Overexpression of the Cell Adhesion Molecules DDR1, Claudin 3, and Ep-CAM in Metaplastic Ovarian Epithelium and Ovarian Cancer

Abstract

Purpose: A better understanding of the molecular pathways underlying the development of epithelial ovarian cancer (EOC) is critical to identify ovarian tumor markers for use in diagnostic or therapeutic applications. The aims of this study were to integrate the results from 14 transcript profiling studies of EOC to identify novel biomarkers and to examine their expression in early and late stages of the disease.Experimental Design: A database incorporating genes identified as being highly up-regulated in each study was constructed. Candidate tumor markers were selected from genes that overlapped between studies and by evidence of surface membrane or secreted expression. The expression patterns of three integral membrane proteins, discoidin domain receptor 1 (DDR1), claudin 3 (CLDN3), and epithelial cell adhesion molecule, all of which are involved in cell adhesion, were evaluated in a cohort of 158 primary EOC using immunohistochemistry.Results: We confirmed that these genes are highly overexpressed in all histological subtypes of EOC compared with normal ovarian surface epithelium, identifying DDR1 and CLDN3 as new biomarkers of EOC. Furthermore, we determined that these genes are also expressed in ovarian epithelial inclusion cysts, a site of metaplastic changes within the normal ovary, in borderline tumors and in low-grade and stage cancer. A trend toward an association between low CLDN3 expression and poor patient outcome was also observed.Conclusions: These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease.

Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma

“…Furthermore we have shown that DDR1 is an independent favourable prognostic marker for early-stage NSCLC patients, and that mutations in DDR1 and DDR2 appear less frequently than previously reported. The collagen-binding RTKs, DDR1 and DDR2, have previously been linked to various human diseases including fibrosis (Alves et al, 1995;Mao et al, 2002;Lee et al, 2004;Avivi-Green et al, 2006), atherosclerosis (Hou et al, 2001;Hou et al, 2002;Ferri et al, 2004), and cancer (Johnson et al, 1993;Alves et al, 1995;Barker et al, 1995;Nemoto et al, 1997;Weiner et al, 2000;Dejmek et al, 2003;Ongusaha et al, 2003;Heinzelmann-Schwarz et al, 2004;Ram et al, 2006;Vogel et al, 2006). The mechanism by which DDRs may contribute to oncogenesis is as yet unknown.…”

Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

“…This could be due to an increased mRNA or protein stability. CLDN-3 and CLDN-4 are upregulated in ovarian and uterine cancers, 10,17,35,36 and CLDN-4 expression has been exploited for therapeutic purposes. 24 CLDN-7 expression is decreased in breast carcinomas, 13,37 but Adenocarcinoma vs bronchial cell (n ¼ 6) upregulated in gastric carcinomas.…”

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

“…Several studies have confirmed the overexpression of claudin-3 and claudin-4 in ovarian cancer [7][8][9][10][11][12][13][14], but the roles of these proteins in tumorigenesis or the mechanisms regulating them are unclear. As a first step in elucidating the role of claudin phosphorylation in ovarian cancer, we have recently shown that claudin-3 can be phosphorylated by PKA at Thr192, and that phosphorylation of this residue could lead to the disruption of TJs in ovarian cancer cells [38].…”

“…However, paradoxically, claudins have also been shown to be elevated in several cancers [5]. For example, we and others have shown that claudin-3 and claudin-4 are highly increased in ovarian cancer [7][8][9][10][11][12][13][14]. These claudins have also been shown to be elevated in prostate, pancreatic, uterine, and breast cancer [15][16][17].…”