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The roles of E-cadherin and hepatocyte growth factor in human ovarian surface epithelial physiology and pathology Wong, Alice Sze Tsai

Abstract

Epithelial ovarian cancer is the most lethal gynecologic malignancy in the Western world. This neoplasm arises de novo from the ovarian surface epithelium (OSE). The OSE is a simple mesothelium which, paradoxically, acquires complex epithelial characteristics in the course of neoplastic progression. The present study investigated the roles of cellular constituents that are known to contribute to epithelial differentiation: Ecadherin and hepatocyte growth factor (HGF). Two experimental culture models were used: (1) OSE from women without (NFH-OSE) and with (FH-OSE) familial histories of ovarian cancer; and (2) OSE at progressive stages of neoplastic transformation, created by sequentially introducing SV40 large T antigen and E-cadherin into normal OSE, which produced lines IOSE-29 and IOSE-29EC. IOSE-29EC was tumorigenic and from the tumor we generated line IOSE-29EC/T4. The data indicate that E-cadherin and HGF receptor Met expression was enhanced and stabilized in FH-OSE and neoplastic OSE, but not in NFHOSE. Importantly, coexpression of HGF and Met, resulting in constitutive activation of Met, was demonstrated in FH-OSE and ovarian cancer cell lines, suggesting an autocrine HGFMet activity in these cells. Such an increased autonomy in FH-OSE may enhance the susceptibility of these cells to neoplastic transformation. HGF stimulated growth in normal OSE, IOSE-29 and the ovarian cancer ceil line OVCAR-3, but inhibited the growth of IOSE- 29EC and IOSE-29EC/T4. HGF induced scattering and branching tubulogenesis in IOSE- 29EC and IOSE-29EC/T4 but not in IOSE-29 or OVCAR-3. These different responses to HGF could be related to different levels and kinetics of ERK activation. Increased expression of CK2 and PI3K effectors (Akt2, GSK3p and p70 S6K), downregulation of PKG and upregulation of MEK6 accompanied the neoplastic transformation of OSE. Akt2 and p70 S6K were constitutively phosphorylated in neoplastic OSE, and to a lesser degree in FH-OSE, but rarely in NFH-OSE. The inhibition of PI3K activity induced apoptosis in OVCAR-3 and metaphase arrest in IOSE-29EC, but had less effect on IOSE-29. These observations, in conjunction with the demonstrated capacity of E-cadherin and HGF to contribute to epithelial differentiation, support the hypothesis that these molecules play a role in the initiation of the aberrant differentiation which characterizes ovarian carcinogenesis.

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