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

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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; https://doi.org/10.3390/cancers3011467
Received: 30 January 2011 / Revised: 9 February 2011 / Accepted: 9 February 2011 / Published: 22 March 2011
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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 an
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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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Open AccessCase Report Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report
Cancers 2011, 3(1), 1454-1466; https://doi.org/10.3390/cancers3011454
Received: 7 January 2011 / Accepted: 21 February 2011 / Published: 17 March 2011
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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 suppression
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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
Open AccessReview The Role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer
Cancers 2011, 3(1), 1426-1453; https://doi.org/10.3390/cancers3011426
Received: 29 December 2010 / Revised: 9 March 2011 / Accepted: 10 March 2011 / Published: 17 March 2011
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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 pemetrexed,
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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 AccessReview Breast Cancer-Initiating Cells: Insights into Novel Treatment Strategies
Cancers 2011, 3(1), 1405-1425; https://doi.org/10.3390/cancers3011405
Received: 14 January 2011 / Revised: 17 February 2011 / Accepted: 2 March 2011 / Published: 16 March 2011
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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 activity
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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 Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer
Cancers 2011, 3(1), 1383-1404; https://doi.org/10.3390/cancers3011383
Received: 30 January 2011 / Revised: 7 March 2011 / Accepted: 8 March 2011 / Published: 16 March 2011
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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 histone
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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 The Potential Use of N-Myristoyltransferase as a Biomarker in the Early Diagnosis of Colon Cancer
Cancers 2011, 3(1), 1372-1382; https://doi.org/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 25%
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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 Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects
Cancers 2011, 3(1), 1351-1371; https://doi.org/10.3390/cancers3011351
Received: 14 January 2011 / Revised: 28 February 2011 / Accepted: 3 March 2011 / Published: 15 March 2011
Cited by 357 | 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, mediated
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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 AccessArticle The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis
Cancers 2011, 3(1), 1329-1350; https://doi.org/10.3390/cancers3011329
Received: 5 February 2011 / Revised: 15 February 2011 / Accepted: 10 March 2011 / Published: 15 March 2011
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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 unnecessary
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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 AccessReview Cancer Stem Cells in Breast Cancer
Cancers 2011, 3(1), 1311-1328; https://doi.org/10.3390/cancers3011311
Received: 17 February 2011 / Revised: 3 March 2011 / Accepted: 11 March 2011 / Published: 15 March 2011
Cited by 9 | 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 cells
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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 Glutathione in Cancer Cell Death
Cancers 2011, 3(1), 1285-1310; https://doi.org/10.3390/cancers3011285
Received: 30 December 2010 / Revised: 22 February 2011 / Accepted: 9 March 2011 / Published: 11 March 2011
Cited by 76 | 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 one
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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 AccessArticle The Prognostic Impact of p53 Expression on Sporadic Colorectal Cancer Is Dependent on p21 Status
Cancers 2011, 3(1), 1274-1284; https://doi.org/10.3390/cancers3011274
Received: 19 January 2011 / Revised: 28 February 2011 / Accepted: 4 March 2011 / Published: 11 March 2011
Cited by 4 | 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
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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 AccessReview Current State of Surgical Management of Pancreatic Cancer
Cancers 2011, 3(1), 1253-1273; https://doi.org/10.3390/cancers3011253
Received: 10 February 2011 / Revised: 19 February 2011 / Accepted: 10 March 2011 / Published: 10 March 2011
Cited by 4 | 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 survival
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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 Cancer Stem Cell Radioresistance and Enrichment: Where Frontline Radiation Therapy May Fail in Lung and Esophageal Cancers
Cancers 2011, 3(1), 1232-1252; https://doi.org/10.3390/cancers3011232
Received: 7 December 2010 / Revised: 25 January 2011 / Accepted: 24 February 2011 / Published: 10 March 2011
Cited by 34 | 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 prognosis.
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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 Analysis of Somatic Mutations in Cancer: Molecular Mechanisms of Activation in the ErbB Family of Receptor Tyrosine Kinases
Cancers 2011, 3(1), 1195-1231; https://doi.org/10.3390/cancers3011195
Received: 7 January 2011 / Revised: 28 February 2011 / Accepted: 1 March 2011 / Published: 10 March 2011
Cited by 8 | 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 is
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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 Cardiac Hormones Target the Ras-MEK 1/2-ERK 1/2 Kinase Cancer Signaling Pathways
Cancers 2011, 3(1), 1182-1194; https://doi.org/10.3390/cancers3011182
Received: 18 February 2011 / Revised: 2 March 2011 / Accepted: 3 March 2011 / Published: 8 March 2011
Cited by 2 | 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, kidney
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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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