months. Virtually no patients are cured of [...] Read more.
Malignant gliomas account for approximately 60% of all primary brain tumors in adults. Prognosis for these patients has not significantly changed in recent years—despite debulking surgery, radiotherapy and cytotoxic chemotherapy—with a median survival of 9–12 months. Virtually no patients are cured of their illness. Malignant gliomas are usually locally invasive tumors, though extra-neural metastases can sometimes occur late in the course of the disease (median of two years). They generally appear after craniotomy although spontaneous metastases have also been reported. The incidence of these metastases from primary intra-cranial malignant gliomas is low; it is estimated at less than 2% of all cases. Extra-neural metastases from gliomas frequently occur late in the course of the disease (median of two years), and generally appear after craniotomy, but spontaneous metastases have also been reported. Malignant glioma metastases usually involve the regional lymph nodes, lungs and pleural cavity, and occasionally the bone and liver. In this review, we present three cases of extra-neural metastasis of malignant gliomas from our department, summarize the main reported cases in literature, and try to understand the mechanisms underlying these systemic metastases. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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Open AccessReview From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis
Cancers 2011, 3(1), 478-493; doi:10.3390/cancers3010478
Received: 21 December 2010 / Revised: 20 January 2011 / Accepted: 20 January 2011 / Published: 27 January 2011
Cited by 12 | PDF Full-text (181 KB) | HTML Full-text | XML Full-text
Abstract
Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the [...] Read more.
Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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Open AccessReview Diagnostic Management of Pancreatic Cancer
Cancers 2011, 3(1), 494-509; doi:10.3390/cancers3010494
Received: 1 December 2010 / Revised: 20 January 2011 / Accepted: 24 January 2011 / Published: 31 January 2011
Cited by 7 | PDF Full-text (157 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer is one of the most deadly solid tumors, with an overall 5-year survival rate of less than 5%. Due to a non-specific clinical presentation, it is often diagnosed at an advanced stage and is rarely amenable for curative treatment. Therefore [...] Read more.
Pancreatic cancer is one of the most deadly solid tumors, with an overall 5-year survival rate of less than 5%. Due to a non-specific clinical presentation, it is often diagnosed at an advanced stage and is rarely amenable for curative treatment. Therefore early diagnosis and appropriate staging are still essential to define the best care and to improve patient survival. Several imaging modalities are currently available for the evaluation of pancreatic cancer. This review focuses on different techniques and discusses the diagnostic management of patients with pancreatic cancer. This review was conducted utilizing Pubmed and was limited to papers published within the last 5 years. The search key words pancreatic cancer, pancreatic adenocarcinoma, pancreatic tumors, diagnosis, radiology, imaging, nuclear imaging, endoscopy, endoscopic ultrasound and biochemical markers were used. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Nerve Growth Factor in Cancer Cell Death and Survival
Cancers 2011, 3(1), 510-530; doi:10.3390/cancers3010510
Received: 7 December 2010 / Revised: 24 January 2011 / Accepted: 25 January 2011 / Published: 1 February 2011
Cited by 17 | PDF Full-text (444 KB) | HTML Full-text | XML Full-text
Abstract
One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling [...] Read more.
One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Protein Kinase C: An Attractive Target for Cancer Therapy
Cancers 2011, 3(1), 531-567; doi:10.3390/cancers3010531
Received: 23 December 2010 / Revised: 19 January 2011 / Accepted: 26 January 2011 / Published: 1 February 2011
Cited by 4 | PDF Full-text (545 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis plays an important role during all stages of carcinogenesis and the development of chemoresistance in tumor cells may be due to their selective defects in the intracellular signaling proteins, central to apoptotic pathways. Consequently, many studies have focused on rendering the [...] Read more.
Apoptosis plays an important role during all stages of carcinogenesis and the development of chemoresistance in tumor cells may be due to their selective defects in the intracellular signaling proteins, central to apoptotic pathways. Consequently, many studies have focused on rendering the chemotherapy more effective in order to prevent chemoresistance and pre-clinical and clinical data has suggested that protein kinase C (PKC) may represent an attractive target for cancer therapy. Therefore, a complete understanding of how PKC regulates apoptosis and chemoresistance may lead to obtaining a PKC-based therapy that is able to reduce drug dosages and to prevent the development of chemoresistance. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Cumulative Epigenetic Abnormalities in Host Genes with Viral and Microbial Infection during Initiation and Progression of Malignant Lymphoma/Leukemia
Cancers 2011, 3(1), 568-581; doi:10.3390/cancers3010568
Received: 31 December 2010 / Revised: 25 January 2011 / Accepted: 25 January 2011 / Published: 4 February 2011
Cited by 3 | PDF Full-text (336 KB) | HTML Full-text | XML Full-text
Abstract
Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles. Aberrant promoter hypermethylation is a prevalent phenomenon in human cancers as well as malignant lymphoma/leukemia. Tumor suppressor genes [...] Read more.
Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles. Aberrant promoter hypermethylation is a prevalent phenomenon in human cancers as well as malignant lymphoma/leukemia. Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs). The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia. In addition, the relevance of this knowledge to malignant lymphoma/leukemia assessment, prevention and early detection will be discussed. Full article
(This article belongs to the Special Issue Epigenetics of Cancer Progression)
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Open AccessReview Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease
Cancers 2011, 3(1), 582-602; doi:10.3390/cancers3010582
Received: 1 December 2010 / Revised: 29 December 2010 / Accepted: 26 January 2011 / Published: 9 February 2011
Cited by 8 | PDF Full-text (113 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropyl)amine (BOP) into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology [...] Read more.
Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropyl)amine (BOP) into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5’ CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Advances in Viral Vector-Based TRAIL Gene Therapy for Cancer
Cancers 2011, 3(1), 603-620; doi:10.3390/cancers3010603
Received: 29 December 2010 / Revised: 28 January 2011 / Accepted: 30 January 2011 / Published: 10 February 2011
Cited by 5 | PDF Full-text (270 KB) | HTML Full-text | XML Full-text
Abstract
Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has shown particular promise in pre-clinical [...] Read more.
Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has shown particular promise in pre-clinical and early clinical trials, due to its preferential ability to induce apoptotic cell death in cancer cells and its minimal toxicity. One limitation of TRAIL use is the fact that many tumor types display an inherent resistance to TRAIL-induced apoptosis. To circumvent this problem, researchers have explored a number of strategies to optimize TRAIL delivery and to improve its efficacy via co-administration with other anti-cancer agents. In this review, we will focus on TRAIL-based gene therapy approaches for the treatment of malignancies. We will discuss the main viral vectors that are being used for TRAIL gene therapy and the strategies that are currently being attempted to improve the efficacy of TRAIL as an anti-cancer therapeutic. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Treatment Resistance Mechanisms of Malignant Glioma Tumor Stem Cells
Cancers 2011, 3(1), 621-635; doi:10.3390/cancers3010621
Received: 22 November 2010 / Revised: 14 December 2010 / Accepted: 26 January 2011 / Published: 10 February 2011
Cited by 11 | PDF Full-text (198 KB) | HTML Full-text | XML Full-text
Abstract
Malignant gliomas are highly lethal because of their resistance to conventional treatments. Recent evidence suggests that a minor subpopulation of cells with stem cell properties reside within these tumors. These tumor stem cells are more resistant to radiation and chemotherapies than their [...] Read more.
Malignant gliomas are highly lethal because of their resistance to conventional treatments. Recent evidence suggests that a minor subpopulation of cells with stem cell properties reside within these tumors. These tumor stem cells are more resistant to radiation and chemotherapies than their counterpart differentiated tumor cells and may underlie the persistence and recurrence of tumors following treatment. The various mechanisms by which tumor stem cells avoid or repair the damaging effects of cancer therapies are discussed. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview Current Surgical Aspects of Palliative Treatment for Unresectable Pancreatic Cancer
Cancers 2011, 3(1), 636-651; doi:10.3390/cancers3010636
Received: 20 December 2010 / Revised: 19 January 2011 / Accepted: 5 February 2011 / Published: 11 February 2011
Cited by 5 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
Despite all improvements in both surgical and other conservative therapies, pancreatic cancer is steadily associated with a poor overall prognosis and remains a major cause of cancer mortality. Radical surgical resection has been established as the best chance these patients have for [...] Read more.
Despite all improvements in both surgical and other conservative therapies, pancreatic cancer is steadily associated with a poor overall prognosis and remains a major cause of cancer mortality. Radical surgical resection has been established as the best chance these patients have for long-term survival. However, in most cases the disease has reached an incurable state at the time of diagnosis, mainly due to the silent clinical course at its early stages. The role of palliative surgery in locally advanced pancreatic cancer mainly involves patients who are found unresectable during open surgical exploration and consists of combined biliary and duodenal bypass procedures. Chemical splanchnicectomy is another modality that should also be applied intraoperatively with good results. There are no randomized controlled trials evaluating the outcomes of palliative pancreatic resection. Nevertheless, data from retrospective reports suggest that this practice, compared with bypass procedures, may lead to improved survival without increasing perioperative morbidity and mortality. All efforts at developing a more effective treatment for unresectable pancreatic cancer have been directed towards neoadjuvant and targeted therapies. The scenario of downstaging tumors in anticipation of a future oncological surgical resection has been advocated by trials combining gemcitabine with radiation therapy or with the tyrosine kinase inhibitor erlotinib, with promising early results. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Palliative Interventional and Surgical Therapy for Unresectable Pancreatic Cancer
Cancers 2011, 3(1), 652-661; doi:10.3390/cancers3010652
Received: 31 December 2010 / Revised: 14 January 2011 / Accepted: 9 February 2011 / Published: 14 February 2011
Cited by 2 | PDF Full-text (111 KB) | HTML Full-text | XML Full-text
Abstract
Palliative treatment concepts are considered in patients with non-curatively resectable and/or metastasized pancreatic cancer. However, patients without metastases, but presented with marginally resectable or locally non-resectable tumors should not be treated by a palliative therapeutic approach. These patients should be enrolled in [...] Read more.
Palliative treatment concepts are considered in patients with non-curatively resectable and/or metastasized pancreatic cancer. However, patients without metastases, but presented with marginally resectable or locally non-resectable tumors should not be treated by a palliative therapeutic approach. These patients should be enrolled in neoadjuvant radiochemotherapy trials because a potentially curative resection can be achieved in approximately one-third of them after finishing treatment and restaging. Within the scope of best possible palliative care, resection of the primary cancer together with excision of metastases represents a therapeutic option to be contemplated in selected cases. Comprehensive palliative therapy is based on treatment of bile duct or duodenal obstruction for certain locally unresectable or metastasized advanced pancreatic cancer. However, endoscopic or percutaneous stenting procedures and surgical bypass provide safe and highly effective therapeutic alternatives. In case of operative drainage of the biliary tract (biliodigestive anastomosis), the prophylactic creation of a gastro-intestinal bypass (double bypass) is recommended. The decision to perform a surgical versus an endoscopic procedure for palliation depends to a great extent on the tumor stage and the estimated prognosis, and should be determined by an interdisciplinary team for each patient individually. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Treatment of Pancreatic Cancer: What Can We Really Predict Today?
Cancers 2011, 3(1), 675-699; doi:10.3390/cancers3010675
Received: 3 December 2010 / Revised: 24 January 2011 / Accepted: 4 February 2011 / Published: 17 February 2011
Cited by 3 | PDF Full-text (250 KB) | HTML Full-text | XML Full-text
Abstract
Managing pancreatic cancer remains a big challenge due to its worse course and prognosis. However, therapeutic options and multimodal strategies are increasing nowadays, including new agents, new regimens and chemoradiation. Recently, the FOLFIRINOX regimen has been reported to be more active than [...] Read more.
Managing pancreatic cancer remains a big challenge due to its worse course and prognosis. However, therapeutic options and multimodal strategies are increasing nowadays, including new agents, new regimens and chemoradiation. Recently, the FOLFIRINOX regimen has been reported to be more active than gemcitabine in selected metastatic patients. In this setting, it will be of utmost interest to guide our therapeutic choice not only on clinical and pathological findings, but also on specific biomarkers that will predict tumor behavior and patient outcome (prognostic markers), and benefit from specific agents or regimens (predictive markers). In the near future, we will have to build both our therapeutic interventions and our clinical research based on an accurate patients’ clinical selection and on biomolecular markers. In this review, we aimed to highlight and discuss some of the recent results reported on biomarkers in pancreatic cancer that may predict, i.e., preferential metastatic diffusion after surgery, like CXCR4, or predict gemcitabine efficacy in an adjuvant setting as well as in advanced disease, like hENT1. An important effort for translational research in pancreatic cancer research is thus required to validate such markers, while some important questions concerning tissue availability and processing, methodology of analysis, and design of future prospective trials, need to be addressed. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Involvement of COUP-TFs in Cancer Progression
Cancers 2011, 3(1), 700-715; doi:10.3390/cancers3010700
Received: 4 January 2011 / Revised: 25 January 2011 / Accepted: 10 February 2011 / Published: 18 February 2011
Cited by 5 | PDF Full-text (385 KB) | HTML Full-text | XML Full-text
Abstract
The orphan receptors COUP-TFI and COUP-TFII are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate organogenesis, as demonstrated by loss-of-function COUP-TFI and/or COUP-TFII mutant mice. Although COUP-TFs are expressed in a wide range of tissues in [...] Read more.
The orphan receptors COUP-TFI and COUP-TFII are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate organogenesis, as demonstrated by loss-of-function COUP-TFI and/or COUP-TFII mutant mice. Although COUP-TFs are expressed in a wide range of tissues in adults, little is known about their functions at later stages of development or in organism homeostasis. COUP-TFs are expressed in cancer cell lines of various origins and increasing studies suggest they play roles in cell fate determination and, potentially, in cancer progression. Nevertheless, the exact roles of COUP-TFs in these processes remain unclear and even controversial. In this review, we report both in vitro and in vivo data describing known and suspected actions of COUP-TFs that suggest that these factors are involved in modification of the phenotype of cancer cells, notably of epithelial origin. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
Open AccessReview Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins?
Cancers 2011, 3(1), 716-729; doi:10.3390/cancers30100716
Received: 8 December 2010 / Revised: 11 February 2011 / Accepted: 12 February 2011 / Published: 21 February 2011
Cited by 113 | PDF Full-text (377 KB) | HTML Full-text | XML Full-text
Abstract
Cancer stem cells (CSCs) are cells within a tumor that possess the capacity to self-renew and maintain tumor-initiating capacity through differentiation into the heterogeneous lineages of cancer cells that comprise the whole tumor. These tumor-initiating cells could provide a resource for cells [...] Read more.
Cancer stem cells (CSCs) are cells within a tumor that possess the capacity to self-renew and maintain tumor-initiating capacity through differentiation into the heterogeneous lineages of cancer cells that comprise the whole tumor. These tumor-initiating cells could provide a resource for cells that cause tumor recurrence after therapy. Although the cell origin of CSCs remains to be fully elucidated, mounting evidence has demonstrated that Epithelial-to-Mesenchymal Transition (EMT), induced by different factors, is associated with tumor aggressiveness and metastasis and these cells share molecular characteristics with CSCs, and thus are often called cancer stem-like cells or tumor-initiating cells. The acquisition of an EMT phenotype is a critical process for switching early stage carcinomas into invasive malignancies, which is often associated with the loss of epithelial differentiation and gain of mesenchymal phenotype. Recent studies have demonstrated that EMT plays a critical role not only in tumor metastasis but also in tumor recurrence and that it is tightly linked with the biology of cancer stem-like cells or cancer-initiating cells. Here we will succinctly summarize the state-of-our-knowledge regarding the molecular similarities between cancer stem-like cells or CSCs and EMT-phenotypic cells that are associated with tumor aggressiveness focusing on solid tumors. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?
Cancers 2011, 3(1), 730-746; doi:10.3390/cancers3010730
Received: 20 December 2010 / Revised: 28 January 2011 / Accepted: 11 February 2011 / Published: 21 February 2011
Cited by 5 | PDF Full-text (185 KB) | HTML Full-text | XML Full-text
Abstract
According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more [...] Read more.
According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma. Full article
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Open AccessReview Recently Identified Biomarkers That Promote Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma
Cancers 2011, 3(1), 747-772; doi:10.3390/cancers3010747
Received: 10 January 2011 / Revised: 9 February 2011 / Accepted: 17 February 2011 / Published: 22 February 2011
Cited by 7 | PDF Full-text (690 KB) | HTML Full-text | XML Full-text
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous cancer that arises in the upper aerodigestive tract. Despite advances in knowledge and treatment of this disease, the five-year survival rate after diagnosis of advanced (stage 3 and 4) HNSCC remains approximately [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous cancer that arises in the upper aerodigestive tract. Despite advances in knowledge and treatment of this disease, the five-year survival rate after diagnosis of advanced (stage 3 and 4) HNSCC remains approximately 50%. One reason for the large degree of mortality associated with late stage HNSCC is the intrinsic ability of tumor cells to undergo locoregional invasion. Lymph nodes in the cervical region are the primary sites of metastasis for HNSCC, occurring before the formation of distant metastases. The presence of lymph node metastases is strongly associated with poor patient outcome, resulting in increased consideration being given to the development and implementation of anti-invasive strategies. In this review, we focus on select proteins that have been recently identified as promoters of lymph node metastasis in HNSCC. The discussed proteins are involved in a wide range of critical cellular functions, and offer a more comprehensive understanding of the factors involved in HNSCC metastasis while additionally providing increased options for consideration in the design of future therapeutic intervention strategies. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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Open AccessReview Growth Factor Mediated Signaling in Pancreatic Pathogenesis
Cancers 2011, 3(1), 841-871; doi:10.3390/cancers3010841
Received: 26 January 2011 / Revised: 12 February 2011 / Accepted: 16 February 2011 / Published: 24 February 2011
Cited by 3 | PDF Full-text (338 KB) | HTML Full-text | XML Full-text
Abstract
Functionally, the pancreas consists of two types of tissues: exocrine and endocrine. Exocrine pancreatic disorders mainly involve acute and chronic pancreatitis. Acute pancreatitis typically is benign, while chronic pancreatitis is considered a risk factor for developing pancreatic cancer. Pancreatic carcinoma is the [...] Read more.
Functionally, the pancreas consists of two types of tissues: exocrine and endocrine. Exocrine pancreatic disorders mainly involve acute and chronic pancreatitis. Acute pancreatitis typically is benign, while chronic pancreatitis is considered a risk factor for developing pancreatic cancer. Pancreatic carcinoma is the fourth leading cause of cancer related deaths worldwide. Most pancreatic cancers develop in the exocrine tissues. Endocrine pancreatic tumors are more uncommon, and typically are less aggressive than exocrine tumors. However, the endocrine pancreatic disorder, diabetes, is a dominant cause of morbidity and mortality. Importantly, different growth factors and their receptors play critical roles in pancreatic pathogenesis. Hence, an improved understanding of how various growth factors affect pancreatitis and pancreatic carcinoma is necessary to determine appropriate treatment. This chapter describes the role of different growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and transforming growth factor (TGF) in various pancreatic pathophysiologies. Finally, the crosstalk between different growth factor axes and their respective signaling mechanisms, which are involved in pancreatitis and pancreatic carcinoma, are also discussed. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Molecular Endoscopic Ultrasound for Diagnosis of Pancreatic Cancer
Cancers 2011, 3(1), 872-882; doi:10.3390/cancers3010872
Received: 18 January 2011 / Revised: 5 February 2011 / Accepted: 22 February 2011 / Published: 24 February 2011
PDF Full-text (311 KB) | HTML Full-text | XML Full-text
Abstract
Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a [...] Read more.
Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
Open AccessReview Components of Cell-Matrix Linkage as Potential New Markers for Prostate Cancer
Cancers 2011, 3(1), 883-896; doi:10.3390/cancers3010883
Received: 25 January 2011 / Revised: 12 February 2011 / Accepted: 17 February 2011 / Published: 25 February 2011
Cited by 4 | PDF Full-text (344 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is one of the most common tumor diseases worldwide. Often being non-aggressive, prostate tumors in these cases do not need immediate treatment. However, about 20% of diagnosed prostate cancers tend to metastasize and require treatment. Existing diagnostic methods may fail [...] Read more.
Prostate cancer is one of the most common tumor diseases worldwide. Often being non-aggressive, prostate tumors in these cases do not need immediate treatment. However, about 20% of diagnosed prostate cancers tend to metastasize and require treatment. Existing diagnostic methods may fail to accurately recognize the transition of a dormant, non-aggressive tumor into highly malignant prostate cancer. Therefore, new diagnostic tools are needed to improve diagnosis and therapy of prostate carcinoma. This review evaluates existing methods to diagnose prostate carcinoma, such as the biochemical marker prostate-specific antigen (PSA), but also discusses the possibility to use the altered expression of integrins and laminin-332 in prostate carcinomas as diagnostic tools and therapeutic targets of prostate cancer. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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Open AccessReview Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer
Cancers 2011, 3(1), 897-912; doi:10.3390/cancers3010897
Received: 13 January 2011 / Revised: 1 February 2011 / Accepted: 14 February 2011 / Published: 25 February 2011
Cited by 5 | PDF Full-text (428 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation [...] Read more.
Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Protein Kinase A in Cancer
Cancers 2011, 3(1), 913-926; doi:10.3390/cancers3010913
Received: 17 January 2011 / Revised: 9 February 2011 / Accepted: 22 February 2011 / Published: 28 February 2011
Cited by 13 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved [...] Read more.
In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved in signal transduction have been extensively studied, for example oncogenes, while modifications in intracellular compartmentalization of these molecules, or changes in the expression of unmodified genes have received less attention. Yet, epigenetic modulation of second messenger systems can deeply modify cellular functioning and in the end may cause instability of many processes, including cell mitosis. It is important to understand the functional meaning of modifications in second messenger intracellular pathways and unravel the role of downstream proteins in the initiation and growth of tumors. Within this framework, the cAMP system has been examined. cAMP is a second messenger involved in regulation of a variety of cellular functions. It acts mainly through its binding to cAMP-activated protein kinases (PKA), that were suggested to participate in the onset and progression of various tumors. PKA may represent a biomarker for tumor detection, identification and staging, and may be a potential target for pharmacological treatment of tumors. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview Inflammation and Tumor Microenvironment in Lymph Node Metastasis
Cancers 2011, 3(1), 927-944; doi:10.3390/cancers3010927
Received: 11 January 2011 / Revised: 17 February 2011 / Accepted: 21 February 2011 / Published: 1 March 2011
Cited by 2 | PDF Full-text (937 KB) | HTML Full-text | XML Full-text
Abstract
In nearly all human cancers, the presence of lymph node (LN) metastasis increases clinical staging and portends worse prognosis (compared to patients without LN metastasis). Herein, principally reviewing experimental and clinical data related to malignant melanoma, we discuss diverse factors that are [...] Read more.
In nearly all human cancers, the presence of lymph node (LN) metastasis increases clinical staging and portends worse prognosis (compared to patients without LN metastasis). Herein, principally reviewing experimental and clinical data related to malignant melanoma, we discuss diverse factors that are mechanistically involved in LN metastasis. We highlight recent data that link tumor microenvironment, including inflammation (at the cellular and cytokine levels) and tumor-induced lymphangiogenesis, with nodal metastasis. Many of the newly identified genes that appear to influence LN metastasis facilitate general motility, chemotactic, or invasive properties that also increase the ability of cancer cells to disseminate and survive at distant organ sites. These new biomarkers will help predict clinical outcome and point to novel future therapies in metastatic melanoma as well as other cancers. Full article
(This article belongs to the Special Issue Organ-Specific Metastasis Formation)
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Open AccessReview An Evolutionary Explanation for the Perturbation of the Dynamics of Metastatic Tumors Induced by Surgery and Acute Inflammation
Cancers 2011, 3(1), 945-970; doi:10.3390/cancers3010945
Received: 4 January 2011 / Revised: 17 February 2011 / Accepted: 22 February 2011 / Published: 2 March 2011
Cited by 1 | PDF Full-text (776 KB) | HTML Full-text | XML Full-text
Abstract
Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized [...] Read more.
Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized as follows: (1) the resection of the primary tumor is able to accelerate the evolution of micrometastasis in early stages, and (2) the outcome is transiently opposed in advanced tumors. The objective of this paper is to give some insight into tumorigenesis and surgery-related effects, by applying the concepts of the evolutionary theory in those tumor behaviors that gompertzian and tissular-centered models are unable to explain. According to this view, tumors are the consequence of natural selection operating at the somatic level, which is the basic mechanism of tumorigenesis, notwithstanding the complementary role of the intrinsic constrictions of complex networks. A tumor is a complicated phenomenon that entails growth, evolution and development simultaneously. So, an evo-devo perspective can explain how and why tumor subclones are able to translate competition from a metabolic level into neoangiogenesis and the immune response. The paper proposes that distant interactions are an extension of the ecological events at the local level. This notion explains the evolutionary basis for tumor dormancy, and warns against the teleological view of tumorigenesis as a process directed towards the maximization of a concrete trait such as aggressiveness. Full article
Open AccessReview Muscarinic Receptor Signaling in Colon Cancer
Cancers 2011, 3(1), 971-981; doi:10.3390/cancers3010971
Received: 31 January 2011 / Revised: 14 February 2011 / Accepted: 24 February 2011 / Published: 2 March 2011
Cited by 7 | PDF Full-text (380 KB) | HTML Full-text | XML Full-text
Abstract
According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased [...] Read more.
According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
Open AccessReview Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer
Cancers 2011, 3(1), 982-993; doi:10.3390/cancers3010982
Received: 15 December 2010 / Revised: 22 February 2011 / Accepted: 24 February 2011 / Published: 3 March 2011
Cited by 7 | PDF Full-text (177 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter [...] Read more.
Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression. Full article
(This article belongs to the Special Issue Epigenetics of Cancer Progression)
Open AccessReview Role of p53 in Cell Death and Human Cancers
Cancers 2011, 3(1), 994-1013; doi:10.3390/cancers3010994
Received: 7 December 2010 / Revised: 22 February 2011 / Accepted: 22 February 2011 / Published: 3 March 2011
Cited by 16 | PDF Full-text (293 KB) | HTML Full-text | XML Full-text
Abstract
p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the [...] Read more.
p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Targets and Mechanisms of Photodynamic Therapy in Lung Cancer Cells: A Brief Overview
Cancers 2011, 3(1), 1014-1041; doi:10.3390/cancers3011014
Received: 31 December 2010 / Revised: 20 February 2011 / Accepted: 1 March 2011 / Published: 3 March 2011
Cited by 18 | PDF Full-text (373 KB) | HTML Full-text | XML Full-text
Abstract
Lung cancer remains one of the most common cancer-related causes of death. This type of cancer typically develops over a period of many years, and if detected at an early enough stage can be eliminated by a variety of treatments including photodynamic [...] Read more.
Lung cancer remains one of the most common cancer-related causes of death. This type of cancer typically develops over a period of many years, and if detected at an early enough stage can be eliminated by a variety of treatments including photodynamic therapy (PDT). A critical discussion on the clinical applications of PDT in lung cancer is well outside the scope of the present report, which, in turn focuses on mechanistic and other aspects of the photodynamic action at a molecular and cellular level. The knowledge of these issues at pre-clinical levels is necessary to develop, check and adopt appropriate clinical protocols in the future. This report, besides providing general information, includes a brief overview of present experimental PDT and provides some non-exhaustive information on current strategies aimed at further improving the efficacy, especially in regard to lung cancer cells. Full article
(This article belongs to the Special Issue Lung Cancer)
Open AccessReview Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies
Cancers 2011, 3(1), 1042-1080; doi:10.3390/cancers3011042
Received: 8 January 2011 / Revised: 18 February 2011 / Accepted: 1 March 2011 / Published: 3 March 2011
Cited by 4 | PDF Full-text (6230 KB) | HTML Full-text | XML Full-text
Abstract
Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this [...] Read more.
Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics
Cancers 2011, 3(1), 1081-1110; doi:10.3390/cancers3011081
Received: 17 December 2010 / Revised: 19 January 2011 / Accepted: 21 January 2011 / Published: 4 March 2011
Cited by 56 | PDF Full-text (1890 KB) | HTML Full-text | XML Full-text
Abstract
The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of [...] Read more.
The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer Therapeutics)
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Open AccessReview Drug Treatment of Cancer Cell Lines: A Way to Select for Cancer Stem Cells?
Cancers 2011, 3(1), 1111-1128; doi:10.3390/cancers3011111
Received: 4 January 2011 / Revised: 31 January 2011 / Accepted: 24 February 2011 / Published: 4 March 2011
Cited by 4 | PDF Full-text (138 KB) | HTML Full-text | XML Full-text
Abstract
Tumors are generally composed of different cell types. In recent years, it has been shown that in many types of cancers a subset of cells show peculiar characteristics, such as the ability to induce tumors when engrafted into host animals, self-renew and [...] Read more.
Tumors are generally composed of different cell types. In recent years, it has been shown that in many types of cancers a subset of cells show peculiar characteristics, such as the ability to induce tumors when engrafted into host animals, self-renew and being immortal, and give rise to a differentiated progeny. These cells have been defined as cancer stem cells (CSCs) or tumor initiating cells. CSCs can be isolated both from tumor specimens and established cancer cell lines on the basis of their ability to exclude fluorescent dyes, express specific cell surface markers or grow in particular culture conditions. A key feature of CSCs is their resistance to chemotherapeutic agents, which could contribute to the remaining of residual cancer cells after therapeutic treatments. It has been shown that CSC-like cells can be isolated after drug treatment of cancer cell lines; in this review, we will describe the strategies so far applied to identify and isolate CSCs. Furthermore, we will discuss the possible use of these selected populations to investigate CSC biology and develop new anticancer drugs. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview Genetic Alterations in Glioma
Cancers 2011, 3(1), 1129-1140; doi:10.3390/cancers3011129
Received: 4 January 2011 / Revised: 28 February 2011 / Accepted: 1 March 2011 / Published: 7 March 2011
Cited by 7 | PDF Full-text (161 KB) | HTML Full-text | XML Full-text
Abstract
Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed [...] Read more.
Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
Open AccessReview Retrotransposon-Encoded Reverse Transcriptase in the Genesis, Progression and Cellular Plasticity of Human Cancer
Cancers 2011, 3(1), 1141-1157; doi:10.3390/cancers3011141
Received: 11 January 2011 / Revised: 21 February 2011 / Accepted: 22 February 2011 / Published: 7 March 2011
Cited by 7 | PDF Full-text (229 KB) | HTML Full-text | XML Full-text
Abstract
LINE-1 (Long Interspersed Nuclear Elements) and HERVs (Human Endogenous Retroviruses) are two families of autonomously replicating retrotransposons that together account for about 28% of the human genome. Genes harbored within LINE-1 and HERV retrotransposons, particularly those encoding the reverse transcriptase (RT) enzyme, [...] Read more.
LINE-1 (Long Interspersed Nuclear Elements) and HERVs (Human Endogenous Retroviruses) are two families of autonomously replicating retrotransposons that together account for about 28% of the human genome. Genes harbored within LINE-1 and HERV retrotransposons, particularly those encoding the reverse transcriptase (RT) enzyme, are generally expressed at low levels in differentiated cells, but their expression is upregulated in transformed cells and embryonic tissues. Here we discuss a recently discovered RT-dependent mechanism that operates in tumorigenesis and reversibly modulates phenotypic and functional variations associated with tumor progression. Downregulation of active LINE-1 elements drastically reduces the tumorigenic potential of cancer cells, paralleled by reduced proliferation and increased differentiation. Pharmacological RT inhibitors (e.g., nevirapine and efavirenz) exert similar effects on tumorigenic cell lines, both in culture and in animal models. The HERV-K family play a distinct complementary role in stress-dependent transition of melanoma cells from an adherent, non-aggressive, to a non-adherent, highly malignant, growth phenotype. In synthesis, the retrotransposon-encoded RT is increasingly emerging as a key regulator of tumor progression and a promising target in a novel anti-cancer therapy. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential
Cancers 2011, 3(1), 1158-1181; doi:10.3390/cancers3011158
Received: 30 January 2011 / Accepted: 23 February 2011 / Published: 7 March 2011
Cited by 12 | PDF Full-text (620 KB) | HTML Full-text | XML Full-text
Abstract
Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular [...] Read more.
Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Cardiac Hormones Target the Ras-MEK 1/2-ERK 1/2 Kinase Cancer Signaling Pathways
Cancers 2011, 3(1), 1182-1194; doi:10.3390/cancers3011182
Received: 18 February 2011 / Revised: 2 March 2011 / Accepted: 3 March 2011 / Published: 8 March 2011
PDF Full-text (340 KB) | HTML Full-text | XML Full-text
Abstract
The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, [...] Read more.
The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells in cell culture. In vivo, these four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers growing in athymic mice. Their signaling in cancer cells includes inhibition of up to 95% of the basal activity of Ras, 98% inhibition of the phosphorylation of the MEK 1/2 kinases and 97% inhibition of the activation of basal activity of the ERK 1/2 kinases mediated via the intracellular messenger cyclic GMP. They also completely block the activity of mitogens such as epidermal growth factor’s ability to stimulate ERK and Ras. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunocytochemical studies to inhibit DNA synthesis within cancer cells. Full article
(This article belongs to the Special Issue Cancer Signaling Pathways and Crosstalk)
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Open AccessReview Analysis of Somatic Mutations in Cancer: Molecular Mechanisms of Activation in the ErbB Family of Receptor Tyrosine Kinases
Cancers 2011, 3(1), 1195-1231; doi:10.3390/cancers3011195
Received: 7 January 2011 / Revised: 28 February 2011 / Accepted: 1 March 2011 / Published: 10 March 2011
Cited by 7 | PDF Full-text (871 KB) | HTML Full-text | XML Full-text
Abstract
The ErbB/EGFR/HER family of kinases consists of four homologous receptor tyrosine kinases which are important regulatory elements in many cellular processes, including cell proliferation, differentiation, and migration. Somatic mutations in, or over-expression of, the ErbB family is found in many cancers and [...] Read more.
The ErbB/EGFR/HER family of kinases consists of four homologous receptor tyrosine kinases which are important regulatory elements in many cellular processes, including cell proliferation, differentiation, and migration. Somatic mutations in, or over-expression of, the ErbB family is found in many cancers and is correlated with a poor prognosis; particularly, clinically identified mutations found in non-small-cell lung cancer (NSCLC) of ErbB1 have been shown to increase its basal kinase activity and patients carrying these mutations respond remarkably to the small tyrosine kinase inhibitor gefitinib. Here, we analyze the potential effects of the currently catalogued clinically identified mutations in the ErbB family kinase domains on the molecular mechanisms of kinase activation. Recently, we identified conserved networks of hydrophilic and hydrophobic interactions characteristic to the active and inactive conformation, respectively. Here, we show that the clinically identified mutants influence the kinase activity in distinctive fashion by affecting the characteristic interaction networks. Full article
(This article belongs to the Special Issue Lung Cancer)
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Open AccessReview Cancer Stem Cell Radioresistance and Enrichment: Where Frontline Radiation Therapy May Fail in Lung and Esophageal Cancers
Cancers 2011, 3(1), 1232-1252; doi:10.3390/cancers3011232
Received: 7 December 2010 / Revised: 25 January 2011 / Accepted: 24 February 2011 / Published: 10 March 2011
Cited by 27 | PDF Full-text (1331 KB) | HTML Full-text | XML Full-text
Abstract
Many studies have highlighted the role cancer stem cells (CSC) play in the development and progression of various types of cancer including lung and esophageal cancer. More recently, it has been proposed that the presence of CSCs affects treatment efficacy and patient [...] Read more.
Many studies have highlighted the role cancer stem cells (CSC) play in the development and progression of various types of cancer including lung and esophageal cancer. More recently, it has been proposed that the presence of CSCs affects treatment efficacy and patient prognosis. In reviewing this new area of cancer biology, we will give an overview of the current literature regarding lung and esophageal CSCs and radioresistance of CSC, and discuss the potential therapeutic applications of these findings. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview Current State of Surgical Management of Pancreatic Cancer
Cancers 2011, 3(1), 1253-1273; doi:10.3390/cancers3011253
Received: 10 February 2011 / Revised: 19 February 2011 / Accepted: 10 March 2011 / Published: 10 March 2011
Cited by 10 | PDF Full-text (444 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer is still associated with a poor prognosis and remains—as the fourth leading cause of cancer related mortality—a therapeutic challenge. Overall long-term survival is about 1–5%, and in only 10–20% of pancreatic cancer patients is potentially curative surgery possible, increasing five-year [...] Read more.
Pancreatic cancer is still associated with a poor prognosis and remains—as the fourth leading cause of cancer related mortality—a therapeutic challenge. Overall long-term survival is about 1–5%, and in only 10–20% of pancreatic cancer patients is potentially curative surgery possible, increasing five-year survival rates to approximately 20–25%. Pancreatic surgery is a technically challenging procedure and has significantly changed during the past decades with regard to technical aspects as well as perioperative care. Standardized resections can be carried out with low morbidity and mortality below 5% in high volume institutions. Furthermore, there is growing evidence that also more extended resections including multivisceral approaches, vessel reconstructions or surgery for tumor recurrence can be carried out safely with favorable outcomes. The impact of adjuvant treatment, especially chemotherapy, has increased dramatically within recent years, leading to significantly improved postoperative survival, making pancreatic cancer therapy an interdisciplinary approach to achieve best results. Full article
(This article belongs to the Special Issue Pancreatic Cancer)
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Open AccessReview Glutathione in Cancer Cell Death
Cancers 2011, 3(1), 1285-1310; doi:10.3390/cancers3011285
Received: 30 December 2010 / Revised: 22 February 2011 / Accepted: 9 March 2011 / Published: 11 March 2011
Cited by 46 | PDF Full-text (641 KB) | HTML Full-text | XML Full-text
Abstract
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is [...] Read more.
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one of the endogenous effectors involved in regulating the mitochondrial permeability transition pore complex and, in consequence, thiol oxidation can be a causal factor in the mitochondrion-based mechanism that leads to cell death. Nevertheless GSH depletion is a common feature not only of apoptosis but also of other types of cell death. Indeed rates of GSH synthesis and fluxes regulate its levels in cellular compartments, and potentially influence switches among different mechanisms of death. How changes in gene expression, post-translational modifications of proteins, and signaling cascades are implicated will be discussed. Furthermore, this review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Cancer Stem Cells in Breast Cancer
Cancers 2011, 3(1), 1311-1328; doi:10.3390/cancers3011311
Received: 17 February 2011 / Revised: 3 March 2011 / Accepted: 11 March 2011 / Published: 15 March 2011
Cited by 11 | PDF Full-text (381 KB) | HTML Full-text | XML Full-text
Abstract
The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem [...] Read more.
The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem cells in self-renewal, the propagation of differentiated progeny, the expression of specific cell markers and stem cell genes, and the utilization of common signaling pathways and the stem cell niche. However, CSCs differ from normal stem cells in their chemoresistance and their tumorigenic and metastatic activities. In this review, we focus on recent reports regarding the identification of CSC markers and the molecular mechanism of CSC phenotypes to understand the basic properties and molecular target of CSCs. In addition, we especially focus on the CSCs of breast cancer since the use of neoadjuvant chemotherapy can lead to the enrichment of CSCs in patients with that disease. The identification of CSC markers and an improved understanding of the molecular mechanism of CSC phenotypes should lead to progress in cancer therapy and improved prognoses for patients with cancer. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessReview Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects
Cancers 2011, 3(1), 1351-1371; doi:10.3390/cancers3011351
Received: 14 January 2011 / Revised: 28 February 2011 / Accepted: 3 March 2011 / Published: 15 March 2011
Cited by 182 | PDF Full-text (329 KB) | HTML Full-text | XML Full-text
Abstract
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, [...] Read more.
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview The Potential Use of N-Myristoyltransferase as a Biomarker in the Early Diagnosis of Colon Cancer
Cancers 2011, 3(1), 1372-1382; doi:10.3390/cancers3011372
Received: 6 February 2011 / Revised: 9 March 2011 / Accepted: 11 March 2011 / Published: 16 March 2011
Cited by 3 | PDF Full-text (511 KB) | HTML Full-text | XML Full-text
Abstract
Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to [...] Read more.
Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to 25% of cancer patients when initially diagnosed. The majority of colon cancers develop from noncancerous adenomatous polyps on the lining of the colon which grow over the years to become cancerous. If detected early, the surgical resections of the growth, often in combination with chemotherapy, significantly increases life expectancy. We have shown that the enzyme N-myristoyltransferase (NMT) which carries out lipid modification of several proteins (including many of those involved in oncogenesis) is expressed at higher levels in cancerous tissues from the colon. We have also shown that in peripheral blood mononuclear cells (PBMC) and bone marrow (BM) cells collected from colon cancer patients and from azoxymethane-induced rats the expression and localization of NMT is altered. We have observed strong positivity for NMT in immunohistochemical analysis for PBMC from colon cancer patients as compared to control groups. Furthermore, in the bone marrow (BM) mononuclear cells, NMT was found to be confined to the nuclei whereas in control groups it was observed to be located in the cytoplasm. In conclusion, this strikingly differential localization offers the basis of a potential investigational tool for screening or diagnosis of individuals at risk for or suspected of having colon cancer. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)
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Open AccessReview Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer
Cancers 2011, 3(1), 1383-1404; doi:10.3390/cancers3011383
Received: 30 January 2011 / Revised: 7 March 2011 / Accepted: 8 March 2011 / Published: 16 March 2011
Cited by 38 | PDF Full-text (563 KB) | HTML Full-text | XML Full-text
Abstract
Similar to genetic alterations, epigenetic aberrations contribute significantly to tumor initiation and progression. In many cases, these changes are caused by activation or inactivation of the regulators that maintain epigenetic states. Here we review our current knowledge on the KDM5/JARID1 family of [...] Read more.
Similar to genetic alterations, epigenetic aberrations contribute significantly to tumor initiation and progression. In many cases, these changes are caused by activation or inactivation of the regulators that maintain epigenetic states. Here we review our current knowledge on the KDM5/JARID1 family of histone demethylases. This family of enzymes contains a JmjC domain and is capable of removing tri- and di- methyl marks from lysine 4 on histone H3. Among these proteins, RBP2 mediates drug resistance while JARID1B is required for melanoma maintenance. Preclinical studies suggest inhibition of these enzymes can suppress tumorigenesis and provide strong rationale for development of their inhibitors for use in cancer therapy. Full article
(This article belongs to the Special Issue Epigenetics of Cancer Progression)
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Open AccessReview Breast Cancer-Initiating Cells: Insights into Novel Treatment Strategies
Cancers 2011, 3(1), 1405-1425; doi:10.3390/cancers3011405
Received: 14 January 2011 / Revised: 17 February 2011 / Accepted: 2 March 2011 / Published: 16 March 2011
Cited by 4 | PDF Full-text (218 KB) | HTML Full-text | XML Full-text
Abstract
There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24/low and/or CD133+ expression) or enzymatic [...] Read more.
There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24/low and/or CD133+ expression) or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), have been demonstrated to have stem/progenitor cell properties, and are tumorigenic when injected in immunocompromized mice at very low concentrations. BCIC have also been isolated and in vitro propagated as non-adherent spheres of undifferentiated cells, and stem cell patterns have been recognized even in cancer cell lines. Recent findings indicate that aberrant regulation of self renewal is central to cancer stem cell biology. Alterations in genes involved in self-renewal pathways, such as Wnt, Notch, sonic hedgehog, PTEN and BMI, proved to play a role in breast cancer progression. Hence, targeting key elements mediating the self renewal of BCIC represents an attractive option, with a solid rationale, clearly identifiable molecular targets, and adequate knowledge of the involved pathways. Possible concerns are related to the poor knowledge of tolerance and efficacy of inhibiting self-renewal mechanisms, because the latter are key pathways for a variety of biological functions and it is unknown whether their interference would kill BCIC or simply temporarily stop them. Thus, efforts to develop BCIC-targeted therapies should not only be focused on interfering on self-renewal, but could seek to identify additional molecular targets, like those involved in regulating EMT-related pathways, in reversing the MDR phenotype, in inducing differentiation and controlling cell survival pathways. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
Open AccessReview The Role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer
Cancers 2011, 3(1), 1426-1453; doi:10.3390/cancers3011426
Received: 29 December 2010 / Revised: 9 March 2011 / Accepted: 10 March 2011 / Published: 17 March 2011
Cited by 12 | PDF Full-text (308 KB) | HTML Full-text | XML Full-text
Abstract
Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or [...] Read more.
Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20–30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC. Full article
(This article belongs to the Special Issue Lung Cancer)
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Open AccessOpinion Tumor Acidity as Evolutionary Spite
Cancers 2011, 3(1), 408-414; doi:10.3390/cancers3010408
Received: 7 December 2010 / Revised: 21 December 2010 / Accepted: 17 January 2011 / Published: 20 January 2011
Cited by 17 | PDF Full-text (280 KB) | HTML Full-text | XML Full-text
Abstract
Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of [...] Read more.
Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of tumor acidity, the tumor microenvironment encourages a selection of certain cell phenotypes that are able to survive in this caustic environment to the detriment of other cell types. This selection can be described by a process which can be modeled upon spite: the tumor cells reduce their own fitness by making an acidic environment, but this reduces the fitness of their competitors to an even greater extent. Moreover, the environment is an important dimension that further drives this spite process. Thus, diminishing the selective environment most probably interferes with the spite process. Such interference has been recently utilized in cancer treatment. Full article
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Open AccessCase Report Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report
Cancers 2011, 3(1), 1454-1466; doi:10.3390/cancers3011454
Received: 7 January 2011 / Accepted: 21 February 2011 / Published: 17 March 2011
PDF Full-text (333 KB) | HTML Full-text | XML Full-text
Abstract
The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the [...] Read more.
The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the suppression of NF-kappaB as a factor triggering the inflammatory response, and chemotherapy with capecitabine. The reduction of tumor mass was evidenced by a continuing decline of CA15-3 and CEA tumor marker serum levels and 18FDG-PET-CT plus magnetic resonance (MR) imaging. It is concluded that such combination treatment might be a useful option for treating already formed metastases and for providing protection against the formation of metastases in ER positive breast cancer. The findings need to be corroborated by clinical trials. Whether similar results can be expected for other malignant tumor phenotypes relying on glycolysis as the main energy source remains to be elucidated. Full article

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