Involvement of SDF‐1α/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma

Abstract

Epithelial ovarian carcinoma (EOC) spreads by implantation of tumor cells onto the human peritoneal mesothelial cells (HPMCs) lining the peritoneal cavity. The aim of this study was to determine whether the stromal cell-derived factor-1a (SDF-1a)/CXCR4 axis is involved in the interaction of EOC cells with HPMCs in peritoneal metastasis. Clinically, we first evaluated CXCR4 expression in sections from 36 primary EOCs using immunohistochemistry. We next examined whether SDF-1a played roles in EOC progression, including in proliferation, cell motility, attachment to HPMCs, and the in vivo development of peritoneal metastasis through CXCR4. Of the 36 carcinomas, 16 cases (44.4%) were positive for CXCR4 immunoexpression. Positive CXCR4 expression significantly predicted poorer overall survival compared with negative expression (p 5 0.0069). We found CXCR4 expression in both EOC cells and HPMCs. In contrast, the level of production of SDF-1a by HPMCs was higher than that by various EOC cells. Functionally, SDF-1a induced enhanced attachment between ES-2 cells and HPMCs or extracellular matrix components. The enhancement of adhesion potential by SDF-1a was inhibited by AMD3100, a CXCR4 antagonist, and by phosphatidylinositol 3 kinase and p44/42 inhibitors. Furthermore, intraperitoneal treatment with AMD3100 resulted in reduced dissemination in nude mice inoculated with ES-2 cells. The present results suggest that there may be a link between the SDF-1a/CXCR4 axis and enhanced intraperitoneal dissemination of EOC and that CXCR4 may be a novel target for the treatment of EOC. ' 2007 Wiley-Liss, Inc.

Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway

“…Elevated CXCR4 expression was correlated to an advanced cancer stage and metastasis. It is similar to previous reports and also suggests that CXCR4 may be a useful marker for cancer progression Kajiyama et al, 2008).…”

Chemokines and Cancer Progression: A Qualitative Review on the Role of Stromal Cell-derived Factor 1-alpha and CXCR4 in Endometrial Cancer

“…Furthermore, overexpression of SDF-1alpha was associated with an increase in perineural invasion of the prostate cancer cells, which can lead to invasion and metastasis. Similarly, Kajiyama et al [22] reported overall survival was significantly worse among epithelial ovarian cancer patients who had positive expression of CXCR4 compared to those with negative expression. An in vitro experiment confirmed the functional ability of SDF-1alpha to increase peritoneal metastasis via an enhanced attachment of the ovarian tumor cells to the cells lining the peritoneal cavity [22].…”

“…Similarly, Kajiyama et al [22] reported overall survival was significantly worse among epithelial ovarian cancer patients who had positive expression of CXCR4 compared to those with negative expression. An in vitro experiment confirmed the functional ability of SDF-1alpha to increase peritoneal metastasis via an enhanced attachment of the ovarian tumor cells to the cells lining the peritoneal cavity [22]. The breast cancer literature has seen a similar difficulty in ascribing a protective or negative role of the SDF-1alpha/CXCR4 pathway and poor outcomes.…”

The emerging role of CXC chemokines in epithelial ovarian cancer

“…The metastatic spread of EOC tumour cells to the peritoneal mesothelium also involves the CXCL12/CXCR4 axis (Kajiyama et al 2008, Miyanishi et al 2010. Furthermore, a significant correlation has been shown between CXCR4 expression in both primary and metastatic ovarian tumours, as well as lymph node metastases (Jiang et al 2006).…”

“…In this in vivo model, CXCL12 and VEGF promoted angiogenesis and the migration of human vascular endothelial cell expressing CXCR4 (Kryczek et al 2005). Importantly, CXCL12 and CXCR4 are not detected in normal ovarian tissues (Jiang et al 2006, Kajiyama et al 2008, even in women with a family history of ovarian cancer (Scotton et al 2002).…”