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：
10541249
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/10541249
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 Epithelium 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 PIK3CG gene Partner in relationship Pathogenesis Pathway interactions Peritoneal Population Study Prevention strategy Preventive Procedures Public Health Reactive Oxygen Species Risk Risk Factors Risk Reduction Role Salpingo-Oophorectomy Serous Site Sterilization Surface System TP53 gene Tamoxifen Testing Transgenic Organisms Translational Research Tubal Excisions Tubal sterilization Tumor Suppressor Genes United States Woman cancer prevention cohort cytokine high risk in vivo inducible Cre mouse model non-genetic novel ovarian cancer prevention ovulation time parity parous 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.

高级浆液性癌（HGSC）是最常见，最致命的“卵巢”癌症。现在，据信大多数HGSC来自远端输卵管的上皮，尽管很少 HGSC缺乏输卵管起源的证据。基于人群的研究已经确定了几个因素与降低的HGSC风险密切相关，包括基于输卵管惊喜的灭菌程序，高奇偶校验和口服避孕（OC）使用。我们不明白OC和高价侵害如何防止 HGSC或如何最大化这些受保护效应。同样，输卵管和 HGSC发病机理中的卵巢及其串扰尚未完全理解。完整的卵巢可以通过含有依托管的上皮来促进HGSC开发出现和/或通过将远端输卵管上皮（FTE）暴露于恐怖和其他因素，包括排卵时释放的卵泡液中的人。考虑到与在转移之前检测HGSC前体和小管HGSC，并影响治疗有必要将广泛转移性HGSC的妇女促进预防这些肿瘤的增强。癌症的基因工程小鼠模型（GEMM）可能会提供可拖动且相对较快的测试癌症预防策略并为人类预防癌症预防试验的系统。到日期，没有任何宝石被证明用于研究已知改变HGSC风险的因素。我们有开发的转基因（OVGP1-ICREERT2）小鼠，该小鼠允许有条件的（他莫昔芬[TAM]诱导）激活 CRE重组酶仅在FTE中。我们还确定了条件肿瘤的特定组合抑制基因（TSG）的改变，优先考虑，因为已知它们经常被灭活人类HGSC（BRCA1，TRP53，RB1，NF1 [BPRN]和BRCA1，TRP53，PTEN [BPP]），导致产卵 TAM处理OVGP1-ICREERT2小鼠后，HGSC也携带条件TSG等位基因。 fte 从这些小鼠可以将其培养为器官并在体外转化，从而使某些危险因素成为与体内研究并行测试。我们的新HGSC GEMM将被雇用以测试因素的影响已知与人类HGSC风险相关，目的是将模型作为一般和生物学相关的工具可以更好地了解特定因素如何降低HGSC风险，并为在测试新型HGSC预防策略中的未来使用。提出了四个目标：1）测试是否高在我们的HGSC的BPRN模型中，奇偶校验减慢了卵形肿瘤的发展和/或进展； 2）确定 OC中存在类型的骑马是否会改变输卵管的发展和/或进展 BPRN小鼠中的HGSC； 3）建立降低风险的分别切除术（RRS）的预防作用以及关于我们在我们的卵巢和/或原发性HGSC发展的Salpingo-Ophororcorto术（RRSO） BPRN和BPP模型； 4）测试卵泡前卵泡液对体外和体内FTE的影响。