Clinical and biological significance of CD157 in ovarian carcinoma

Ovarian cancer is one of the most common and lethal gynaecological malignancies. The poor prognosis of ovarian cancer is due to the difficulty of early diagnosis, and the lack of effective therapies for advanced-stage disease. Hence, there is a need for new therapeutic targets and for better understanding of the molecular mechanisms underpinning ovarian cancer cell invasion and dissemination. CD157 (BST-1) is a cell surface NADase/ADP-ribosyl cyclase that mediates leukocyte adhesion to extracellular matrix proteins and diapedesis at site of inflammation. We demonstrated that CD157 is expressed in epithelial ovarian cancer primary cell cultures and tissues, and it is involved in interactions among tumor cells, extracellular matrix proteins, and mesothelium which ultimately control tumor cell migration and invasion. Using stable CD157-overexpression and -knockdown in the ovarian cancer cells lines NIH:OVCAR-3 and OV-90 as model systems, we demonstrated that CD157 promotes morphological and functional changes characterized by i) enhanced matrix metalloproteinases secretion, ii) reduced intercellular cohesion and iii) increased cell motility and invasiveness driven by a mechanism involving the MAPK and PI3K/Akt pathways. The analysis of gene expression profile highlighted 402 unique genes differentially expressed in CD157-positive vs CD157-negative tumor cells (223 up-regulated and 179 down-regulated). Remarkably, functional grouping and ontological analyses revealed that a large proportion of these genes were related to developmental/differentiation processes (including epithelial-to mesenchymal transition); cell-adhesion, migration and cell projection organization; and cell death and apoptosis. At molecular level, CD157 expression induced an E- to N-cadherin switch and an over-expression of EpCAM and CD24, generating cells with combined features of mesenchymal and cancer stem-like cells. Collectively, these data suggest a novel CD157-regulated pathway that could confer an aggressive, mesenchymal/stem cell-like phenotype to ovarian cancer cells. The results inferred in vitro were validated by clinical evidence. CD157 is expressed by >90% of ovarian cancers and high CD157 expression is associated with poor outcome in patients. Multivariable Cox regression showed that CD157 is an independent prognostic factor of survival and relapse shortly after surgical debulking of serous ovarian cancer. Overall these data suggest that CD157 may find clinical applications.