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: 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
• 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

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。 据信大多数HGSC源于dislopian管中的上皮，尽管很少 HGSC缺乏基于POPTION的研究的证据。 与HGSC风险的降低密切相关，包括基于输卵管的灭菌程序，高 均等和口服避孕（OC）使用。 HGSC或这些保护作用如何最大化。 完整的卵巢会议coud。 通过携带异位输卵管上皮来促进HGSC开发 出现和/或通过将远端输卵管上皮（FTE）暴露于激素和其他因素，包括 卵泡液在产卵时释放的人。 在转移之前确定HGSC前体和小管HGSC，并影响治疗 有必要提高对预防肿瘤的关注的妇女。 癌症的基因工程小鼠模型（GEMM）可能会提供可拖动和相对快速的 在人类中测试癌症预防策略和IND癌症试验的系统 日期，没有凭证用于研究已知的HGSC风险的因素 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中确定了条件肿瘤的特定组合 抑制基因（TSG）的改变，优先级，因为已知在 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也携带有条件的TSG等位基因 从这些小鼠可以作为器官培养并在体外转化，允许某些危险因素成为继续 与体内研究并行测试。 已知与HGSC风险相关，目的是将模型证明为遗传 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 未来在测试新型HGSC预防策略中使用了四个目标：1） 奇偶校验在我们的HGSC的BPRN模型中减慢了卵形肿瘤的发展和/或进展 OC中存在类型的激素是否会改变输卵管的发展和/或进展 BPRN小鼠中的HGSC； 以及关于我们在我们的卵巢和/或原发性Peritional HGSC开发的Salpingo-opophorectome（RRSO） BPRN和BPP模型；