| Summary: | 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. === Medicine, Faculty of === Obstetrics and Gynaecology, Department of === Graduate
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