Endothelial protein C receptor is overexpressed in colorectal cancer as a result of amplification and hypomethylation of chromosome 20q

Abstract

Endothelial Protein C Receptor (EPCR) is a Major Histocompatibility Complex homologue, with established roles downregulating coagulation and in endothelial protection. Expressed predominantly on endothelium, EPCR affects inflammatory, apoptotic and cell proliferation pathways by binding to activated protein C (APC). However, EPCR can also be expressed on cancer cells, although the underlying reasons are unclear. Moreover, although EPCR has been linked with chemosensitivity in lung cancer, its clinical significance in many tumours is unknown. Here, we explored its significance in colorectal cancer (CRC). Bioinformatic methods revealed EPCR overexpression in many epithelial cancers, which was confirmed on CRC epithelial tumour cells by immunohistochemistry. EPCR upregulation resulted from gene amplification and DNA hypomethylation, and occurred in concert with a cohort of neighbouring genes on chromosome 20q, a region previously implicated in chemoresistance. As in endothelial cells, EPCR reproducibly mediated ERK pathway activation in a model CRC cell line following APC treatment. However, EPCR knockdown studies failed to highlight compelling EPCR‐intrinsic impact on CRC cell phenotype, with limited effects on chemosensitivity and no effect on invasion observed, while EPCR appeared to decrease CRC cell migration. Consistent with these observations, differential EPCR expression did not influence response to chemotherapy in a human CRC cohort. Our results provide a compelling explanation for how EPCR is upregulated in diverse epithelial malignancies. They indicate that the clinical significance of EPCR varies across different tumour types. Furthermore, they raise the possibility that the prognostic significance of EPCR in certain tumours relates significantly to co‐upregulation of neighbouring genes on chromosome 20q. Therefore, efforts to exploit EPCR as a prognostic marker should be focussed on specific tumours, and in such scenarios EPCR‐co‐dysregulated genes may represent potential axes for therapeutic intervention.

Recasting Human Vδ1 Lymphocytes in an Adaptive Role

“…Interestingly, although EPCR expression was not enhanced by CMV infection, LES γδ T cell activation was dependent on a TCR-extrinsic ‘multimolecular stress signature’, which included induction of increased expression of intercellular adhesion molecule 1 (ICAM-1) on target cells after CMV infection [55] . Moreover, while similar changes were evident in some tumour lines, it is also clear that overexpression of EPCR itself is linked to genetic changes during tumourigenesis [65] , and has also been linked to chemoresistance [66] . Conceivably, the dependence of effector function on TCR-extrinsic changes in addition to the presence of TCR ligands could be an important factor in the maintenance of γδ T cell tolerance in the absence of relevant microbial and/or non-microbial stress stimuli.…”

Endothelial Protein C Receptor (EPCR), Protease Activated Receptor-1 (PAR-1) and Their Interplay in Cancer Growth and Metastatic Dissemination

“…The EPCR-mediated role in vascular barrier function and cytoprotective features in endothelium may potentially contribute to cancer development and progression. Various cancer cells express the EPCR (e.g., colorectal cancer, lung cancer, malignant pleural mesothelioma, breast cancer, ovarian cancer, gastric cancer) [41,42,43,44,45,46]. Upregulation of EPCR in malignant cells results from gene amplification and DNA hypomethylation [41]; however, its distribution varies.…”

“…Various cancer cells express the EPCR (e.g., colorectal cancer, lung cancer, malignant pleural mesothelioma, breast cancer, ovarian cancer, gastric cancer) [41,42,43,44,45,46]. Upregulation of EPCR in malignant cells results from gene amplification and DNA hypomethylation [41]; however, its distribution varies. In studies of gynecological cancers, EPCR was absent from microparticles derived from the ovarian adenocarcinoma cell line (OVCAR-3), but was detected on intact OVCAR-3 cells [46].…”

“…The clinical significance of the APC/EPCR complex in cancer biology appears to vary depending on the tumor subtype (Table 2). Animal model-based studies revealed that increased expression of EPCR in cancer cells inhibits proliferation and migration through the extracellular signal-regulated kinase, ERK/AKT-dependent signaling pathway [41,44] and promotes apoptosis via BAX and BCL2 factors, thereby limiting tumor growth and dissemination [11,44]. Transgenic mice overexpressing EPCR (Tie2-EPCR) had a 50–92% decrease in liver and lung metastases compared with wildtype animals.…”

The distinct MHC‐unrestricted immunobiology of innate‐like and adaptive‐like human γδ T cell subsets—Nature's CAR‐T cells

“…these features, LES/EPCR interaction may feasibly hold wider significance as a canonical example of adaptive T effector γδ TCR ligand recognition. In this context, it is noteworthy that EPCR is expressed on endothelial cells, a key site of CMV infection in vivo, and is also upregulated on certain tumor cell lines,115 some of which can activate the LES clone and LES TCR-transfected reporter lines.…”