Modeling high-grade serous ovarian carcinogenesis from the fallopian tube

Abstract

High-grade serous ovarian carcinoma (HGSOC) is a lethal disease for which improved screening and treatment strategies are urgently needed. Progress in these areas is impeded by our poor understanding of HGSOC pathogenesis. Most ovarian cancer research is based on the hypothesis that HGSOC arises from ovarian surface epithelial cells. However, recent studies suggest that >50% of high-grade serous carcinomas involving the ovary likely arise from fallopian tube epithelium. Therefore, limiting HGSOC research to modeling based on ovarian surface epithelium alone is inadequate. To address the need for a fallopian tube-based model of HGSOC, we have developed a system for studying human fallopian tube secretory epithelial cell (FTSEC) transformation. Our model is based on (i) immortalization of FTSECs isolated from primary samples of normal, nondiseased human fallopian tubes, (ii) transformation of FTSECs with defined genetic elements, and (iii) xenograft-based tumorigenic assays. We use our model to show that FTSECs immortalized with human telomerase reverse transcriptase (hTERT) plus SV40 large T and small T antigens are transformed by either oncogenic Ras (H-Ras V12 ) or c-Myc expression, leading to increased proliferation, clonogenicity, and anchorage-independent growth. Additionally, we demonstrate that FTSECs remain susceptible to c-Myc-mediated transformation in the absence of viral oncoproteins, by replacing SV40 large T and small T antigens with sh-p53, mutant CDK4 (CDK4 R24C ), and sh-PP2A-B56γ. Importantly, all transformed FTSECs gave rise to highgrade Müllerian carcinomas that were grossly, histologically, immunophenotypically, and genomically similar to human HGSOC. With this model, we will now be able to assess the transformative effects of specific genetic alterations on FTSECs in order to characterize their respective roles in HGSOC development.varian cancer is the fifth deadliest cancer among American women (1). It has a disproportionately high mortality rate, attributed primarily to difficulties in diagnosing early stage disease and to the development of drug resistance in tumors that were initially chemosensitive (2). To improve ovarian cancer screening and treatment strategies, we must better understand the cancer's origin and pathogenesis. The most common histologic subtype, accounting for >50% of ovarian epithelial malignancies, is serous ovarian carcinoma (3-5). Because of inadequate early detection tools, the vast majority of serous ovarian carcinomas (>80%) are diagnosed at late stage [International Federation of Gynecology and Obstetrics (FIGO) stages III-IV], for which the 5-y survival rate is only 9-34% (6). Most of these (>50%) are classified as "high-grade" based on their degree of nuclear atypia and high mitotic index (7). High-grade serous ovarian carcinoma (HGSOC) stands out from other subtypes both for its aggressive nature and because it harbors unique genetic alterations. For example, clear cell, endometrioid, low-grade serous, and mucinous ovarian carcinomas typically present as indo...

Stem‐Like Epithelial Cells Are Concentrated in the Distal End of the Fallopian Tube: A Site for Injury and Serous Cancer Initiation

“…It is now believed that dissemination of serous cancers may occur by exfoliation of tumor cells originating from the distally located TICs (reviewed in [7]). Recent mouse models have shown transformation of human and mouse fallopian tube tissue into serous cancers through multiple genetic mutations [35,37]. These data suggest that serous cancers may arise from the fallopian tube.…”

“…The FTE is actively being explored as a site of initiation for serous cancers [35][36][37]. Dysplastic lesions identified typically in the distal end of the fallopian tube have been hypothesized to be precursor lesions for invasive serous cancers [38][39][40][41].…”

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

“…Embryologically OSE originates from the coelomic epithelium, which also gives rise to the epithelia lining the Fallopian tube, endometrium, cervix, and upper part of vagina. It has recently been advocated that besides OSE, epithelial neoplasms may also arise from the distal part of Fallopian tubes including fimbria (Karst et al 2011) and later get deposited onto the OSE. This should not be of any concern as both OSE and oviductal epithelium have a common origin in coelomic epithelium (Auersperg 2013).…”

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

“…To validate our screening results, we reintroduced GAB2 into HA1E-M cells and found that tumors formed in mice at the same rate (7 of 12, 58%) as that induced by the ovarian cancer oncogene, ID4 (5) (8 of 14, 57%). To determine whether GAB2 expression also transforms immortalized cells relevant to ovarian cancer, we introduced GAB2 into human immortalized ovarian surface epithelial (IOSE) cells expressing the SV40 ER, hTERT, and an activated MEK1-DD allele and immortalized fallopian tube secretory epithelial cells (FTSECs) expressing hTERT and the SV40 large and small T antigens (18). Expression of GAB2 induced significantly larger tumors than control or LACZexpressing control IOSE cells when injected into immunodeficient NOD/IL2Rγ c /SCID mice ( Fig.…”