Mechanisms Underlying the Omental Support of Ovarian Cancer Peritoneal Metastasis

项目总结 超过80%的卵巢癌(OC)病例在确诊时已经转移到腹膜腔， 这些患者的五年存活率为25%。在腹膜腔内，最常见的部位 转移是大网膜，是一种血管丰富的特化脂肪组织，起源于大弯。 胃部的。由于大网膜促进肿瘤生长，因此将其作为患者护理的标准被移除。 腹膜转移。在小鼠OC模型中，大网膜是早期转移的部位，移除 肿瘤植入前的大网膜减慢了肿瘤的扩张速度。一旦OC细胞从卵巢中排出 原发肿瘤形成球体，有些与邻近的大网膜结合，这被认为是跨体腔的。 转移。其他数据显示，OC细胞可以从腹膜腔出来，通过 循环系统，强调血源性腹膜转移途径。总体而言，该机制由 哪些大网膜促进了肿瘤的生长仍是未知的，识别它对我们开发具有重要意义 更具体的治疗策略。研究表明，大网膜巨噬细胞、血管或淋巴样细胞 被称为乳斑的聚集体是支持肿瘤生长的关键特征。除了这些不祥之兆 脂肪细胞本身，也就是将大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来代谢支持肿瘤的增殖，或者可能 正如我的初步数据显示的那样，通过支持乳斑的形成，间接促进了肿瘤的生长。搬家 除了这些有价值的观察性研究外，我在这里建议使用老鼠模型，而老鼠缺乏 白色和棕色脂肪细胞，使腹膜无脂肪细胞，探讨大网膜的作用 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。至 为了克服这种全身代谢综合征，脂肪营养不良的小鼠接受了皮下脂肪移植， 被称为脂肪营养不良症(DARL)小鼠的远端脂肪细胞拯救。乳房虫控制组也会收到脂肪 移植，被称为DARC小鼠，用于远端接受脂肪的对照组小鼠。我假设转移瘤 小鼠OC细胞在无脂肪细胞的大网膜及相关腹膜内的种植和扩散 在缺乏局部成熟脂肪细胞的情况下会受到损害。在检验这一假设时，我将评估 大网膜脂肪细胞的丢失影响了DARL小鼠的整个大网膜结构。我会分析一下 不含脂肪细胞和富含脂肪细胞的大网膜对肿瘤生长的影响。最后，我将探讨 血源性和跨体腔扩散到富含脂肪细胞或不含脂肪细胞的大网膜，并考虑 大网膜细胞是否支持在腹膜腔内扩散的球形肿瘤。我会继续追查 这些目标是在包括内科科学家在内的咨询委员会的指导下实现的。这次培训将 帮助提高我对转移的理解，这样我就可以最终确定我的 肿瘤学家兼科学家的职业生涯。

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.