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. © 2007 Wiley‐Liss, Inc.

Presence of the Coxsackievirus and Adenovirus Receptor (CAR) in human neoplasms: a multitumour array analysis

“…In line with prior reports, we noted abundant CAR presence in several subtypes of thyroid carcinoma (Marsee et al , 2005; Giaginis et al , 2010), in lung cancer (Wang et al , 2006; Chen et al , 2013), as well as in neuro- and medulloblastomas (Persson et al , 2006). Moreover, in agreement with previous reports we found significantly hightened CAR presence in cancers of the endometrium (Giaginis et al , 2008), ovary (Reimer et al , 2007) and cervix (Dietel et al , 2011). These data suggest that CAR overexpression occurs preferentially in cancers of the female reproductive system, contrary to reduced CAR presence in neoplasms of the testis and prostate.…”

“…In contrast, CAR upregulation was found in cancers of the endometrium, ovary, cervix, breast and lung, as well as neuroblastomas and medulloblastomas (Martino et al , 2000; Martin et al , 2005; Persson et al , 2006; Wang et al , 2006; Reimer et al , 2007; Giaginis et al , 2008; Dietel et al , 2011). In breast and lung cancer types, high CAR expression has been linked to poor overall survival and shorter disease-free survival, respectively (Martin et al , 2005; Wunder et al , 2012a).…”

Expression of coxsackie-adenovirus receptor is related to estrogen sensitivity in breast cancer

“…Integrity was evaluated by assessing the 18S-and 28-S-ribosomal RNA bands in 1% ethidium bromide-stained agarose gels. DNAse treatment and reverse transcription were performed as described recently [11].…”

“…In ovarian cancer, however, no prognostic relevance was pointed out for the membranous form of CAR, but expression of the soluble CAR isoforms CAR 3/7 and 4/7 was shown to be an independent prognosticator predicting unfavorable progression-free (CAR 4/7) and overall survival (CAR 3/7 and CAR 4/7) [11].…”

Isoform-Specific Regulation and Localization of the Coxsackie and Adenovirus Receptor in Human Airway Epithelia

“…In experimental murine models, soluble CAR is able to inhibit viral infection but also results in toxicity [12]–[16]. Although the mechanism of toxicity is unknown, soluble CAR may be predicted to alter CAR-CAR interactions and thus epithelial cell adhesion [17].…”