Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

Abstract

The coxsackie-adenovirus receptor (hCAR) has been extensively studied in context of adenoviral-based gene therapy for cancer. However, there is strong evidence that besides its decisive role in coxsackie and adenovirus cell-entry, hCAR is a component of epithelial tight junctions and involved in cell-cell adhesions in normal and cancer cells. Furthermore, this adhesion molecule behaves like a cell surface receptor endowed with tumor suppressive properties via signal transduction. Moreover, 3 truncated soluble isoforms of hCAR were recently identified. We investigated the quantitative expression of all known CAR isoforms in a training set of 140 ovarian cancer samples and 21 controls by RT-PCR. The expression levels of the various isoforms were compared with clinicopathologic parameters and their prognostic significance was assessed. Expression levels of all CAR isoforms were elevated in ovarian carcinomas as compared with those of non-malignant controls. mRNA-expression correlated with protein levels. Moreover, expression of the soluble isoforms CAR 3/7 and CAR 4/7 but not that of hCAR was significantly increased in advanced ovarian cancer as revealed by a highly significant correlation with FIGO stage and residual disease > 2 cm in diameter after debulking surgery. High expression of CAR 3/7 and 4/7 was shown to be of independent prognostic relevance for progression-free (CAR 4/7) and overall survival (CAR 3/7 and CAR 4/7). In conclusion, soluble CAR isoforms 3/7 and 4/7 may play a pivotal role in ovarian cancer biology, possibly by counteracting migration- and growth-inhibitory properties of the membranous hCAR and thus favoring cancer cell dissemination throughout the peritoneal cavity.