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Colorectal cancer (CRC) is a common malignancy with a high mortality rate worldwide. It is a complex, multifactorial disease that is strongly impacted by both hereditary and environmental factors. The role of microbes (e.g., viruses) in the pathogenesis of CRC is poorly understood. In the current study, we explored the status of high-risk human papillomaviruses (HPV) and Epstein&ndash, Barr virus (EBV) in a well-defined CRC cohort using immunohistochemistry and polymerase chain reaction assays. Our data showed that high-risk HPVs were common (~80%) and EBV had a low presence (14&ndash, 25%) in the CRC samples. The most common high-risk HPVs are HPV16, 31, 18, 51, 52 and 45 genotypes. The co-presence of high-risk HPV and EBV was observed in ~16% of the sample population without any significant association with the clinicopathological variables. We conclude that high-risk HPVs are very prevalent in CRC samples while EBV positivity is relatively low. The co-expression of the two viruses was observed in a minority of cases and without any correlation with the studied parameters. Further studies are necessary to confirm the clinical relevance and potential therapeutic (preventive) effects of the observations reported herein.

In spite of the growing importance of endothelial protein C receptor/active protein C (EPCR/aPC) in tumor biology, their impact on immunological homeostasis remains largely unexplored. The objective of this study was to assess whether soluble plasma endothelial protein C receptor (sEPCR), which is a regulator of circulating aPC, is involved in innate immune response in cancer patients. In the Ovcar-3 ovarian cancer line, the role of aPC in secretion of cytokines was analyzed. In parallel, in 33 patients, with a diagnosis of ovarian epithelial cancer, sEPCR was quantified, blood immune cell phenotypes were determined by flow cytometry and plasma cytokines were evaluated using a protein array. Spearman's rank correlation coefficients (r) and coefficient significance was determined by a statistical hypothesis test (α=0.05). Our results show that i) aPC induced the secretion of several cytokines in Ovcar-3 cells; ii) 61% of patients exhibited a concentration of plasma sEPCR well above the baseline (normal plasma level, 100 ± 28 ng/ml); iii) comparing immune cell phenotypes in patients having a normal level of sEPCR with those having a high level of sEPCR, it was found that sEPCR levels were correlated with high intensity of cells expressing CD45ra, CD3, CD8, CD25 and low intensity of cells expressing CD56 (NK cells), CD294 (TH2 cells), IL-2, IL-10, IL-17a (TH17 cells), IL-21 (TH21 cells) and CD29 markers (r ≥ 0.60); and iv) high levels of sEPCR correlate with high levels of plasma bioactive proteins such as insulin-like growth factor-2 (IGFII), IL-13rα, macrophage inflammatory protein (MIP1α) and matrix metalloproteinase-7 (MMP-7) that have already been proposed as biomarkers for ovarian cancer and particularly those with poor prognosis. In conclusion, sEPCR produced by ovarian cancer cells, by modulating circulating aPC, influences the secretory behavior of tumor cells (cytokines and interleukins). Consequently, sEPCR in turn acts on the innate immune response by decreasing effector cells such as natural killer and T helper cells (TH2, TH17 and TH21).

Coagulation disorders often accompany cancer onset and evolution, which, if not properly managed, could have grave consequences. Endothelial protein C is an important regulator of homeostasis and acts through its high affinity binding to its transmembrane receptor (EPCR). Soluble (sEPCR) which results from the proteolytic cleavage of the membrane bound form can trap activated endothelial protein C and deprive it of its anti-coagulant function. In this study, the expression of EPCR and its soluble form (sEPCR) released into plasma as a result of proteolytic cleavage were investigated in ovarian, breast, lung and colorectal cancer biopsies, as well as in ascitic cell clusters and peritoneal fluid from ovarian cancer samples. In parallel, breast, ovarian, lung and colorectal cancer cell lines were investigated for the expression of EPCR. The integrity of the EPCR gene sequence as well gene haplotypes were ascertained in the established cancer cell lines in order to understand their eventual regulatory functions. The results from the present study indicate that in cancer patients, the levels of sEPCR are significantly higher than the normal range compared to healthy volunteers. The increase in the levels of sEPCR parallels the increase in CA125, showing a close correlation. Therefore, the detection of sEPCR in cancer and during the post-treatment period could be taken into account as an additional marker that could re-inforce the one obtained using CA125 alone as a marker of cancer cell mass.

Background The early peritoneal invasion of epithelial ovarian cancer (EOC) by tumoral aggregates presents in ascites is a major concern. The role of the microenvironment seems to be important in this process but the lack of adequate models to study cellular interactions between cancer cells and stromal cells does not allow to uncover the molecular pathways involved. Our goal was to study the interactions between ovarian cancer cells (OCC) and mesenchymal stem cells (MSC) using a 3D model. Methods We used millimetric pieces of amniochorionic membrane - referred to as amniotic membrane scaffold (AMS) - to create 3D peritoneal nodules mimicking EOC early invasion. We were able to measure the distribution and the depth of infiltration using confocal microsopy. We extracted MSC from the amniochorionic membrane using the markers CD34-, CD45-, CD73+, CD90+, CD105+ and CD29+ at the Fluorescence Activated Cell Sorting (FACS) analysis. We used transwell and wound healing tests to test OCC migration and invasion in vitro. Results Here we show that OCC tumors were located in regions rich in MSC (70%). The tumors infiltrated deeper within AMS in regions rich in MSC (p Conclusions The use of tridimensional models using AMS could be a useful tool to decipher early molecular events in ovarian cancer metastasis. Cytokine inhibitors interrupting the cross-talk between OCCs and MSCs such as IL6 should be investigated as a new therapeutic approach in ovarian cancer.

Epithelial ovarian cancer is the most lethal gynecologic malignancy with the majority of cases being diagnosed after the disease has become metastatic according to the report by Obstetrics and Gynecology, Duke University Medical Center USA, 2008. Consequently, genetic and epigenetic changes that disturb motility are likely to be important for the pathogenesis of ovarian cancer. Although ovarian cancer can be cured in up to 90% of cases while still confined to the ovary, approximately 70% are diagnosed after the occurrence of peritoneal dissemination, when the cure rate reduces to less than 30% according to recent studies by Global Cancer Statistic, CA Cancer 2011. Recent reports have shown 25% of most cancerous cells within tumors have the features of cancer stem cells (CSCs). CSCs have been identified on the basis of their ability to self-renew and to have the capacity to differentiate into cancer cells and also form tumors in animal model. We already demonstrated that the majority of cells of o...

Epithelial ovarian carcinoma (EOC) is the sixth most common malignancy in women and the leading cause of death from gynecological cancer in the world. One of the main differences between ovarian cancers and other neoplasm is burden of local extension. Hence the majority of mortality in ovarian cancer is due to extensive peritoneal disease, with a high rate of mortality and an overall survival rate ranging from 20% to 30% five years after surgery according to various studies. As for any metastatic process, the tumor cells have to go through the steps of detaching from the primary tumor, adhering to the peritoneal surface and then invading the peritoneum. Each of these steps might be critical in the development of a metastatic lesion. Therefore it is essential to understand the molecular background of peritoneal adhesion and invasion in order to define new therapeutic targets. It may be that classic 2-dimensional cultures do not represent an ideal model for the initiation of metastasis, and therefore studies using only 2-dimensional cell cultures might not replicate the reality of ovarian cancer physiology. The goal of our study was to define new 3-dimensional culture models that will mimic the peritoneal tissue. The constraints were; to use an easily accessible tissue, in relevant quantities, as close as possible to the peritoneum, with great manipulability. We demonstrated that we could keep the amniotic membrane in culture and mimic adhesion and the early invasion of ovarian cancer cell aggregates. We were then able to follow the invasive process within the membrane and determine different cell behavior. Developing reproducible 3-dimensional models of ovarian cancer aggregates and early adhesion and invasion will help us gain a more accurate understanding of the molecular mechanisms involved in the ovarian cancer metastatic process and define potential new therapeutic targets hindered by the use of classic 2-dimensional models.