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E-cadherin promotes tumorigenicity in human ovarian surface epithelium

University of British Columbia

Ovarian cancer is the most lethal gynecological cancer in the Western world, but comparatively little is known about its development. Epithelial ovarian carcinomas are thought to originate in the ovarian surface epithelium (OSE), i.e. the mesothelium covering the ovary, but experimental evidence for this origin has been lacking. Contrary to most epithelia where neoplastic progression is associated with loss of E-cadherin, this cell-cell adhesion molecule is sparse in normal human OSE but its expression increases in ovarian epithelial metaplasia and neoplasia. Concurrently, the tumors tend to acquire characteristics of the complex epithelia of the oviduct and uterus. The high proportion of ovarian cancers where such aberrant Mullerian differentiation occurs suggests that this change may confer a selective advantage on the transforming cells. Previous studies in our laboratory showed that increased E-cadherin expression may be a cause of such Mullerian differentiation. E-cadherin was transfected into SV40 large T antigen-immortalized, E-cadherin-negative cells derived from normal OSE. Constitutive expression of E-cadherin re-established normal epithelial markers that had been lost in culture, such as keratin, and induced markers of metaplasia and neoplasia, such as CA125. In the present study, SV40-immortalized, E-cadherin-transfected cells, but not the E-cadherinnegative controls, were found to be anchorage independent and formed transplantable, invasive subcutaneous and intraperitoneal adenocarcinomas in 100% of injected SOD mice. Intraperitoneally injected tumor cells seeded the mesenteries and omentum, invaded the liver and thigh musculature, and produced ascites. The presence of SV40 large T antigen in the tumor cell nuclei confirmed their origin in the transfected OSE cells. This is the first experimental model of ovarian adenocarcinomas derived by genetic manipulations of normal human OSE. The results confirm the potential of OSE to give rise to ovarian epithelial carcinomas and suggest that upregulation of E-cadherin may play a pivotal role in their progression.

Thesis/Dissertation

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2009-06-26

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http://hdl.handle.net/2429/9760

Reproductive and Developmental Sciences

University of British Columbia

UBCV

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