Mechanisms Underlying the Omental Support of Ovarian Cancer Peritoneal Metastasis

项目摘要 超过80%的卵巢癌（OC）病例在诊断时已经转移到腹膜腔， 这些患者的五年生存率是25%。在腹膜腔内，最常见的部位是 转移是网膜，一种血管化良好的特化脂肪组织，从大弯上升起 的胃。因为网膜促进肿瘤生长，所以将其切除作为患者的护理标准 腹膜转移在小鼠OC模型中，网膜是早期转移部位，并且去除网膜是早期转移部位。 在肿瘤植入前切除大网膜可降低肿瘤扩张的速度。一旦OC细胞从 原发性肿瘤并形成球状体，一些结合到相邻的网膜，这被认为是跨体腔的 转移其他数据显示OC细胞可以离开腹膜腔并通过腹膜腔返回网膜。 循环系统，强调血行腹膜转移途径。总的来说，该机制 网膜促进肿瘤生长的机制仍然未知，识别它很重要， 更具体的治疗策略。研究表明，网膜巨噬细胞、血管或淋巴 称为乳斑的聚集物是支持肿瘤生长的关键特征。除了这些网膜 特征，脂肪细胞本身，将网膜定义为脂肪垫的细胞，可能对 肿瘤扩张脂肪细胞可以直接提供脂肪酸以代谢支持肿瘤增殖，或者可以 通过支持乳斑形成间接促进肿瘤生长，正如我的初步数据所显示的那样。移动 除了这些有价值的观察性研究，我在此建议使用小鼠模型，其中小鼠缺乏 白色和棕色脂肪细胞，使腹膜腔无脂肪细胞，以探讨网膜的作用 在没有成熟脂肪细胞的OC转移中。由于完全缺乏脂肪，小鼠变得脂肪营养不良。到 克服这种全身代谢综合征，脂肪营养不良的小鼠接受皮下脂肪移植， 称为脂肪营养不良（DARL）小鼠的远端脂肪细胞拯救。同窝对照组也接受脂肪 移植，称为DARC小鼠，用于远端脂肪接受对照小鼠。我假设转移性肿瘤 小鼠OC细胞在无脂肪细胞的网膜和相关腹膜内的接种和播散 将在缺乏局部成熟脂肪细胞的情况下受损。在测试这一假设时，我将评估 网膜脂肪细胞的损失影响DARL小鼠的整体网膜结构。我将分析 无脂肪细胞与富含脂肪细胞的网膜对肿瘤生长的影响。最后，我将探讨 血行和跨体腔扩散到富含脂肪细胞或无脂肪细胞的网膜，并考虑 网膜细胞是否支持肿瘤作为球状体在腹膜腔内扩散。我要追赶 这些目标在一个包括医生和科学家的咨询委员会的指导下实现。本次培训将 帮助提高我对转移的理解，以便我最终能够在我的治疗中确定新的治疗策略。 作为一名肿瘤学家和科学家。

PROJECT SUMMARY More than 80% of ovarian cancer (OC) cases have already metastasized to the peritoneal cavity at diagnosis, and the five-year survival for these patients is 25%. Within the peritoneal cavity, the most common site of metastasis is the omentum, a well-vascularized, specialized adipose tissue that arises off the greater curvature of the stomach. Because the omentum promotes tumor growth, it is removed as a standard of care for patients with peritoneal metastases. In mouse OC models, the omentum is an early metastatic site, and removing the omentum before tumor implantation reduces the pace of tumor expansion. Once OC cells shed from the primary tumor and form spheroids, some bind to the adjacent omentum, which is considered transcoelomic metastasis. Other data show that OC cells can exit the peritoneal cavity and travel back to the omentum via the circulatory system, underscoring a hematogenous peritoneal metastatic pathway. Overall, the mechanism by which the omentum promotes tumor growth is still unknown and is important to identify so that we can develop more specific therapeutic strategies. Studies suggest that omental macrophages, blood vessels, or lymphoid aggregates called milky spots, are key features that support tumor growth. In addition to these omental features, the adipocytes themselves, the cells that define the omentum as a fat pad, are likely important for tumor expansion. Adipocytes can directly provide fatty acids to metabolically support tumor proliferation or may indirectly foster tumor growth by supporting milky spot formation, as my preliminary data suggest. To move beyond these valuable observational studies, I herein propose using a mouse model wherein the mouse lacks white and brown adipocytes, rendering the peritoneal cavity adipocyte-free, to explore the role of the omentum in OC metastasis without mature adipocytes. Due to a total lack of fat, the mice become lipodystrophic. To overcome this systemic metabolic syndrome, the lipodystrophic mice receive subcutaneous fat transplants, referred to as distal adipocyte rescue of lipodystrophy (DARL) mice. Littermate controls also receive the fat transplant, known as DARC mice for distal adipose-receiving control mice. I hypothesize that the metastatic seeding and dissemination of murine OC cells within the adipocyte-free omentum and associated peritoneum will be impaired in the absence of local, mature adipocytes. While testing this hypothesis, I will assess how the loss of omental adipocytes impacts the overall omental architecture in DARL mice. I will analyze the impact of an adipocyte-free versus adipocyte-rich omentum on tumor growth. Lastly, I will explore the role of hematogenous and transcoelomic spread to the adipocyte-rich or adipocyte-free omentum and consider whether omentum cells support tumors as spheroids that disseminate within the peritoneal cavity. I will pursue these aims under the mentorship of an advisory committee that includes physician-scientists. This training will help improve my understanding of metastasis so that I can ultimately identify new treatment strategies in my career as an oncologist-scientist.