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

高级别浆液性癌(HGSC)是最常见、最致命的卵巢癌。 大多数HGSCs现在被认为起源于输卵管远端的上皮，尽管有一小部分 HGSC缺乏输卵管起源的证据。基于人口的研究已经确定了以下几个因素 与降低HGSC风险密切相关，包括基于输卵管切除术的绝育手术，高 生育、口服避孕药(OC)的使用。我们不了解OCS和高奇偶校验是如何防止 或者如何最大限度地发挥这些保护作用。同样，输卵管和输卵管的作用 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 通过容纳异位输卵管上皮促进HGSC的发育，非输卵管性HGSC可能来自异位输卵管上皮 引起和/或通过使输卵管远端上皮(FTE)暴露于激素和其他因素，包括 卵泡液中的激素在排卵时释放。鉴于与以下方面相关的许多挑战 在转移前检测HGSC前体和小输卵管HGSC，并对其进行治疗 对于患有广泛转移的HGSC的女性，有必要加强对这些肿瘤的预防。 癌症的基因工程小鼠模型(GEMM)可能会提供容易处理和相对快速的 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。至 到目前为止，还没有GEMM被批准用于研究已知的改变HGSC风险的因素。我们有 已开发的转基因(Ovgp1-iCreERT2)小鼠允许条件(他莫昔芬[]可诱导的)激活 Cre重组酶仅在FTE中存在。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，因为已知它们经常在 人类HGSCs(BRCA1、TrP53、Rb1、Nf1[BPRN]和BRCA1、TrP53、Pten[BPP])与输卵管通畅 治疗也携带条件性TSG等位基因的Ovgp1-iCreERT2小鼠后的HGSC。FTE 可以将这些小鼠培养成有机化合物并在体外转化，从而允许一些危险因素 在体内研究的同时进行测试。我们将使用新的HGSC GEMM来测试因素的影响 已知与人类HGSC风险有关，目标是将这些模型认证为遗传和 生物学上相关的工具，用来更好地了解特定因素如何降低HGSC风险，以及 未来用于测试新的HGSC预防策略。提出了四个目标：1)测试是否高 在我们的HGSC BPRN模型中，产次减缓输卵管肿瘤的发展和/或进展；2)确定 OCS中存在的各种激素是否会改变输卵管的发育和/或进展 建立双侧减危输卵管切除术(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发展的影响 BPRN和BPP模型；4)体内外检测排卵前卵泡液对FTE的影响。

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.