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Cancers — Open Access Journal of Oncology

Cancers (ISSN 2072-6694; CODEN: CANCCT) is a peer-reviewed open access journal of oncology published monthly online by MDPI. The Irish Association for Cancer Research (IACR) is affiliated with Cancers and their members receive a discount on the article processing charges.

Open Access - free for readers, with article processing charges (APC) paid by authors or their institutions.
High visibility: indexed by the Science Citation Index Expanded (Web of Science) and BIOSIS Previews. Citations available in PubMed, full-text archived in PubMed Central. Indexed in BIOSIS Previews, Scopus and other databases.
Rapid publication: manuscripts are peer-reviewed and a first decision provided to authors approximately 18 days after submission; acceptance to publication is undertaken in 4.1 days (median values for papers published in the first six months of 2018).
Recognition of reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.

Impact Factor: 5.326 (2017)

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Latest Articles

Open AccessArticle

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

by Yunami Yamada, Hironori Fujii, Daichi Watanabe, Hiroko Kato-Hayashi, Koichi Ohata, Ryo Kobayashi, Takuma Ishihara, Shinya Uemura, Takuji Iwashita, Masahito Shimizu and Akio Suzuki

Cancers 2018, 10(11), 454; https://doi.org/10.3390/cancers10110454 (registering DOI) - 16 November 2018

Abstract

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While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients (30 males and 21 females) with advanced pancreatic cancer who received modified FOLFIRINOX (2h bolus injection of oxaliplatin at 85 mg/m², 2 h bolus injection of L-leucovorin at 200 mg/m², 90min bolus injection of irinotecan at 150 mg/m², followed by continuous infusion of 5-fluorouracil for 46 h at 2400 mg/m² without bolus 5-fluorouracil) during the period from January 2014 to May 2018. No patients had prior history of chemotherapy. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were secondary endpoints. Severe neutropenia (grade ≥3) occurred in 39 patients (76.4%), and Cox proportional hazard analysis identified high total bilirubin level as a significant risk factor. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (21.3 months versus 8.9 months, p = 0.020). Moreover, there was a significant correlation between OS and the grade of neutropenia (r = 0.306, p = 0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRINOX therapy. Full article

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Open AccessReview

Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition

by Elizabeth Santana dos Santos, François Lallemand, Leslie Burke, Dominique Stoppa-Lyonnet, Melissa Brown, Sandrine M. Caputo and Etienne Rouleau

Cancers 2018, 10(11), 453; https://doi.org/10.3390/cancers10110453 (registering DOI) - 16 November 2018

Abstract

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BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition. Full article

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Open AccessArticle

Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells

by Marie Alexandra Albaret, Claudine Vermot-Desroches, Arnaud Paré, Jean-Xavier Roca-Martinez, Lucie Malet, Jad Esseily, Laetitia Gerossier, Johan Brière, Nathalie Pion, Virginie Marcel, Frédéric Catez, Geneviève De Souza, Boris Vuillermoz, Franck Doerflinger, Emilie Lavocat, Olivier Subiger, Carine Rousset, Corinne Bresson, Elodie Mandon, Anass Jawhari, Pierre Falson, Mélissa Jasmin, Yohann Coute, Hichem-Claude Mertani, Pierre Saintigny and Jean-Jacques Diaz

Cancers 2018, 10(11), 452; https://doi.org/10.3390/cancers10110452 (registering DOI) - 16 November 2018

Abstract

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Accumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer therapy, the mechanisms via which they impact cancer biology remain largely unexplored. The aim of this study was to expose an externalized form of cytokeratin 8 (eK8) as a key player of colorectal tumorigenesis and characterize its mode of action. To achieve this, we generated a unique antagonist monoclonal antibody (D-A10 MAb) targeting an eight-amino-acid-long domain of eK8, which enabled us to ascertain the pro-tumoral activity of eK8 in both KRAS-mutant and wild-type colorectal cancers (CRC). We showed that this pro-tumoral activity involves a bidirectional eK8-dependent control of caspase-mediated apoptosis in vivo and of the plasminogen-induced invasion process in cellulo. Furthermore, we demonstrated that eK8 is anchored at the plasma membrane supporting this dual function. We, therefore, identified eK8 as an innovative therapeutic target in CRC and provided a unique MAb targeting eK8 that displays anti-neoplastic activities that could be useful to treat CRC, including those harboring KRAS mutations. Full article

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Open AccessArticle

Targeted Therapy-Resistant Melanoma Cells Acquire Transcriptomic Similarities with Human Melanoblasts

by Lionel Larribère, Silke Kuphal, Christos Sachpekidis, Sachindra, Laura Hüser, Anja Bosserhoff and Jochen Utikal

Cancers 2018, 10(11), 451; https://doi.org/10.3390/cancers10110451 (registering DOI) - 16 November 2018

Abstract

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The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate human melanoblasts: (1) via differentiation from induced pluripotent stem cells (iPSCs) and (2) via dedifferentiation from melanocytes. The melanoblast transcriptomes were then compared to the transcriptome of MAPK inhibitor-resistant melanoma cells. We observed that the expression of genes associated with cell cycle control, DNA damage control, metabolism, and cancer was altered in both melanoblast populations and in both adaptive and acquired resistant melanoma samples, compared to drug-sensitive samples. However, genes involved in antigen presentation and cellular movement were only regulated in the melanoblast populations and in the acquired resistant melanoma samples, compared to the drug-sensitive samples. Moreover, melanocyte-derived melanoblasts and adaptive resistant melanoma samples were characterized by different expression levels of certain transcription factors or genes involved in the CDK5 pathway. In conclusion, we show here that in vitro models of human melanoblasts are very important tools to comprehend the expression profiles of drug-resistant melanoma. Full article

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Open AccessReview

Cancer-Associated Thrombosis in Cirrhotic Patients with Hepatocellular Carcinoma

by Alberto Zanetto, Elena Campello, Luca Spiezia, Patrizia Burra, Paolo Simioni and Francesco Paolo Russo

Cancers 2018, 10(11), 450; https://doi.org/10.3390/cancers10110450 (registering DOI) - 16 November 2018

Abstract

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It is common knowledge that cancer patients are more prone to develop venous thromboembolic complications (VTE). It is therefore not surprising that patients with hepatocellular carcinoma (HCC) present with a significant risk of VTE, with the portal vein being the most frequent site (PVT). However, patients with HCC are peculiar as both cancer and liver cirrhosis are conditions that can perturb the hemostatic balance towards a prothrombotic state. Because HCC-related hypercoagulability is not clarified at all, the aim of the present review is to summarize the currently available knowledge on epidemiology and pathogenesis of non-malignant thrombotic complications in patients with liver cirrhosis and HCC. They are at increased risk to develop both PVT and non-splanchnic VTE, indicating that both local and systemic factors can foster the development of site-specific thrombosis. Recent studies have suggested multiple and often interrelated mechanisms through which HCC can tip the hemostatic balance of liver cirrhosis towards hypercoagulability. Described mechanisms include increased fibrinogen concentration/polymerization, thrombocytosis, and release of tissue factor-expressing extracellular vesicles. Currently, there are no specific guidelines on the use of thromboprophylaxis in this unique population. There is the urgent need of prospective studies assessing which patients have the highest prothrombotic profile and would therefore benefit from early thromboprophylaxis. Full article

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Open AccessArticle

Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation

by Xinyan Ji, Lihua Song, Li Sheng, Anhui Gao, Yang Zhao, Shixun Han, Yuchao Zhang, Chu Zhu, Simeng Zhao, Zhe Wang, Bohan Xu, Li Li, Jia Li, Ninghua Tan and Bin Zhao

Cancers 2018, 10(11), 449; https://doi.org/10.3390/cancers10110449 (registering DOI) - 16 November 2018

Abstract

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The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation. Full article

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Open AccessArticle

Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition

by Candace J. Poole, Wenli Zheng, Haesung Lee, Danielle Young, Atul Lodh, Ahmed Chadli and Jan van Riggelen

Cancers 2018, 10(11), 448; https://doi.org/10.3390/cancers10110448 (registering DOI) - 16 November 2018

Abstract

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Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma. Full article

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Open AccessReview

Lipid Metabolic Reprogramming in Hepatocellular Carcinoma

by Hayato Nakagawa, Yuki Hayata, Satoshi Kawamura, Tomoharu Yamada, Naoto Fujiwara and Kazuhiko Koike

Cancers 2018, 10(11), 447; https://doi.org/10.3390/cancers10110447 - 15 November 2018

Abstract

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Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming. Full article

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Open AccessArticle

Tumor-Targeted Immunotherapy by Using Primary Adipose-Derived Stem Cells and an Antigen-Specific Protein Vaccine

by Jui-Hua Lu, Bou-Yue Peng, Chun-Chao Chang, Navneet Kumar Dubey, Wen-Cheng Lo, Hsin-Chung Cheng, Joseph R. Wang, Hong-Jian Wei and Win-Ping Deng

Cancers 2018, 10(11), 446; https://doi.org/10.3390/cancers10110446 - 15 November 2018

Abstract

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Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, such as improperly immortalized mesenchymal stem cells (MSCs) along with transfected oncogenic antigens in them. To overcome the limitations of this platform for future clinical application, we freshly prepared primary adipose-derived stem cells (ADSCs) and modified the E7’ antigen (E7’) as a non-oncogenic protein. Either subcutaneously co-inoculated with cancer cells or systemically administered after tumor growth, ADSC labeled with enhanced green fluorescent protein (eGFP) and combined with modified E7’ (ADSC-E7’-eGFP) cells showed significant antitumor activity when combined with the protein vaccine in both colon and lung cancer in mice. Specifically, this combined therapy inhibited tumor through inducing cell apoptosis. The significantly reduced endothelial cell markers, CD31 and vascular endothelial growth factor (VEGF), indicated strongly inhibited tumor angiogenesis. The activated immune system was demonstrated through the response of CD4+ T and natural killer (NK) cells, and a notable antitumor activity might be contributed by CD8+ T cells. Conclusively, these evidences imply that this promising immunotherapeutic platform might be a potential candidate for the future clinical application against cancer. Full article

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Open AccessArticle

Pharmacokinetics of Sublingually Delivered Fentanyl in Head and Neck Cancer Patients Treated with Curatively Aimed Chemo or Bioradiotherapy

by Evelien J. M. Kuip, Wendy H. Oldenmenger, Esther Oomen-de Hoop, Gerda M. Verduijn, Martine F. Thijs-Visser, Peter de Bruijn, Esther van Meerten, Stijn L. W. Koolen, Ron H. J. Mathijssen and Carin C. D. van der Rijt

Cancers 2018, 10(11), 445; https://doi.org/10.3390/cancers10110445 - 15 November 2018

Abstract

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Over 90% of patients treated for head and neck cancer with curatively aimed chemo or bioradiotherapy will develop painful mucositis and xerostomia. Sublingually delivered fentanyl (SDL) is a rapid acting opioid to treat breakthrough pain. It is unclear how SDL is absorbed by the mucosa of these patients. Therefore, the aim of this study was to investigate the effects of mucositis and xerostomia on the absorption of SDL. Thirteen patients who received chemo or bioradiotherapy (RT), were given a single dose of fentanyl: Before start of RT, 3 and 6 weeks after start of RT, and 6 weeks after finishing RT. Pharmacokinetic samples were taken. The primary endpoint was the relative difference (RD) between systemic exposure to fentanyl (area under the curve; AUC) at baseline (AUC_baseline) and fentanyl AUC in the presence of mucositis grade ≥2. The secondary endpoint was the RD between AUC_baseline and fentanyl AUC in the presence of xerostomia, which were analyzed by means of a paired t-test on log-transformed data. Mucositis resulted in a 12.7% higher AUC (n = 13; 95% CI: −10.7% to +42.2%, p = 0.29) compared to baseline levels and xerostomia resulted in a 22.4% lower AUC (n = 8; 95% CI: −51.9% to +25.3%, p = 0.25) compared to baseline levels. Mucositis grade ≥2 or xerostomia caused by chemo or bioradiotherapy does not significantly alter the systemic exposure to SDL. Patients with pain during and after chemo or bioradiotherapy may be safely treated with SDL. Full article

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Open AccessReview

Molecular Mechanisms Regulating Organ-Specific Metastases in Epithelial Ovarian Carcinoma

by Maria V. Barbolina

Cancers 2018, 10(11), 444; https://doi.org/10.3390/cancers10110444 - 15 November 2018

Abstract

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Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and lymphogenously spread metastases also occur. In this review, we describe molecular mechanisms known to regulate organ-specific metastasis from epithelial ovarian carcinoma. We begin by discussing the sites colonized by metastatic ovarian carcinoma and rank them in the order of prevalence. Next, we review the mechanisms regulating the transcoelomic metastasis. Within this chapter, we specifically focus on the mechanisms that were demonstrated to regulate peritoneal adhesion—one of the first steps in the transcoelomic metastatic cascade. Furthermore, we describe mechanisms of the transcoelomic metastasis known to regulate colonization of specific sites within the peritoneal cavity, including the omentum. Mechanisms underlying hematogenous and lymphogenous metastatic spread are less comprehensively studied in ovarian cancer, and we summarize mechanisms that were identified to date. Lastly, we discuss the outcomes of the clinical trials that attempted to target some of the mechanisms described in this review. Full article

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Open AccessArticle

MiR-375 Regulation of LDHB Plays Distinct Roles in Polyomavirus-Positive and -Negative Merkel Cell Carcinoma

by Satendra Kumar, Hong Xie, Patrick Scicluna, Linkiat Lee, Viveca Björnhagen, Anders Höög, Catharina Larsson and Weng-Onn Lui

Cancers 2018, 10(11), 443; https://doi.org/10.3390/cancers10110443 - 14 November 2018

Abstract

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MicroRNA-375 (miR-375) is deregulated in multiple tumor types and regulates important targets involved in tumorigenesis and metastasis. This miRNA is highly expressed in Merkel cell carcinoma (MCC) compared to normal skin and other non-MCC skin cancers, and its expression is high in Merkel cell polyomavirus (MCPyV)-positive (MCPyV+) and low in MCPyV-negative (MCPyV−) MCC tumors. In this study, we characterized the function and target of miR-375 in MCPyV+ and MCPyV− MCC cell lines. Ectopic expression of miR-375 in MCPyV− MCC cells resulted in decreased cell proliferation and migration, as well as increased cell apoptosis and cell cycle arrest. However, in MCPyV+ MCC cells, inhibition of miR-375 expression reduced cell growth and induced apoptosis. Additionally, the expression of lactate dehydrogenase B (LDHB), a known target of miR-375, was inversely correlated with miR-375. Silencing of LDHB reduced cell growth in MCPyV− cell lines, while its silencing in MCPyV+ cell lines rescued the cell growth effect mediated by miR-375 inhibition. Together, our results suggest dual roles of miR-375 and LDHB in MCPyV and non-MCPyV-associated MCCs. We propose that LDHB could be a therapeutic target in MCC and different strategies should be applied in virus- and non-virus-associated MCCs. Full article

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Open AccessArticle

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

by Magdalena Koczkowska, Natalia Krawczynska, Maciej Stukan, Alina Kuzniacka, Izabela Brozek, Marcin Sniadecki, Jaroslaw Debniak, Dariusz Wydra, Wojciech Biernat, Piotr Kozlowski, Janusz Limon, Bartosz Wasag and Magdalena Ratajska

Cancers 2018, 10(11), 442; https://doi.org/10.3390/cancers10110442 - 14 November 2018

Abstract

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Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of great clinical importance. Here, we established the prevalence and spectrum of the germline pathogenic variants in the BRCA1/2 and 23 other cancer-related genes in a large Polish population of 333 unselected OC cases. Approximately 21% of cases (71/333) carried the BRCA1/2 pathogenic or likely pathogenic variants, with c.5266dup (p.Gln1756Profs*74) and c.3700_3704del (p.Val1234Glnfs*8) being the most prevalent. Additionally, ~6% of women (20/333) were carriers of the pathogenic or likely pathogenic variants in other cancer-related genes, with NBN and CHEK2 reported as the most frequently mutated, accounting for 1.8% (6/333) and 1.2% (4/333) of cases, respectively. We also found ten pathogenic or likely pathogenic variants in other genes: 1/333 in APC, 1/333 in ATM, 2/333 in BLM, 1/333 in BRIP1, 1/333 in MRE11A, 2/333 in PALB2, 1/333 in RAD50, and 1/333 in RAD51C, accounting for 50% of all detected variants in moderate- and low-penetrant genes. Our findings confirmed the presence of the additional OC-associated genes in the Polish population that may improve the personalized risk assessment of these individuals. Full article

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Open AccessReview

Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis

by Léa Plantureux, Diane Mège, Lydie Crescence, Françoise Dignat-George, Christophe Dubois and Laurence Panicot-Dubois

Cancers 2018, 10(11), 441; https://doi.org/10.3390/cancers10110441 - 14 November 2018

Abstract

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Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer cells. On one hand, cancer can “educate” platelets, influencing their RNA profiles, the numbers of circulating platelets and their activation states. On the other hand, tumor-educated platelets contain a plethora of active biomolecules, including platelet-specific and circulating ingested biomolecules, that are released upon platelet activation and participate in the progression of malignancy. The numerous mechanisms by which the primary tumor induces the production, activation and aggregation of platelets (also known as tumor cell induced platelet aggregation, or TCIPA) are directly related to the pro-thrombotic state of cancer patients. Moreover, the activation of platelets is critical for tumor growth and successful metastatic outbreak. The development or use of existing drugs targeting the activation of platelets, adhesive proteins responsible for cancer cell-platelet interactions and platelet agonists should be used to reduce cancer-associated thrombosis and tumor progression. Full article

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Open AccessReview

Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer

by Bernadette Neve, Nicolas Jonckheere, Audrey Vincent and Isabelle Van Seuningen

Cancers 2018, 10(11), 440; https://doi.org/10.3390/cancers10110440 - 14 November 2018

Abstract

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Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells. Full article

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Open AccessArticle

The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas

by Vanessa Delcroix, Olivier Mauduit, Nolwenn Tessier, Anaïs Montillaud, Tom Lesluyes, Thomas Ducret, Frédéric Chibon, Fabien Van Coppenolle, Sylvie Ducreux and Pierre Vacher

Cancers 2018, 10(11), 439; https://doi.org/10.3390/cancers10110439 - 14 November 2018

Abstract

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By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca²⁺)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca²⁺-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca²⁺-responses and demonstrated that KL increases the reticular Ca²⁺-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS. Full article

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Open AccessArticle

Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone

by Jacqui A. McGovern, Abbas Shafiee, Ferdinand Wagner, Christoph A. Lahr, Marietta Landgraf, Christoph Meinert, Elizabeth D. Williams, Pamela J. Russell, Judith A. Clements, Daniela Loessner, Boris M. Holzapfel, Gail P. Risbridger and Dietmar W. Hutmacher

Cancers 2018, 10(11), 438; https://doi.org/10.3390/cancers10110438 - 13 November 2018

Abstract

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The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVEC), to humanized tissue-engineered bone constructs (hTEBC) in NOD-SCID IL2Rγ^null (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized prostate cancer model developed via convergence of cancer research and tissue engineering concepts provides an important platform to study species-specific PCa bone metastasis and to develop and test therapeutic strategies. Full article

Open AccessArticle

CCND1 Splice Variant as A Novel Diagnostic and Predictive Biomarker for Thyroid Cancer

by Sora Jeon, Yourha Kim, Young Mun Jeong, Ja Seong Bae and Chan Kwon Jung

Cancers 2018, 10(11), 437; https://doi.org/10.3390/cancers10110437 - 13 November 2018

Abstract

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Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease. Full article

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Open AccessArticle

Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia

by Victor Pallarès, Montserrat Hoyos, M. Carmen Chillón, Eva Barragán, M. Isabel Prieto Conde, Marta Llop, Aïda Falgàs, María Virtudes Céspedes, Pau Montesinos, Josep F. Nomdedeu, Salut Brunet, Miguel Ángel Sanz, Marcos González-Díaz, Jorge Sierra, Ramon Mangues and Isolda Casanova

Cancers 2018, 10(11), 436; https://doi.org/10.3390/cancers10110436 - 13 November 2018

Abstract

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In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment. Full article

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Open AccessReview

Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer

by Jeanna M. McCuaig, Susan Randall Armel, Melanie Care, Alexandra Volenik, Raymond H. Kim and Kelly A. Metcalfe

Cancers 2018, 10(11), 435; https://doi.org/10.3390/cancers10110435 - 13 November 2018

Abstract

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The combination of increased referral for genetic testing and the current shortage of genetic counselors has necessitated the development and implementation of alternative models of genetic counseling and testing for hereditary cancer assessment. The purpose of this scoping review is to provide an overview of the patient outcomes that are associated with alternative models of genetic testing and genetic counseling for hereditary cancer, including germline-only and tumor testing models. Seven databases were searched, selecting studies that were: (1) full-text articles published ≥2007 or conference abstracts published ≥2015, and (2) assessing patient outcomes of an alternative model of genetic counseling or testing. A total of 79 publications were included for review and synthesis. Data-charting was completed using a data-charting form that was developed by the study team for this review. Seven alternative models were identified, including four models that involved a genetic counselor: telephone, telegenic, group, and embedded genetic counseling models; and three models that did not: mainstreaming, direct, and tumor-first genetic testing models. Overall, these models may be an acceptable alternative to traditional models on knowledge, patient satisfaction, psychosocial measures, and the uptake of genetic testing; however, particular populations may be better served by traditional in-person genetic counseling. As precision medicine initiatives continue to advance, institutions should consider the implementation of new models of genetic service delivery, utilizing a model that will best serve the needs of their unique patient populations. Full article

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