Tumorigenesis and peritoneal colonization from fallopian tube epithelium.

Sharon L. Eddie,Jian-Jun Wei,Georgette Moyle-Heyrman,Dan D. Lantvit,Joanna E. Burdette,Eoghainin Ó hAinmhire,Barbara C. Vanderhyden,Suzanne M. Quartuccio

doi:10.18632/oncotarget.3985

Abstract

Ovarian cancer is the most lethal gynecological malignancy, primarily because its origin and initiation factors are unknown. A secretory murine oviductal epithelial (MOE) model was generated to address the hypothesis that the fallopian tube is an origin for high-grade serous cancer. MOE cells were stably altered to express mutation in p53, silence PTEN, activate AKT, and amplify KRAS alone and in combination, to define if this cell type gives rise to tumors and what genetic alterations are required to drive malignancy. Cell lines were characterized in vitro and allografted into mice. Silencing PTEN formed high-grade carcinoma with wide spread tumor explants including metastasis into the ovary. Addition of p53 mutation to PTEN silencing did not enhance this phenotype, whereas addition of KRAS mutation reduced survival. Interestingly, PTEN silencing and KRAS mutation originating from ovarian surface epithelium generated endometrioid carcinoma, suggesting that different cellular origins with identical genetic manipulations can give rise to distinct cancer histotypes. Defining the roles of specific signaling modifications in tumorigenesis from the fallopian tube/oviduct is essential for early detection and development of targeted therapeutics. Further, syngeneic MOE allografts provide an ideal model for pre-clinical testing in an in vivo environment with an intact immune system.

Highlights

Ovarian cancer is a heterogeneous disease composed of several histotypes including mucinous, clear cell, endometrioid, low-grade and high-grade serous
To examine the effects of genetic alterations similar to those observed in Highgrade serous carcinoma (HGSC) patients, murine oviductal epithelial (MOE) cells were stably transfected with mutation in p53 R273H (p53R273H), silenced PTEN via shRNA (PTENshRNA), activation of AKT via myristolation (AKTMYR) and activating mutation in KRAS G12V (KRASG12V)
To address origin and initiation factors leading to HGSC tumorigenesis, murine oviductal epithelial cells (MOE) were modified to stably express alterations in key pathways affected in HGCS patients

Summary

Introduction

Ovarian cancer is a heterogeneous disease composed of several histotypes including mucinous, clear cell, endometrioid, low-grade and high-grade serous. In the United States, 23,000 women will be diagnosed and 14,000 will succumb to these diseases each year [1]. Highgrade serous carcinoma (HGSC) is the most common and lethal histotype and is suggested to arise from the fallopian tube fimbria. Lesions are thought to arise from the mutation of p53, followed by subsequent oncogenic events that confer expansion into serous tubal intraepithelial carcinoma (STIC) and into HGSC [2]. HGSC are primarily diagnosed at the metastatic stage (75% of cases) and are treated with debulking surgery and a combination of paclitaxel and carboplatin, but patients often develop chemoresistance [3]. Defining the molecular events leading to HGSC carcinogenesis and progression from the fallopian tube is essential for identification of targets for early detection and personalized drug therapy

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