Abstract A8: Mature ovarian follicle and stroma attract transformed fimbriae secretory cells and provides a more supportive microenvironment than the fimbriae stroma
Authors: Tang-Yuan Chu, Kai-Hung Wang, Sung-Chao Chu, Meng-Ya Chang
Journal: Clinical Cancer Research (2013)

Abstract Background: High-grade serous carcinoma (HGSC) of the ovary is the most popular and lethal gynecologic malignancy. Precursors or early carcinoma of HGSC have been exclusively found in the fimbriae epithelium of the fallopian tube but not the ovarian surface. The natural history of this early fimbriae lesion and its relationship to local and ovarian microenvironments are unknown. We propose a model of homing of fimbriae carcinoma cells toward ovulating ovarian follicle with subsequent development of HGSC at the more supportive microenvironment. Materials and methods: We transduced human fallopian tube fimbriae secretory cells with lentiviruses expressing HPV16-E6/E7, hTERT and mutant KRAS to generate immortalized and transformed cell lines, named FE-25 and FE-RAS, respectively. Xenograft tumor of FE-RAS gave a histological picture of poorly differentiated adenocarcinoma with PAX8 expression and TP53 silencing. FE-RAS resembles various ovarian HGSC cell lines on its mRNA profile. Conditioned medium (CM) of primary cells from the mature ovarian follicle (FC), ovarian stroma (OVSC) and fallopian tube fimbriae stroma (FTSC) as well as follicular fluid (FF) procured from IVF program were tested for their effect on chemotaxis, proliferation, migration, anchorage independent growth (AIG) and xenograft tumorigenesis on FE-KRAS and SKOV3 cells. Results: FF as well as CM of FC and OVSC readily conferred chemotaxis of FE-RAS cell. CM of FC enhanced proliferation of FE-25 cells, whereas CM of FTSC suppressed the proliferation. For FE-RAS and SKOV3 cells, CM of FC had a better enhancing effect than that of OVSC, whereas that of FTSC was neutral. As to AIG of FE-RAS, CM of OVSC had a neutral effect and that of FTSC was mildly suppressive. Upon s.c. coinjection to NOD-SCID mice, FTSC markedly suppressed tumorigenesis of SKOV3 and FE-RAS cells, whereas OVSC suppressed tumorigenesis of FE-RAS but not SKOV3. Conclusion: Microenvironment in the ovarian follicle attracts transformed fimbriae secretory cell and enhances the cell proliferation. The stromal microenvironment of the fallopian tube fimbriae suppresses the AIG and tumorigenesis of both transformed fimbriae cells and ovarian HGSC cells, whereas that of ovarian stroma suppresses transformed fimbriae cells but not the ovarian HGSC cells. The study revealed a mitogenic effect of the new ovarian microenvironment to the homed fimbriae carcinoma cells, but a further evolutionary transformation of either the cancer cell or the microenvironment may be needed for the homed fimbriae carcinoma cells to survival and progress in the new microenvironment. Citation Format: Tang-Yuan Chu, Kai-Hung Wang, Sung-Chao Chu, Meng-Ya Chang. Mature ovarian follicle and stroma attract transformed fimbriae secretory cells and provides a more supportive microenvironment than the fimbriae stroma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A8.