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.

项目摘要 超过80％的卵巢癌（OC）病例已经在诊断时已转移到腹膜腔， 这些患者的五年生存率为25％。在腹膜腔内，最常见的位置 转移是脑体，一种血管良好的专门脂肪组织，源于更大的曲率 胃。由于大脑会促进肿瘤的生长，因此将其作为患者的护理标准去除 腹膜转移。在鼠标OC模型中，omentum是一个早期的转移部位，并删除 肿瘤植入前的小膜减少了肿瘤膨胀的速度。一旦OC细胞从 原发性肿瘤和形成球体，有些与相邻的大脑结合，这被认为是跨胶体的 转移。其他数据表明，OC细胞可以退出腹膜腔，并通过 循环系统，强调血源性腹膜转移途径。总体而言，机制通过 omentum促进肿瘤生长仍然未知，很重要，以便我们可以发展 更具体的治疗策略。研究表明，巨噬细胞，血管或淋巴样 称为乳白点的聚集体是支持肿瘤生长的关键特征。除了这些昏迷 特征，脂肪细胞本身，将大脑定义为脂肪垫的细胞可能很重要 肿瘤扩张。脂肪细胞可以直接提供脂肪酸来代谢支持肿瘤增殖或可能 正如我的初步数据所表明的那样，通过支持乳白色斑的形成来间接促进肿瘤的生长。移动 除了这些有价值的观察性研究之外，我在这里建议使用鼠标模型，其中鼠标缺乏 白色和棕色的脂肪细胞，使腹膜腔脂肪细胞无脂肪细胞，以探索大膜的作用 在没有成熟脂肪细胞的OC转移中。由于完全缺乏脂肪，因此小鼠成为脂肪营养不良。到 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）小鼠的远端脂肪细胞营救。同窝窝控制也会收到脂肪 移植，被称为远端脂肪接种对照小鼠的DARC小鼠。我假设转移 无脂肪细胞和相关腹膜内鼠OC细胞的播种和传播 如果没有局部成熟的脂肪细胞，将受到损害。在检验这一假设时，我将评估 肿瘤脂肪细胞的丧失会影响Darl小鼠的整体粘膜建筑。我将分析 无脂肪细胞与富含脂肪细胞的肿瘤生长有关。最后，我将探索 血源性和转染料组传播到富含脂肪细胞或无脂肪细胞的脑类 大脑细胞是否支持肿瘤作为在腹膜腔内传播的球体。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。这个培训将 帮助提高我对转移的理解，以便我最终可以确定自己的新治疗策略 作为肿瘤学家科学家的职业。