AUTONOMY OF THE EPITHELIAL PHENOTYPE IN HUMAN OVARIAN SURFACE EPITHELIUM - CHANGES WITH NEOPLASTIC PROGRESSION AND WITH A FAMILY HISTORY OFOVARIAN-CANCER

Epithelial ovarian carcinomas originate in the ovarian surface epithel ium (OSE). In culture, OSE undergoes epithelio-mesenchymal conversion, an event mimicking a wound response, while ovarian carcinomas retain complex epithelial characteristics. To define the onset of this increa sed epithelial autonomy in ovarian neoplastic progression, we examined mesenchymal conversion in OSE from 25 women with no family histories (NFH-OSE) and 13 women with family histories (FH-OSE) of breast/ovaria n cancer (including 8 with mutated BRCA1 or 17 q linkage) and in 8 ova rian cancer lines. After 3-6 passages in monolayer culture, most NFH-O SE exhibited reduced keratin expression and high collagen type III exp ression. In contrast, keratin remained high but collagen expression wa s lower in p. 3-6 FH-OSE. This difference was lost in SV40-transformed lines, which all resembled FH-OSE. Most carcinoma lines remained epit helial and did not undergo mesenchymal conversion. In 3-dimensional (3 -D) sponge culture, NFH-OSE cells dispersed and secreted abundant extr acellular matrix (ECM). FH-OSE remained epithelial and did not secrete ECM. ECM production was also reduced in SV40-transformed lines. Carci noma lines in 3-D formed epithelial cysts, aggregates and papillae and lacked ECM. Sponge contraction (a mesenchymal characteristic) was gre ater in NFH-OSE than in FH-OSE both before and after SV40 transformati on and was absent in the cancer lines. Our results suggest that increa sed autonomy of epithelial characteristics is an early indicator of ov arian neoplastic progression and that phenotypic changes indicative of such autonomy are found already in overtly normal OSE from women with histories of familial breast/ovarian cancer. (C) 1996 Wiley-Liss, Inc .