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

• 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
• 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

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）是最常见和最致命的“卵巢”癌类型。 现在认为大多数HGSC起源于输卵管远端的上皮细胞，尽管少数HGSC在输卵管远端的上皮细胞中存在。 HGSC缺乏输卵管起源的证据。基于人口的研究已经确定了几个因素， 与降低HGSC风险密切相关，包括基于输卵管切除的绝育手术，高 产次和口服避孕药（OC）的使用。我们不明白业主立案法团和高平价如何防止 HGSC或如何最大限度地发挥这些保护作用。同样，输卵管的作用和 卵巢及其在HGSC发病机制中的相互作用仍不完全清楚。完整的卵巢可以 通过窝藏异位输卵管上皮促进HGSC的发育， 出现，和/或通过将远端输卵管上皮（FTE）暴露于激素和其他因素，包括 排卵时卵泡液中释放的那些。考虑到与之相关的许多挑战， 在HGSC前体和小输卵管HGSC转移之前检测它们， 对于广泛转移性HGSC的女性，加强对预防这些肿瘤的关注是必要的。 癌症的基因工程小鼠模型（GEMM）可以提供易于处理且相对快速的癌症模型。 用于测试癌症预防策略并为人类癌症预防试验提供信息的系统。到 迄今为止，没有GEMM被认证用于研究已知改变HGSC风险的因素。我们有 开发的转基因（Ovgp 1-iCreERT 2）小鼠，允许条件性（他莫昔芬[TAM]诱导）激活 Cre重组酶仅在FTE中。我们还确定了条件性肿瘤的特定组合， 抑制基因（TSG）改变，优先考虑，因为已知它们在体内经常失活 人HGSC（Brca 1，Trp 53，Rb 1，Nf 1 [BPRN]和Brca 1，Trp 53，Pten [BPP]），其导致输卵管 TAM处理也携带条件性TSG等位基因的Ovgp 1-iCreERT 2小鼠后的HGSC。FTE 可以培养为类器官并在体外转化，从而使一些风险因素 与体内研究平行测试。我们新的HGSC GEMM将用于测试因素的影响 已知与人类HGSC风险相关，目的是将模型认证为遗传和 生物学相关工具，用于更好地了解特定因素如何降低HGSC风险， 未来用于测试新的HGSC预防策略。提出了四个目的：1）测试是否高 在我们的HGSC的BPRN模型中，产次减缓输卵管肿瘤的发展和/或进展; 2）为了确定 OC中存在的激素类型是否改变输卵管的发育和/或进展， 3）确定双侧输卵管切除术（RRS）的预防作用 和输卵管卵巢切除术（RRSO）对卵巢和/或原发性腹膜HGSC的发育的影响。 BPRN和BPP模型;和4）测试排卵前卵泡液在体外和体内对FTE的影响。