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Cancers, Volume 10, Issue 7 (July 2018) – 31 articles

Cover Story (view full-size image): Oncoviruses are capable of subverting the cell signaling machinery and metabolic pathways and exploit them for infection, replication, and persistence. Some viral oncoproteins are able to directly bind to and degrade p53, others cause the functionally inactivation of the oncosuppressor and deregulated expression of many genes orchestrated by p53. New drugs are being developed to target the interaction between viral oncoproteins and p53, as well as the negative regulators MDM2/MDMX and p53, and are already at the preclinical study stage and early-phase clinical trials. View this paper
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38 pages, 1075 KiB  
Review
Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism
by Nikolaos Tsesmetzis, Cynthia B. J. Paulin, Sean G. Rudd and Nikolas Herold
Cancers 2018, 10(7), 240; https://doi.org/10.3390/cancers10070240 - 23 Jul 2018
Cited by 78 | Viewed by 10103
Abstract
Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, [...] Read more.
Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine. Full article
(This article belongs to the Special Issue Drug Resistance in Cancers)
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24 pages, 4530 KiB  
Article
Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms
by I Made Winarsa Ruma, Rie Kinoshita, Nahoko Tomonobu, Yusuke Inoue, Eisaku Kondo, Akira Yamauchi, Hiroki Sato, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka, Masahiro Nishibori and Masakiyo Sakaguchi
Cancers 2018, 10(7), 239; https://doi.org/10.3390/cancers10070239 - 23 Jul 2018
Cited by 12 | Viewed by 4793
Abstract
Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin’s roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down [...] Read more.
Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin’s roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid- and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients. Full article
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14 pages, 1590 KiB  
Review
Micelles Structure Development as a Strategy to Improve Smart Cancer Therapy
by Nemany A. N. Hanafy, Maged El-Kemary and Stefano Leporatti
Cancers 2018, 10(7), 238; https://doi.org/10.3390/cancers10070238 - 20 Jul 2018
Cited by 179 | Viewed by 8355
Abstract
Micelles as colloidal suspension have attracted considerable attention due to their potential use for both cancer diagnosis and therapy. These structures have proven their ability to deliver poorly water-soluble anticancer drugs, improve drug stability, and have good penetration and site-specificity, leading to enhance [...] Read more.
Micelles as colloidal suspension have attracted considerable attention due to their potential use for both cancer diagnosis and therapy. These structures have proven their ability to deliver poorly water-soluble anticancer drugs, improve drug stability, and have good penetration and site-specificity, leading to enhance therapeutic efficacy. Micelles are composed of hydrophobic and hydrophilic components assembled into nanosized spherical, ellipsoid, cylindrical, or unilamellar structures. For their simple formation, they are widely studied, either by using opposite polymers attachment consisting of two or more block copolymers, or by using fatty acid molecules that can modify themselves in a rounded shape. Recently, hybrid and responsive stimuli nanomicelles are formed either by integration with metal nanoparticles such as silver, gold, iron oxide nanoparticles inside micelles or by a combination of lipids and polymers into single composite. Herein, through this special issue, an updated overview of micelles development and their application for cancer therapy will be discussed. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer)
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20 pages, 1651 KiB  
Article
Infection of Epstein–Barr Virus in Type III Latency Modulates Biogenesis of Exosomes and the Expression Profile of Exosomal miRNAs in the Burkitt Lymphoma Mutu Cell Lines
by Asuka Nanbo, Harutaka Katano, Michiyo Kataoka, Shiho Hoshina, Tsuyoshi Sekizuka, Makoto Kuroda and Yusuke Ohba
Cancers 2018, 10(7), 237; https://doi.org/10.3390/cancers10070237 - 19 Jul 2018
Cited by 23 | Viewed by 5350
Abstract
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates [...] Read more.
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates the profile of microRNAs in the cells, little is known about the microRNAs in exosomes released from infected cells. Here, we characterized the expression profile of intracellular and exosomal microRNAs in EBV-negative, and two related EBV-infected Burkitt lymphoma cell lines having type I and type III latency by next-generation sequencing. We found that the biogenesis of exosomes is upregulated in type III latently infected cells compared with EBV-negative and type I latently infected cells. We also observed that viral and several specific host microRNAs were predominantly incorporated in the exosomes released from the cells in type III latency. We confirmed that multiple viral microRNAs were transferred to the epithelial cells cocultured with EBV-infected B cells. Our findings indicate that EBV infection, in particular in type III latency, modulates the biogenesis of exosomes and the profile of exosomal microRNAs, potentially contributing to phenotypic changes in cells receiving these exosomes. Full article
(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)
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22 pages, 279 KiB  
Review
A Review of Recent Advances in the Treatment of Elderly and Poor Performance NSCLC
by Juliet A. Carmichael, Daisy Wing-san Mak and Mary O’Brien
Cancers 2018, 10(7), 236; https://doi.org/10.3390/cancers10070236 - 18 Jul 2018
Cited by 34 | Viewed by 4480
Abstract
Until recently, chemotherapy has remained the mainstay of treatment for the majority of patients with advanced non-small cell lung cancer (NSCLC). Excellent responses have been observed with immune-checkpoint inhibitors, and targeted treatments for those tumours with actionable mutations, resulting in a paradigm shift [...] Read more.
Until recently, chemotherapy has remained the mainstay of treatment for the majority of patients with advanced non-small cell lung cancer (NSCLC). Excellent responses have been observed with immune-checkpoint inhibitors, and targeted treatments for those tumours with actionable mutations, resulting in a paradigm shift in the treatment approach for these patients. Elderly patients and those with poor performance status (PS), such as Eastern Cooperative Oncology Group (ECOG) 2, have historically been excluded from clinical trials due to poor outcomes. There is therefore a lack of data to define the optimal treatment strategy for these patients. Due to improved tolerability of novel therapies, inclusion of these patients in clinical trials has increased, and sub-group analyses have identified many treatments demonstrating potential activity. Here, we summarise key recent advances in the treatment of NSCLC, specifically evaluating their efficacy and tolerability in these patient cohorts. Full article
(This article belongs to the Special Issue Recent Advances in Non-Small Cell Lung Cancer)
8 pages, 1437 KiB  
Perspective
Pancreatic Cancer Related Health Disparities: A Commentary
by Lisa Scarton, Saunjoo Yoon, Sungho Oh, Edward Agyare, Jose Trevino, Bo Han, Eunsook Lee, Veronica Wendy Setiawan, Jennifer B. Permuth, Thomas D. Schmittgen, Folakemi G. Odedina and Diana J. Wilkie
Cancers 2018, 10(7), 235; https://doi.org/10.3390/cancers10070235 - 18 Jul 2018
Cited by 31 | Viewed by 4495
Abstract
We summarize the risk factors that may significantly contribute to racial disparities in pancreatic cancer, which is now the third leading cause of cancer deaths and projected to be second around 2030 in 12 years. For decades, the incidence rate of pancreatic cancer [...] Read more.
We summarize the risk factors that may significantly contribute to racial disparities in pancreatic cancer, which is now the third leading cause of cancer deaths and projected to be second around 2030 in 12 years. For decades, the incidence rate of pancreatic cancer among Blacks has been 30% to 70% higher than other racial groups in the United States and the 5-year survival rate is approximately 5%. Diabetes and obesity have been identified as potentially predisposing factors to pancreatic cancer and both are more common among Blacks. Smoking continues to be one of the most important risk factors for pancreatic cancer and smoking rates are higher among Blacks compared to other racial groups. The overall risk of pancreatic cancer due to changes in DNA is thought to be the same for most racial groups; however, DNA methylation levels have been observed to be significantly different between Blacks and Whites. This finding may underlie the racial disparities in pancreatic cancer. Identification and prevention of these factors may be effective strategies to reduce the high incidence and mortality rates for pancreatic cancer among Blacks. Full article
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12 pages, 2231 KiB  
Article
Morphomechanical Alterations Induced by Transforming Growth Factor-β1 in Epithelial Breast Cancer Cells
by Mariafrancesca Cascione, Valeria De Matteis, Chiara C. Toma and Stefano Leporatti
Cancers 2018, 10(7), 234; https://doi.org/10.3390/cancers10070234 - 16 Jul 2018
Cited by 12 | Viewed by 3625
Abstract
The Epithelial to mesenchymal transition (EMT) is the process that drives epithelial tumor cells to acquire an invasive phenotype. The role of transforming growth factor-β1 (TGF-β1) in EMT is still debated. We used confocal laser scanning microscopy and scanning force spectroscopy to perform [...] Read more.
The Epithelial to mesenchymal transition (EMT) is the process that drives epithelial tumor cells to acquire an invasive phenotype. The role of transforming growth factor-β1 (TGF-β1) in EMT is still debated. We used confocal laser scanning microscopy and scanning force spectroscopy to perform a morphomechanical analysis on epithelial breast cancer cells (MCF-7), comparing them before and after TGF-β1 exogenous stimulation (5 ng/mL for 48 h). After TGF-β1 treatment, loss of cell–cell adherence (mainly due to the reduction of E-cadherin expression of about 24%) and disaggregation of actin cortical fibers were observed in treated MCF-7. In addition, TGF-β1 induced an alteration of MCF-7 nuclei morphology as well as a decrease in the Young’s modulus, owing to a rearrangement that involved the cytoskeletal networks and the nuclear region. These relevant variations in morphological features and mechanical properties, elicited by TGF-β1, suggested an increased capacity of MCF-7 to migrate, which was confirmed by a wound healing assay. By means of our biophysical approach, we highlighted the malignant progression of breast cancer cells induced by TGF-β1 exposure. We are confirming TGF-β1’s role in EMT by means of morphomechanical evidence that could represent a turning point in understanding the molecular mechanisms involved in cancer progression. Full article
(This article belongs to the Special Issue Nanotechnology and Cancer)
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23 pages, 11044 KiB  
Article
Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability
by Corina Cuceu, Bruno Colicchio, Eric Jeandidier, Steffen Junker, François Plassa, Grace Shim, Justyna Mika, Monika Frenzel, Mustafa AL Jawhari, William M. Hempel, Sylwia Kabacik, Aude Lenain, Luc Morat, Theodore Girinsky, Alain Dieterlen, Joanna Polanska, Christophe Badie, Patrice Carde and Radhia M’Kacher
Cancers 2018, 10(7), 233; https://doi.org/10.3390/cancers10070233 - 13 Jul 2018
Cited by 14 | Viewed by 4965
Abstract
Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite [...] Read more.
Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed high MSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. The MC-HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL and MC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL. Full article
(This article belongs to the Special Issue Hodgkin's Lymphoma)
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18 pages, 279 KiB  
Review
Bridging Strategies to Allogeneic Transplant for Older AML Patients
by Judith Hecker, Isabella Miller, Katharina S. Götze and Mareike Verbeek
Cancers 2018, 10(7), 232; https://doi.org/10.3390/cancers10070232 - 11 Jul 2018
Cited by 6 | Viewed by 3908
Abstract
Treatment options for older patients with intermediate or high-risk acute myeloid leukemia (AML) remain unsatisfactory. Allogeneic stem cell transplantation, the treatment of choice for the majority of younger AML patients, has been hampered in elderly patients by higher treatment related mortality, comorbidities and [...] Read more.
Treatment options for older patients with intermediate or high-risk acute myeloid leukemia (AML) remain unsatisfactory. Allogeneic stem cell transplantation, the treatment of choice for the majority of younger AML patients, has been hampered in elderly patients by higher treatment related mortality, comorbidities and lack of a suitable donor. With the higher availability of suitable donors as well as of reduced intensity conditioning regimens, novel low intensity treatments prior to transplantation and optimized supportive care, the number of older AML patients being successfully transplanted is steadily increasing. Against this background, we review current treatment strategies for older AML patients planned for allogeneic stem cell transplantation based on clinical trial data, discussing differences between approaches with advantages and pitfalls of each. We summarize pre-treatment considerations that need to be taken into account in this highly heterogeneous older population. Finally, we offer an outlook on areas of ongoing clinical research, including novel immunotherapeutic approaches that may improve access to curative therapies for a larger number of older AML patients. Full article
(This article belongs to the Special Issue Treatment of Older Adults with Acute Myeloid Leukemia)
14 pages, 1749 KiB  
Article
Vaccinia Virus Shuffling: deVV5, a Novel Chimeric Poxvirus with Improved Oncolytic Potency
by Marine Ricordel, Johann Foloppe, Delphine Antoine, Annie Findeli, Juliette Kempf, Pascale Cordier, Aude Gerbaud, Benoit Grellier, Monika Lusky, Eric Quemeneur and Philippe Erbs
Cancers 2018, 10(7), 231; https://doi.org/10.3390/cancers10070231 - 10 Jul 2018
Cited by 14 | Viewed by 4518
Abstract
Oncolytic virus (OV) therapy has emerged as a promising approach for cancer treatment with the potential to be less toxic and more efficient than classic cancer therapies. Various types of OVs in clinical development, including Vaccinia virus (VACV)-derived OVs, have shown good safety [...] Read more.
Oncolytic virus (OV) therapy has emerged as a promising approach for cancer treatment with the potential to be less toxic and more efficient than classic cancer therapies. Various types of OVs in clinical development, including Vaccinia virus (VACV)-derived OVs, have shown good safety profiles, but limited therapeutic efficacy as monotherapy in some cancer models. Many different methods have been employed to improve the oncolytic potency of OVs. In this study, we used a directed evolution process, pooling different strains of VACV, including Copenhagen, Western Reserve and Wyeth strains and the attenuated modified vaccinia virus Ankara (MVA), to generate a new recombinant poxvirus with increased oncolytic properties. Through selective pressure, a chimeric VACV, deVV5, with increased cancer cell killing capacity and tumor selectivity in vitro was derived. The chimeric viral genome contains sequences of all parental strains. To further improve the tumor selectivity and anti-tumor activity of deVV5, we generated a thymidine kinase (TK)-deleted chimeric virus armed with the suicide gene FCU1. This TK-deleted virus, deVV5-fcu1 replicated efficiently in human tumor cells, and was notably attenuated in normal primary cells. These studies demonstrate the potential of directed evolution as an efficient way to generate recombinant poxviruses with increased oncolytic potency, and with high therapeutic index to improve cancer therapy. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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20 pages, 2574 KiB  
Review
With Great Age Comes Great Metastatic Ability: Ovarian Cancer and the Appeal of the Aging Peritoneal Microenvironment
by Elizabeth I. Harper, Emma F. Sheedy and M. Sharon Stack
Cancers 2018, 10(7), 230; https://doi.org/10.3390/cancers10070230 - 10 Jul 2018
Cited by 25 | Viewed by 4888
Abstract
Age is one of the biggest risk factors for ovarian cancer. Older women have higher rates of diagnosis and death associated with the disease. In mouse models, it was shown that aged mice had greater tumor burden than their younger counterparts when intraperitoneally [...] Read more.
Age is one of the biggest risk factors for ovarian cancer. Older women have higher rates of diagnosis and death associated with the disease. In mouse models, it was shown that aged mice had greater tumor burden than their younger counterparts when intraperitoneally injected with ovarian tumor cells. While very few papers have been published looking at the direct link between ovarian cancer metastasis and age, there is a wealth of information on how age affects metastatic microenvironments. Mesothelial cells, the peritoneal extracellular matrix (ECM), fibroblasts, adipocytes and immune cells all exhibit distinct changes with age. The aged peritoneum hosts a higher number of senescent cells than its younger counterpart, in both the mesothelium and the stroma. These senescent cells promote an inflammatory profile and overexpress Matrix Metalloproteinases (MMPs), which remodel the ECM. The aged ECM is also modified by dysregulated collagen and laminin synthesis, increases in age-related crosslinking and increasing ovarian cancer invasion into the matrix. These changes contribute to a vastly different microenvironment in young and aged models for circulating ovarian cancer cells, creating a more welcoming “soil”. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of High Grade Serous Ovarian Cancer)
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16 pages, 1306 KiB  
Review
Epithelioid Hemangioendothelioma as a Model of YAP/TAZ-Driven Cancer: Insights from a Rare Fusion Sarcoma
by John M. Lamar, Vijeyaluxmy Motilal Nehru and Guy Weinberg
Cancers 2018, 10(7), 229; https://doi.org/10.3390/cancers10070229 - 10 Jul 2018
Cited by 33 | Viewed by 7242
Abstract
Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central [...] Read more.
Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central nervous system-specific transcription activator. The 10% of EHEs that lack the TAZ–CAMTA1 fusion instead have a fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3). YAP and TAZ are well-defined downstream effectors in the Hippo pathway that promote cell growth when translocated to the nucleus. The TAZ–CAMTA1 fusion transcript is insensitive to the Hippo inhibitory signals that normally prevent this process and thus constitutively activates the TAZ transcriptome. In EHE, this causes tumors to form in a variety of organs and tissue types, most commonly the liver, lung, and bone. Its clinical course is unpredictable and highly variable. TAZ activation is known to contribute to key aspects of the cancer phenotype, including metastasis and fibrosis, and increased expression of TAZ is thought to be causally related to the progression of many cancers, including breast, lung, and liver. Therefore, understanding TAZ biology and the molecular mechanisms by which it promotes unregulated cell proliferation will yield insights and possibly improved treatments for both EHE as well as much more common cancers. Full article
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18 pages, 3900 KiB  
Article
NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration and Chemoresistance
by Javadi Monisha, Nand Kishor Roy, Ganesan Padmavathi, Kishore Banik, Devivasha Bordoloi, Amrita Devi Khwairakpam, Frank Arfuso, Arunachalam Chinnathambi, Tahani Awad Alahmadi, Sulaiman Ali Alharbi, Gautam Sethi, Alan Prem Kumar and Ajaikumar B. Kunnumakkara
Cancers 2018, 10(7), 228; https://doi.org/10.3390/cancers10070228 - 10 Jul 2018
Cited by 67 | Viewed by 5453
Abstract
Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our [...] Read more.
Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study, we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer in comparison to normal tissues. The downregulation of NGAL was strongly correlated with both degree of differentiation and stage (I–IV); it can also serve as a prognostic biomarker for oral cancer. Additionally, tobacco carcinogens were found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration; it also induced resistance against cisplatin. Silencing of NGAL activated mammalian target of rapamycin (mTOR)signaling and reduced autophagy by the liver kinase B1 (LKB1)-activated protein kinase (AMPK)-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and matrix metalloproteinase-9 (MMP-9) were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study, it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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19 pages, 1206 KiB  
Review
Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment
by Yan Xu
Cancers 2018, 10(7), 227; https://doi.org/10.3390/cancers10070227 - 09 Jul 2018
Cited by 39 | Viewed by 5329
Abstract
As one of the important cancer hallmarks, metabolism reprogramming, including lipid metabolism alterations, occurs in tumor cells and the tumor microenvironment (TME). It plays an important role in tumorigenesis, progression, and metastasis. Lipids, and several lysophospholipids in particular, are elevated in the blood, [...] Read more.
As one of the important cancer hallmarks, metabolism reprogramming, including lipid metabolism alterations, occurs in tumor cells and the tumor microenvironment (TME). It plays an important role in tumorigenesis, progression, and metastasis. Lipids, and several lysophospholipids in particular, are elevated in the blood, ascites, and/or epithelial ovarian cancer (EOC) tissues, making them not only useful biomarkers, but also potential therapeutic targets. While the roles and signaling of these lipids in tumor cells are extensively studied, there is a significant gap in our understanding of their regulations and functions in the context of the microenvironment. This review focuses on the recent study development in several oncolipids, including lysophosphatidic acid and sphingosine-1-phosphate, with emphasis on TME in ovarian cancer. Full article
(This article belongs to the Special Issue The Tumor Microenvironment of High Grade Serous Ovarian Cancer)
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17 pages, 842 KiB  
Review
Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors
by Maider Varela-Guruceaga, Sonia Tejada-Solís, Marc García-Moure, Juan Fueyo, Candelaria Gomez-Manzano, Ana Patiño-García and Marta M. Alonso
Cancers 2018, 10(7), 226; https://doi.org/10.3390/cancers10070226 - 09 Jul 2018
Cited by 22 | Viewed by 4269
Abstract
In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of [...] Read more.
In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In this review, we summarize the OVs evaluated in different types of PBTs, mostly in pre-clinical studies, and we discuss the possible future direction of research in this field. In this sense, one important aspect of OVs antitumoral effect is the stimulation of an immune response against the tumor which is necessary for a complete response in preclinical immunocompetent models and in the clinic. The role of the immune system in the response of OVs needs to be evaluated in PBTs and represents an experimental challenge due to the limited immunocompetent models of these diseases available for pre-clinical research. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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11 pages, 235 KiB  
Review
Geriatric Assessment in Older Patients with Acute Myeloid Leukemia
by Kah Poh Loh and Heidi D. Klepin
Cancers 2018, 10(7), 225; https://doi.org/10.3390/cancers10070225 - 06 Jul 2018
Cited by 21 | Viewed by 3879
Abstract
The incidence of acute myeloid leukemia (AML) increases with age, but the outcomes for older adults with AML are poor due to underlying tumor biology, poor tolerance to aggressive treatment, and the physiologic changes of aging. Because of the underlying heterogeneity in health [...] Read more.
The incidence of acute myeloid leukemia (AML) increases with age, but the outcomes for older adults with AML are poor due to underlying tumor biology, poor tolerance to aggressive treatment, and the physiologic changes of aging. Because of the underlying heterogeneity in health status, treatment decisions are difficult in this population. A geriatric assessment (GA) refers to the use of various validated tools to assess domains that are important in older adults including physical function, cognition, comorbidities, polypharmacy, social support, and nutritional status. In older patients with cancer, a GA can guide treatment decision-making, predict treatment toxicity, and guide supportive care interventions. Compared to solids tumors, there is a relative lack of studies evaluating the use of a GA in older patients with AML. In this review, we will discuss the principles, common domains, feasibility, and benefits of GA, with a focus on older patients with AML that includes practical applications for clinical management. Full article
(This article belongs to the Special Issue Treatment of Older Adults with Acute Myeloid Leukemia)
17 pages, 1665 KiB  
Review
Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance
by Zachary Schrank, Gagan Chhabra, Leo Lin, Tsatsral Iderzorig, Chike Osude, Nabiha Khan, Adijan Kuckovic, Sanjana Singh, Rachel J. Miller and Neelu Puri
Cancers 2018, 10(7), 224; https://doi.org/10.3390/cancers10070224 - 04 Jul 2018
Cited by 88 | Viewed by 11106
Abstract
Lung cancer is treated with many conventional therapies, such as surgery, radiation, and chemotherapy. However, these therapies have multiple undesirable side effects. To bypass the side effects elicited by these conventional treatments, molecularly-targeted therapies are currently in use or under development. Current molecularly-targeted [...] Read more.
Lung cancer is treated with many conventional therapies, such as surgery, radiation, and chemotherapy. However, these therapies have multiple undesirable side effects. To bypass the side effects elicited by these conventional treatments, molecularly-targeted therapies are currently in use or under development. Current molecularly-targeted therapies effectively target specific biomarkers, which are commonly overexpressed in lung cancers and can cause increased tumorigenicity. Unfortunately, several molecularly-targeted therapies are associated with initial dramatic responses followed by acquired resistance due to spontaneous mutations or activation of signaling pathways. Acquired resistance to molecularly targeted therapies presents a major clinical challenge in the treatment of lung cancer. Therefore, to address this clinical challenge and to improve lung cancer patient prognosis, we need to understand the mechanism of acquired resistance to current therapies and develop additional novel therapies. This review concentrates on various lung cancer biomarkers, including EGFR, ALK, and BRAF, as well as their potential mechanisms of drug resistance. Full article
(This article belongs to the Special Issue Recent Advances in Non-Small Cell Lung Cancer)
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11 pages, 1264 KiB  
Review
Measuring Surgery Outcomes of Lung Cancer Patients with Concomitant Pulmonary Fibrosis: A Review of the Literature
by Taichiro Goto
Cancers 2018, 10(7), 223; https://doi.org/10.3390/cancers10070223 - 04 Jul 2018
Cited by 22 | Viewed by 3242
Abstract
Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonias, often progresses to restrictive respiratory disturbance and mortality, typically within 10 years. IPF frequently coexists with lung cancer, and the combination of these two disease entities is far more difficult to [...] Read more.
Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonias, often progresses to restrictive respiratory disturbance and mortality, typically within 10 years. IPF frequently coexists with lung cancer, and the combination of these two disease entities is far more difficult to treat than either lung cancer or IPF alone. In particular, surgery for lung cancer with IPF in the background increases postoperative morbidity and mortality by exacerbating pre-existing IPF, i.e., acute exacerbation of IPF (AEIPF). Furthermore, the long-term outcome after lung cancer surgery is considerably worsened by the presence of IPF. We present here a comprehensive review of AEIPF and the long-term outcomes after surgery. Full article
(This article belongs to the Special Issue Recent Advances in Non-Small Cell Lung Cancer)
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16 pages, 584 KiB  
Review
Radiation Pneumonitis: Old Problem, New Tricks
by Varsha Jain and Abigail T. Berman
Cancers 2018, 10(7), 222; https://doi.org/10.3390/cancers10070222 - 03 Jul 2018
Cited by 101 | Viewed by 8001
Abstract
Radiation therapy is a major treatment modality for management of non-small cell lung cancer. Radiation pneumonitis is a dose limiting toxicity of radiotherapy, affecting its therapeutic ratio. This review presents patient and treatment related factors associated with the development of radiation pneumonitis. Research [...] Read more.
Radiation therapy is a major treatment modality for management of non-small cell lung cancer. Radiation pneumonitis is a dose limiting toxicity of radiotherapy, affecting its therapeutic ratio. This review presents patient and treatment related factors associated with the development of radiation pneumonitis. Research focusing on reducing the incidence of radiation pneumonitis by using information about lung ventilation, imaging-based biomarkers as well as normal tissue complication models is discussed. Recent advances in our understanding of molecular mechanisms underlying lung injury has led to the development of several targeted interventions, which are also explored in this review. Full article
(This article belongs to the Special Issue Recent Advances in Non-Small Cell Lung Cancer)
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17 pages, 1650 KiB  
Review
Dynamics of p14ARF and Focal Adhesion Kinase-Mediated Autophagy in Cancer
by Rosa Fontana and Maria Vivo
Cancers 2018, 10(7), 221; https://doi.org/10.3390/cancers10070221 - 29 Jun 2018
Cited by 8 | Viewed by 4863
Abstract
It has been widely shown that the focal adhesion kinase (FAK) is involved in nearly every aspect of cancer, from invasion to metastasis to epithelial–mesenchymal transition and maintenance of cancer stem cells. FAK has been shown to interact with p14ARF (alternative reading frame)—a [...] Read more.
It has been widely shown that the focal adhesion kinase (FAK) is involved in nearly every aspect of cancer, from invasion to metastasis to epithelial–mesenchymal transition and maintenance of cancer stem cells. FAK has been shown to interact with p14ARF (alternative reading frame)—a well-established tumor suppressor—and functions in the negative regulation of cancer through both p53-dependent and -independent pathways. Interestingly, both FAK and ARF (human and mouse counterpart) proteins, as well as p53, are involved in autophagy—a process of “self-digestion”—whose main function is the recycling of cellular components and quality control of proteins and organelles. In the last years, an unexpected role of p14ARF in the survival of cancer cells has been underlined in different cellular contexts, suggesting a novel pro-oncogenic function of this protein. In this review, the mechanisms whereby ARF and FAK control autophagy are presented, as well as the role of autophagy in cell migration and spreading. Integrated investigation of these cell functions is extremely important to understand the mechanism of the basis of cell transformation and migration and thus cancer development. Full article
(This article belongs to the Special Issue FAK Signaling Pathway in Cancers)
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15 pages, 2729 KiB  
Article
Establishing a Dedicated Lung Cancer Biobank at the University Center Hospital of Nice (France). Why and How?
by Kevin Washetine, Simon Heeke, Christelle Bonnetaud, Mehdi Kara-Borni, Marius Ilié, Sandra Lassalle, Catherine Butori, Elodie Long-Mira, Charles Hugo Marquette, Charlotte Cohen, Jérôme Mouroux, Eric Selva, Virginie Tanga, Coraline Bence, Jean-Marc Félix, Loic Gazoppi, Taycir Skhiri, Emmanuelle Gormally, Pascal Boucher, Bruno Clément, Georges Dagher, Véronique Hofman and Paul Hofmanadd Show full author list remove Hide full author list
Cancers 2018, 10(7), 220; https://doi.org/10.3390/cancers10070220 - 29 Jun 2018
Cited by 13 | Viewed by 5063
Abstract
Lung cancer is the major cause of death from cancer in the world and its incidence is increasing in women. Despite the progress made in developing immunotherapies and therapies targeting genomic alterations, improvement in the survival rate of advanced stages or metastatic patients [...] Read more.
Lung cancer is the major cause of death from cancer in the world and its incidence is increasing in women. Despite the progress made in developing immunotherapies and therapies targeting genomic alterations, improvement in the survival rate of advanced stages or metastatic patients remains low. Thus, urgent development of effective therapeutic molecules is needed. The discovery of novel therapeutic targets and their validation requires high quality biological material and associated clinical data. With this aim, we established a biobank dedicated to lung cancers. We describe here our strategy and the indicators used and, through an overall assessment, present the strengths, weaknesses, opportunities and associated risks of this biobank. Full article
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13 pages, 748 KiB  
Review
Role of p53 in the Regulation of the Inflammatory Tumor Microenvironment and Tumor Suppression
by Ikuno Uehara and Nobuyuki Tanaka
Cancers 2018, 10(7), 219; https://doi.org/10.3390/cancers10070219 - 27 Jun 2018
Cited by 76 | Viewed by 7513
Abstract
p53 has functional roles in tumor suppression as a guardian of the genome, surveillant of oncogenic cell transformation, and as recently demonstrated, a regulator of intracellular metabolism. Accumulating evidence has shown that the tumor microenvironment, accompanied by inflammation and tissue remodeling, is important [...] Read more.
p53 has functional roles in tumor suppression as a guardian of the genome, surveillant of oncogenic cell transformation, and as recently demonstrated, a regulator of intracellular metabolism. Accumulating evidence has shown that the tumor microenvironment, accompanied by inflammation and tissue remodeling, is important for cancer proliferation, metastasis, and maintenance of cancer stem cells (CSCs) that self-renew and generate the diverse cells comprising the tumor. Furthermore, p53 has been demonstrated to inhibit inflammatory responses, and functional loss of p53 causes excessive inflammatory reactions. Moreover, the generation and maintenance of CSCs are supported by the inflammatory tumor microenvironment. Considering that the functions of p53 inhibit reprogramming of somatic cells to stem cells, p53 may have a major role in the inflammatory microenvironment as a tumor suppressor. Here, we review our current understanding of the mechanisms underlying the roles of p53 in regulation of the inflammatory microenvironment, tumor microenvironment, and tumor suppression. Full article
(This article belongs to the Special Issue p53 Signaling in Cancers)
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18 pages, 4800 KiB  
Review
The Osteoclast in Bone Metastasis: Player and Target
by Antonio Maurizi and Nadia Rucci
Cancers 2018, 10(7), 218; https://doi.org/10.3390/cancers10070218 - 27 Jun 2018
Cited by 116 | Viewed by 10177
Abstract
Bone metastases are frequently the final fate of breast and prostate cancer patients. According to the definition of metastasis as an incurable disease, to date there are no effective treatments for tumor-associated bone metastases and this represents a real challenge for the researchers [...] Read more.
Bone metastases are frequently the final fate of breast and prostate cancer patients. According to the definition of metastasis as an incurable disease, to date there are no effective treatments for tumor-associated bone metastases and this represents a real challenge for the researchers in the field. The bone is a heterogeneous environment that represents a fertile soil for tumor cells, supporting their growth. Among the different cell types present in the bone, in this review we will focus our attention on the osteoclasts, which are crucial players in the so called “vicious cycle”, a phenomenon triggered by tumor cells eventually leading to both tumor proliferation as well as bone deregulation, thus fueling the development of bone metastasis. The complex network, linking tumor cells to the bone by activating osteoclasts, represents a fruitful target for the treatment of bone metastases. In this review we will describe how tumor cells perturb the bone microenvironment by actively influencing osteoclast formation and activity. Moreover, we will describe the current antiresorptive drugs employed in the treatment of bone metastases as well as new, targeted therapies able to affect both cancer cells and osteoclasts. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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13 pages, 3095 KiB  
Article
Nano-Pulse Stimulation for the Treatment of Pancreatic Cancer and the Changes in Immune Profile
by Siqi Guo, Niculina I. Burcus, James Hornef, Yu Jing, Chunqi Jiang, Richard Heller and Stephen J. Beebe
Cancers 2018, 10(7), 217; https://doi.org/10.3390/cancers10070217 - 27 Jun 2018
Cited by 24 | Viewed by 4895
Abstract
A Pancreatic cancer is a notorious malignant neoplasm with an extremely poor prognosis. Current standard of care is rarely effective against late-stage pancreatic cancer. In this study, we assessed nanopulse stimulation (NPS) as a local treatment for pancreatic cancer in a syngeneic mouse [...] Read more.
A Pancreatic cancer is a notorious malignant neoplasm with an extremely poor prognosis. Current standard of care is rarely effective against late-stage pancreatic cancer. In this study, we assessed nanopulse stimulation (NPS) as a local treatment for pancreatic cancer in a syngeneic mouse Pan02 pancreatic cancer model and characterized corresponding changes in the immune profile. A single NPS treatment either achieved complete tumor regression or prolonged overall survival in animals with partial tumor regression. While this is very encouraging, we also explored if this local ablation effect could also result in immune stimulation, as was observed when NPS led to the induction of immune-mediated protection from a second tumor challenge in orthotopic mouse breast and rat liver cancer models. In the Pan02 model, there were insufficient abscopal effects (1/10) and vaccine-like protective effects (1/15) suggesting that NPS-induced immune mechanisms in this model were limited. To evaluate this further, the immune landscape was analyzed. The numbers of both T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSCs) in blood were significantly reduced, but memory (CD44+) T-cells were absent. Furthermore, the numbers of Tregs and MDSCs did not reduce in spleens compared to tumor-bearing mice. Very few T-cells, but large numbers of MDSCs were present in the NPS treated tumor microenvironment (TME). The number of dendritic cells in the TME was increased and multiple activation markers were upregulated following NPS treatment. Overall, NPS treatments used here are effective for pancreatic tumor ablation, but require further optimization for induction of immunity or the need to include effective combinational NPS therapeutic strategy for pancreatic cancer. Full article
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19 pages, 644 KiB  
Review
Fusogenic Viruses in Oncolytic Immunotherapy
by Teresa Krabbe and Jennifer Altomonte
Cancers 2018, 10(7), 216; https://doi.org/10.3390/cancers10070216 - 26 Jun 2018
Cited by 36 | Viewed by 5901
Abstract
Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune [...] Read more.
Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune responses directed against the tumor, make oncolytic viruses highly attractive candidates for immunotherapy. Increasing evidence indicates that a subclass of oncolytic viruses, which encodes for fusion proteins, could outperform non-fusogenic viruses, both in their direct oncolytic potential, as well as their immune-stimulatory properties. Tumor cell infection with these viruses leads to characteristic syncytia formation and cell death due to fusion, as infected cells become fused with neighboring cells, which promotes intratumoral spread of the infection and releases additional immunogenic signals. In this review, we discuss the potential of fusogenic oncolytic viruses as optimal candidates to enhance immunotherapy and initiate broad antitumor responses. We provide an overview of the cytopathic mechanism of syncytia formation through viral-mediated expression of fusion proteins, either endogenous or engineered, and their benefits for cancer therapy. Growing evidence indicates that fusogenicity could be an important feature to consider in the design of optimal oncolytic virus platforms for combinatorial oncolytic immunotherapy. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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15 pages, 755 KiB  
Review
Role of Minimal (Measurable) Residual Disease Assessment in Older Patients with Acute Myeloid Leukemia
by Francesco Buccisano, Richard Dillon, Sylvie D. Freeman and Adriano Venditti
Cancers 2018, 10(7), 215; https://doi.org/10.3390/cancers10070215 - 26 Jun 2018
Cited by 19 | Viewed by 4339
Abstract
Minimal (or measurable) residual (MRD) disease provides a biomarker of response quality for which there is robust validation in the context of modern intensive treatment for younger patients with Acute Myeloid Leukemia (AML). Nevertheless, it remains a relatively unexplored area in older patients [...] Read more.
Minimal (or measurable) residual (MRD) disease provides a biomarker of response quality for which there is robust validation in the context of modern intensive treatment for younger patients with Acute Myeloid Leukemia (AML). Nevertheless, it remains a relatively unexplored area in older patients with AML. The lack of progress in this field can be attributed to two main reasons. First, physicians have a general reluctance to submitting older adults to intensive chemotherapy due to their frailty and to the unfavourable biological disease profile predicting a poor outcome following conventional chemotherapy. Second, with the increasing use of low-intensity therapies (i.e., hypomethylating agents) differing from conventional drugs in mechanism of action and dynamics of response, there has been concomitant skepticism that these schedules can produce deep hematological responses. Furthermore, age dependent differences in disease biology also contribute to uncertainty on the prognostic/predictive impact in older adults of certain genetic abnormalities including those validated for MRD monitoring in younger patients. This review examines the evidence for the role of MRD as a prognosticator in older AML, together with the possible pitfalls of MRD evaluation in older age. Full article
(This article belongs to the Special Issue Treatment of Older Adults with Acute Myeloid Leukemia)
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15 pages, 1711 KiB  
Case Report
A Novel Acquired t(2;4)(q36.1;q24) with a Concurrent Submicroscopic del(4)(q23q24) in An Adult with Polycythemia Vera
by Eigil Kjeldsen
Cancers 2018, 10(7), 214; https://doi.org/10.3390/cancers10070214 - 25 Jun 2018
Cited by 1 | Viewed by 3391
Abstract
Background: Polycythemia vera (PV) is a clonal myeloid stem cell disease characterized by a growth-factor independent erythroid proliferation with an inherent tendency to transform into overt acute myeloid malignancy. Approximately 95% of the PV patients harbor the JAK2V617F mutation while less [...] Read more.
Background: Polycythemia vera (PV) is a clonal myeloid stem cell disease characterized by a growth-factor independent erythroid proliferation with an inherent tendency to transform into overt acute myeloid malignancy. Approximately 95% of the PV patients harbor the JAK2V617F mutation while less than 35% of the patients harbor cytogenetic abnormalities at the time of diagnosis. Methods and Results: Here we present a JAK2V617F positive PV patient where G-banding revealed an apparently balanced t(2;4)(q35;q21), which was confirmed by 24-color karyotyping. Oligonucleotide array-based Comparative Genomic Hybridization (aCGH) analysis revealed an interstitial 5.4 Mb large deletion at 4q23q24. Locus-specific fluorescent in situ hybridization (FISH) analyses confirmed the mono-allelic 4q deletion and that it was located on der(4)t(2;4). Additional locus-specific bacterial artificial chromosome (BAC) probes and mBanding refined the breakpoint on chromosome 2. With these methods the karyotype was revised to 46,XX,t(2;4)(q36.1;q24)[18]/46,XX[7]. Conclusions: This is the first report on a PV patient associated with an acquired novel t(2;4)(q36.1;q24) and a concurrent submicroscopic deletion del(4)(q23q24). The study also underscores the benefit of combined usage of FISH and oligo-based aCGH analysis in characterizing chromosomal abnormalities. The present findings provide additional clues to unravel important molecular pathways in PV to obtain the full spectrum of acquired chromosomal and genomic aberrations, which eventually may improve treatment options. Full article
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14 pages, 1587 KiB  
Review
Human Oncoviruses and p53 Tumor Suppressor Pathway Deregulation at the Origin of Human Cancers
by Maria Lina Tornesello, Clorinda Annunziata, Anna Lucia Tornesello, Luigi Buonaguro and Franco Maria Buonaguro
Cancers 2018, 10(7), 213; https://doi.org/10.3390/cancers10070213 - 22 Jun 2018
Cited by 60 | Viewed by 10897
Abstract
Viral oncogenesis is a multistep process largely depending on the complex interplay between viruses and host factors. The oncoviruses are capable of subverting the cell signaling machinery and metabolic pathways and exploit them for infection, replication, and persistence. Several viral oncoproteins are able [...] Read more.
Viral oncogenesis is a multistep process largely depending on the complex interplay between viruses and host factors. The oncoviruses are capable of subverting the cell signaling machinery and metabolic pathways and exploit them for infection, replication, and persistence. Several viral oncoproteins are able to functionally inactivate the tumor suppressor p53, causing deregulated expression of many genes orchestrated by p53, such as those involved in apoptosis, DNA stability, and cell proliferation. The Epstein–Barr virus (EBV) BZLF1, the high-risk human papillomavirus (HPV) E6, and the hepatitis C virus (HCV) NS5 proteins have shown to directly bind to and degrade p53. The hepatitis B virus (HBV) HBx and the human T cell lymphotropic virus-1 (HTLV-1) Tax proteins inhibit p53 activity through the modulation of p300/CBP nuclear factors, while the Kaposi’s sarcoma herpesvirus (HHV8) LANA, vIRF-1 and vIRF-3 proteins have been shown to destabilize the oncosuppressor, causing a decrease in its levels in the infected cells. The large T antigen of the Merkel cell polyomavirus (MCPyV) does not bind to p53 but significantly reduces p53-dependent transcription. This review describes the main molecular mechanisms involved in the interaction between viral oncoproteins and p53-related pathways as well as in the development of therapeutic strategies targeting such interactions. Full article
(This article belongs to the Special Issue p53 Signaling in Cancers)
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16 pages, 1509 KiB  
Review
Understanding Intratumor Heterogeneity and Evolution in NSCLC and Potential New Therapeutic Approach
by Taichiro Goto, Yosuke Hirotsu, Kenji Amemiya, Hitoshi Mochizuki and Masao Omata
Cancers 2018, 10(7), 212; https://doi.org/10.3390/cancers10070212 - 22 Jun 2018
Cited by 15 | Viewed by 4886
Abstract
Advances in innovative technology, including next-generation sequencing, have allowed comprehensive genomic analysis and the elucidation of the genomic aspect of intratumor heterogeneity (ITH). Moreover, models of the evolution of the cancer genome have been proposed by integrating these analyses. Cancer has been considered [...] Read more.
Advances in innovative technology, including next-generation sequencing, have allowed comprehensive genomic analysis and the elucidation of the genomic aspect of intratumor heterogeneity (ITH). Moreover, models of the evolution of the cancer genome have been proposed by integrating these analyses. Cancer has been considered to accumulate genetic abnormalities for clonal evolution in time and space, and these evolutionary patterns vary depending on the organs of primary sites. Selection pressure is an important determinant of such evolutionary patterns. With weak selection pressure, more diverse clones coexist, and heterogeneity increases. Heterogeneity is maximized when there is no selection pressure; in other words, neutral evolution occurs. Some types of cancer such as lung cancer evolve in conditions that have maintained close to neutral evolution and produce diverse variants. This ITH is a key factor contributing to the lethal outcome of cancer, therapeutic failure, and drug resistance. This factor reaffirms the complexity and subtle adaptability of cancer. It is expected that further understanding of ITH and cancer genome evolution will facilitate the development of new therapeutic strategies to overcome ITH. Full article
(This article belongs to the Special Issue Recent Advances in Non-Small Cell Lung Cancer)
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12 pages, 1232 KiB  
Review
Immunosenescence and Immunotherapy in Elderly Acute Myeloid Leukemia Patients: Time for a Biology-Driven Approach
by Alessandro Isidori, Federica Loscocco, Marilena Ciciarello, Giulia Corradi, Mariangela Lecciso, Darina Ocadlikova, Sarah Parisi, Valentina Salvestrini, Sergio Amadori, Giuseppe Visani and Antonio Curti
Cancers 2018, 10(7), 211; https://doi.org/10.3390/cancers10070211 - 22 Jun 2018
Cited by 7 | Viewed by 7201
Abstract
Acute myeloid leukemia (AML) is a disease, which mainly affects the elderly population. Unfortunately, the prognosis of patients aged >65 years is dismal, with 1-year overall survival approaching 10% with conventional therapies. The hypothesis of harnessing the immune system against cancer, including leukemia, [...] Read more.
Acute myeloid leukemia (AML) is a disease, which mainly affects the elderly population. Unfortunately, the prognosis of patients aged >65 years is dismal, with 1-year overall survival approaching 10% with conventional therapies. The hypothesis of harnessing the immune system against cancer, including leukemia, has been postulated for a long time, and several clinical attempts have been made in this field. In the last years, we increased our knowledge about the interplay between AML and immune cells, but no major improvement has been translated, up to now, from bench to bedside. However, the outstanding results coming from the modern immuno-oncology trials with new drugs have granted a new interest for immunotherapy in AML. Accordingly, the elderly population represents an ideal target, given the low percentage of patients eligible for allogeneic stem cell transplant. With that in mind, in the era of immunotherapy, we consider immunosenescence as the optimal background to start investigating a biology-driven approach to AML therapy in the elderly. By taking into account the physiological age-related changes of immune response, more personalized and tailored use of the new drugs and strategies harnessing the immune system against AML, has the potential to increase their efficacy and impact on clinical outcomes. Full article
(This article belongs to the Special Issue Treatment of Older Adults with Acute Myeloid Leukemia)
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