Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion.

Jose A Colina,Sarah R Wagner,Seth Baligod,Emma S Gargus,Kailiang Li,Laura M Sanchez,Kanella Eliadis,Kristine J Moss,Joanna E Burdette,Benjamin K Tsang,Teresa K Woodruff,Katherine E Zink,Reza Salehi,Brenna J Kirkpatrick

doi:10.3390/cancers13081925

Abstract

Simple SummaryThe area between the fallopian tube and the ovary is of interest since the ends of the fimbria are the progenitor site for high grade serous cancer. Metabolomics revealed that androgens are induced at this site, which then increased proliferation of normal fallopian tube cells and their migration.The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.

Highlights

This year an estimated 21,750 women will be diagnosed with ovarian cancer in the United States and an estimated 13,940 will die of the disease [1]
Developed methods for observing small molecule ovarian secretions using imagining mass spectrometry (IMS) have allowed us to explore novel salpingeal-ovarian metabolomics [32]. We demonstrate how this small molecule interaction can shift toward local androgen production in the presence of tumorigenic cell lines derived from the fallopian tube and how this hyperandrogenic microenvironment impacts the fallopian tube epithelium (FTE)
The fimbriated ends of the fallopian tube that are in proximity of the ovary display serous tubal intraepithelial carcinoma in situ, a lesion thought to give rise to high grade serous cancer

Summary

Introduction

This year an estimated 21,750 women will be diagnosed with ovarian cancer in the United States and an estimated 13,940 will die of the disease [1]. Serous tubal intraepithelial carcinomas (STICs) are premalignant lesions formed by neoplastic transformation of the fallopian tube secretory epithelium and are thought to progress into HGSOC. Our lab previously demonstrated that reduction of PTEN expression in murine secretory oviductal cells induced high grade, metastatic tumors that homed to the ovary and the peritoneum in allograft mice and PTEN deleted transgenic mice develop serous tumors in vivo [6,7]. Paired box 2 (PAX2) is a transcription factor that is generally lost in HGSOC and lost in secretory cell outgrowths (SCOUT), a putative precursor lesion in the FTE [8,9,10]. We deploy both PTEN deficient and PAX2 deficient oviductal cell lines to study androgen action in fallopian tube

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