The Role of the Oncofetal Glycoprotein 5T4 in Ovarian Cancer Metastasis

Abstract

Ovarian cancer is the most lethal gynaecological cancer which frequently presents in advanced stages with the majority of patients succumbing to their disease. Cancer related mortality is generally caused by metastases, yet there is a paucity of information in the literature pertaining to investigations of the mechanisms involved in ovarian cancer metastasis.5T4 is an oncofetal antigen; its expression in ovarian cancer has been previously found to be associated with advanced stages (cancer spread) and poor clinical outcome. Recent work in embryonic cells has suggested roles for 5T4 in both epithelial mesenchymal transition (EMT) and the functional cell-surface expression of the chemokine receptor CXCR4. In addition, Waif1, zebrafish homologous 5T4, was shown to inhibit canonical wnt signalling while activating the planar cell polarity (PCP) pathway. EMT, CXCR4-mediated chemotaxis and PCP pathway have all been implicated in cancer invasiveness and spread.In this project several ovarian cancer cell lines have been investigated in terms of their phenotype as defined by the expression of 5T4, CXCL12 receptors (CXCR4 and CXCR7) and EMT markers (E-cadherin and N-cadherin), and their chemotactic response to CXCL12.Two cell lines, SKOV-3 and Hoc-8, emerged as a useful model to investigate 5T4 biology further, the former expressed 5T4 and responded chemotactically to CXCL12 while the latter did not express 5T4 nor did it respond to CXCL12 in spite of showing surface CXCR4 expression.5T4 knockdown in SKOV-3 cells abrogated the chemotaxis response to CXCL12, reduced non-directional cell motility and induced mesenchymal to epithelial transition. 5T4 overexpression in Hoc-8 promoted the reverse transition EMT and improved cell motility. In addition, 5T4 knockdown in SKOV-3 cells supressed non-canonical wnt signalling, and facilitated β-catenin dependent canonical pathway.Analysis of 11 paired (primary & metastatic) human epithelial ovarian cancer samples showed higher 5T4 expression in the metastatic samples which was accompanied with a reciprocal change in the expression of cytokeratins and JNK expression.Overall, this study has found 5T4 to be upregulated in metastatic ovarian cancers; also changes in its expression in vitro supported a metastatic phenotype making 5T4 a potential marker and a therapeutic target in metastatic ovarian disease.

Date of Award	1 Aug 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Peter Stern (Supervisor) & Henry Kitchener (Supervisor)