GnRH promotes peritoneal adhesion and dissemination of ovarian cancer cells

Abstract

Ovarian cancer has the highest mortality of all gynecological cancers. It is often diagnosed at a late stage characterized by widespread peritoneal dissemination and malignant ascites. A key initial step in metastasis is the adhesion of ovarian cancer cells to the peritoneal mesothelium and extracellular matrix (ECM). Gonadotropin-releasing hormone (GnRH) receptor is present in 80% of ovarian carcinomas and its role in ovarian cancer cell migration/invasion has recently been revealed. Here, we show for the first time a role for GnRH in promoting ovarian cancer cell adhesion to the peritoneum. We observed that GnRH agonist (GnRHa)-stimulated cells were able to adhere to the peritoneal mesothelium efficiently. Moreover, the expression of integrins (α2, α5 and β1) in ECM recognition for collagen I, laminin, and fibronectin were upregulated and activated by GnRHa. The adhesion of ovarian cancer cells to the mesothelium/ECM components activated by GnRHa could be blocked by neutralizing antibodies to α2, α5 and β1 integrin. Knockdown of the GnRH receptor using small interfering RNA significantly abrogated the GnRH-induced cell adhesion and integrin expression, confirming that these effects were GnRH receptor specific. Furthermore, we showed that downregulation of β1 integrin and GnRH receptor with short hairpin RNA-mediated gene silencing significantly reduced ascites formation and intra-abdominal metastasis in intraperitoneal xenografts of human ovarian cancer in nude mice. These results indicate that GnRH may play a critical role in the peritoneal adhesion and dissemination of ovarian carcinomas and could be a promising target in ovarian cancer.