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Modeling Factors Associated with Risk of High-Grade Serous Carcinoma in Mice

与小鼠高级别浆液性癌风险相关的建模因素

基本信息

批准号：
10322419
负责人：
KATHLEEN R. CHO
金额：
$ 49.82万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322419
关键词：
Alleles Bilateral Cancer Model Cancer Prevention Trial Carcinoma Carcinoma in Situ Cells Contraceptive Usage Credentialing Development Disease Distal Endosalpingiosis Engineering Enterobacteria phage P1 Cre recombinase Epidemiology Epithelial Estradiol Event Exposure to Follicular Fluid Functional disorder Funding Opportunities Future Gene Mutation Gene Targeting Genetic Genetically Engineered Mouse Genomics Goals Hormones Human Human Characteristics In Vitro Inflammatory Lead Lesion LoxP-flanked allele Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Mediating Medroxyprogesterone 17-Acetate Microscopic Minority Modeling Multiple Pregnancy Mus Mutation NF1 gene Neoplasm Metastasis Neoplastic Cell Transformation Nulliparity Oral Contraceptives Organoids Ovarian Ovary Ovulation Partner in relationship Pathogenesis Pathway interactions Peritoneal Population Study Prevention strategy Preventive Procedures Public Health Reactive Oxygen Species Risk Risk Factors Role Salpingo-Oophorectomy Serous Site Sterilization Surface System TP53 gene Tamoxifen Testing Transgenic Organisms Translational Research Tubal Excisions Tubal sterilization Tube Tumor Suppressor Genes United States Woman base cancer prevention cohort cytokine high risk in vivo inducible gene expression mouse model non-genetic novel ovarian cancer prevention ovulation time parity prevent protective effect response tool tumor tumor heterogeneity

项目摘要

High-grade serous carcinoma (HGSC) is the most common and most lethal type of “ovarian” cancer. Most HGSCs are now believed to arise from epithelium in the distal fallopian tube, though a minority of HGSCs lack evidence of tubal origin. Population-based studies have identified several factors that are strongly associated with reduced HGSC risk, including sterilization procedures based on tubal excision, high parity, and oral contraceptive (OC) use. We do not understand how OCs and high parity protect against HGSC or how these protective effects can be maximized. Likewise, the roles of the fallopian tubes and ovaries and their cross-talk in HGSC pathogenesis remain incompletely understood. Intact ovaries could contribute to HGSC development by harboring ectopic tubal epithelium from which non-tubal HGSCs may arise, and/or by exposing the distal fallopian tube epithelium (FTE) to hormones and other factors, including those in follicular fluid released at the time of ovulation. Given the many challenges associated with detecting HGSC precursors and small tubal HGSCs before they have metastasized, and effecting cures for women with widely metastatic HGSC, an enhanced focus on preventing these tumors is warranted. Genetically engineered mouse models (GEMMs) of cancer may provide tractable and relatively rapid systems with which to test cancer prevention strategies and inform cancer prevention trials in humans. To date, no GEMMs have been credentialed for use in studying factors known to alter HGSC risk. We have developed transgenic (Ovgp1-iCreERT2) mice that allow conditional (tamoxifen [TAM]-inducible) activation of Cre recombinase exclusively in the FTE. We have also identified specific combinations of conditional tumor suppressor gene (TSG) alterations, prioritized because they are known to be frequently inactivated in human HGSCs (Brca1, Trp53, Rb1, Nf1 [BPRN] and Brca1,Trp53, Pten [BPP]), that lead to oviductal HGSCs following TAM treatment of Ovgp1-iCreERT2 mice that also carry the conditional TSG alleles. FTE from these mice can be cultured as organoids and transformed in vitro, allowing some risk factors to be tested in parallel with studies in vivo. Our new HGSC GEMMs will be employed to test the impact of factors known to be associated with human HGSC risk, with the goal of credentialing the models as genetically and biologically relevant tools with which to better understand how specific factors reduce HGSC risk, and for future use in testing novel HGSC prevention strategies. Four Aims are proposed: 1) To test whether high parity slows oviductal tumor development and/or progression in our BPRN model of HGSC; 2) To determine whether hormones of the types present in OCs alter the development and/or progression of oviductal HGSCs in BPRN mice; 3) To establish the preventive effects of bilateral risk-reducing salpingectomy (RRS) and salpingo-oophorectomy (RRSO) on the development of ovarian and/or primary peritoneal HGSC in our BPRN and BPP models; and 4) To test effects of pre-ovulatory follicular fluid on FTE in vitro and in vivo.

高级别浆液性癌（HGSC）是卵巢癌中最常见和最致命的类型。