Mechanisms Underlying the Omental Support of Ovarian Cancer Peritoneal Metastasis

卵巢癌腹膜转移的大网膜支持机制

• 批准号: 10678068
• 负责人: Rachel Mintz
• 金额: $ 5.27万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678068
• 关键词: Adipocytes; Adipose tissue; Advisory Committees; Affect; Architecture; B-Lymphocytes; Back; Binding; Blood Vessels; Cancer Model; Cancer Patient; Cardiovascular system; Cells; Data; Diagnosis; Distal; Enzymes; Fatty Acids; Fatty acid glycerol esters; Flow Cytometry; Fluorescence; Fostering; Greater curvature of stomach; Greater sac of peritoneum; Growth; Hematogenous; Image; Immune; Impairment; Label; Lipodystrophy; Location; Lymphoid; Macrophage; Maintenance; Malignant neoplasm of ovary; Mentorship; Metabolic; Metabolic syndrome; Microscopy; Monitor; Mus; Neoplasm Metastasis; Observational Study; Omentum; Oncologist; Pathway interactions; Patient Care; Patients; Peritoneal; Peritoneum; Phenotype; Physicians; Population; Primary Neoplasm; Proliferating; Role; Route; Scientist; Site; Spottings; Stains; Stromal Cells; Supporting Cell; T-Lymphocyte; Testing; Therapeutic; Time; Training; Transplantation; Travel; Tumor Burden; Tumor Expansion; Tumor Promotion; Vascularization; bioluminescence imaging; cancer cell; cancer seeding; career; design; effective therapy; fluorescence imaging; implantation; improved; improved outcome; insight; intraperitoneal; mouse model; novel therapeutic intervention; ovarian neoplasm; peritoneal cancer; single-cell RNA sequencing; standard of care; subcutaneous; treatment strategy; tumor; tumor growth; tumor progression

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.

项目概要 超过 80% 的卵巢癌 (OC) 病例在诊断时已转移至腹膜腔， 这些患者的五年生存率为 25%。在腹膜腔内，最常见的部位是 转移是大网膜，这是一种血管丰富的、特化的脂肪组织，产生于大弯 胃的。由于大网膜会促进肿瘤生长，因此将其作为患者护理标准予以切除 伴有腹膜转移。在小鼠 OC 模型中，大网膜是早期转移部位，去除大网膜后， 肿瘤植入前的大网膜可降低肿瘤扩张的速度。一旦 OC 细胞从 原发肿瘤形成球状体，一些与邻近的大网膜结合，被认为是跨体腔瘤 转移。其他数据表明 OC 细胞可以离开腹膜腔并通过腹膜返回大网膜。 循环系统，强调血行腹膜转移途径。总体而言，该机制通过 大网膜促进肿瘤生长的方式仍不清楚，识别这一点很重要，以便我们能够开发 更具体的治疗策略。研究表明网膜巨噬细胞、血管或淋巴 称为乳白色斑点的聚集体是支持肿瘤生长的关键特征。除了这些大网膜 特征，脂肪细胞本身，将网膜定义为脂肪垫的细胞，可能对于 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 正如我的初步数据表明的那样，通过支持乳白色斑点的形成来间接促进肿瘤生长。移动 除了这些有价值的观察性研究之外，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，渲染腹腔无脂肪细胞，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，小鼠出现脂肪营养不良。到 为了克服这种全身代谢综合征，脂肪营养不良小鼠接受皮下脂肪移植， 被称为脂肪营养不良（DARL）小鼠远端脂肪细胞拯救。同窝对照也接受脂肪 移植，称为 DARC 小鼠，用于远端脂肪接收对照小鼠。我推测转移性 小鼠 OC 细胞在无脂肪细胞网膜和相关腹膜内的播种和传播 如果没有局部成熟的脂肪细胞，脂肪细胞就会受到损害。在检验这个假设时，我将评估如何 大网膜脂肪细胞的损失影响 DARL 小鼠的整体网膜结构。我来分析一下影响 无脂肪细胞与富含脂肪细胞的网膜对肿瘤生长的影响。最后我要探讨的角色 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 大网膜细胞是否支持肿瘤作为在腹膜腔内播散的球体。我会追求 这些目标是在包括医师科学家在内的咨询委员会的指导下实现的。此次培训将 帮助提高我对转移的理解，以便我最终能够确定新的治疗策略 肿瘤学家科学家的职业生涯。