Abstract: SAT 135

The Role of the Ovary in Fallopian tube-Derived Ovarian Cancer

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Abstract


High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube epithelium (FTE) and then metastasize to the ovary. The objectives of this research were to 1) determine if ovarian colonization facilitates spread of FTE-derived tumors and 2) identify factors secreted by the ovary that stimulate migration of the FTE. Murine oviductal epithelial (MOE) cells (50,000) stabling expressing PTENshRNA+KRASG12V were allografted into the ovarian bursa (IB) or peritoneum (IP) of nude mice. view more

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube epithelium (FTE) and then metastasize to the ovary. The objectives of this research were to 1) determine if ovarian colonization facilitates spread of FTE-derived tumors and 2) identify factors secreted by the ovary that stimulate migration of the FTE. Murine oviductal epithelial (MOE) cells (50,000) stabling expressing PTENshRNA+KRASG12V were allografted into the ovarian bursa (IB) or peritoneum (IP) of nude mice. IB allograft resulted in aggressive tumor formation throughout the abdominal cavity, with all mice sacrificed by day 83. In contrast, one IP allografted mice was sacrificed at day 123 for unrelated health reasons and no tumors were found. The remaining 4 IP treated mice survived, disease free, until day 150 when the experiment was ended. To identify secreted factors that stimulate migration of MOE cells, murine ovaries were embedded in an alginate matrix and cultured in serum free media for 3 days to produce ovarian conditioned media (OCM). OCM increased migration of MOE cell by 220%, but fallopian tube conditioned media (TCM) only increased migration by 60%. Size fractionation indicated the active component(s) were over 3 kDa, suggesting a protein. This was confirmed by heat-inactivation and protease K treatment. LC-MS identified 650 proteins in OCM and 75 proteins in TCM. Bioinformatic mining with UniProt, SignalP, and SecretomeP identified 465 proteins in OCM that were secreted, of these 429 were unique to OCM. Inhibin βA was identified in OCM, a component of the well known ovarian hormone activin A. Murine superovulation resulted in intense phospho-Smad2/3 immunostaining in the FTE. Across four studies in Oncomine that compared serous tumors to normal ovaries, ACVR1B and ACVR2A were significantly higher in serous tumors. In contrast, INHA and TGFB3 (which inhibit activin A signaling) were significantly lower. Kaplan-Meier plots from OVMARK showed that high expression of INHBA and ACVR2A were associated with shorter disease-free survival. Functionally, activin A increased migration of MOE cells in a dose-dependent manner, peaking at 10 ng/ml. Conversely, TGFβ1 had no effect on migration, and a dominant-negative Smad2 construct did not abrogate activin A-induced migration. Instead, activin A also increased phospho-AKT and phospho-ERK levels, and inhibition of either of these pathways (with MK2206 and U0126, respectively) completely blocked the migratory effect of activin. Confirming that migratory effect of activin A in a HGSOC cell line, activin A also stimulated migration of OVCAR3 cells through AKT and MEK. In conclusion, colonization of the ovary resulted in more aggressive FTE-derived tumors and the activin A stimulated migration of FTE and HGSOC cells. These results indicate that inhibiting colonization of the ovary may be a therapeutic target in women at risk for HGSOC.

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