Ovarian Epithelial Cancer Progenitor Cell Population

卵巢上皮癌祖细胞群

• 批准号: 10060282
• 负责人: XiangXi Mike Xu
• 金额: $ 15.78万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10060282
• 关键词: Aneuploidy; Cancer Biology; Carcinoma; Cell model; Cells; Coculture Techniques; Development; Devices; Endocrine; Environment; Epithelial; Epithelial Cells; Epithelial ovarian cancer; Epithelium; Event; Growth; Homeostasis; Human; Lesion; MT3 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Menopause; Molecular; Mosaicism; Mus; Mutation; Ovarian; Ovarian Follicle; Ovarian Granulosa Cell; Ovarian Tissue; Pathway interactions; Population; Property; Publishing; Regulation; Research; Research Project Grants; Research Project Summaries; Role; TP53 gene; Testing; Tissues; Transgenic Organisms; Tumor Suppression; Woman; Work; base; cancer risk; cancer stem cell; carcinogenesis; design; epithelial stem cell; experimental study; granulosa cell; insight; mouse model; mullerian-inhibiting hormone; mutant mouse model; paracrine; precursor cell; receptor; response; stem cell population; stem cells; stem-like cell; tumor

Project Summary This research project is to study a putative ovarian cancer progenitor and stem cell population, and the impact of menopause on the potential for the cells to undergo transformation. We have made a surprising discovery that a mosaic subpopulation of ovarian and fallopian tube epithelial cells is derived from MISR2 (Mullerian inhibitory substance receptor type 2) lineage. Furthermore, these cells of MISR2-derived subpopulation have high proliferative potential and develop epithelial tumors in mice that ovarian follicles are depleted. Based on our recent studies (published and unpublished), we have developed a unique hypothesis that the MISR2-derived subpopulation of ovarian and fallopian tube epithelial cells are epithelial stem cells and precursors of ovarian cancer. Additionally, these cells are responsive to suppression by MIS/AMH (Mullerian inhibitory substance/anti- Mullerian hormone) produced by granulosa cells of ovarian follicles. We plan to test these ideas by studying the MISR2-containing ovarian and fallopian tube epithelial cells for their growth and stem cell properties, and also study their response to the MIS factor, in both mouse models and human cells and tissues. Previously, we found that ovarian follicles and granulosa cells produce a growth inhibitory factor(s) towards ovarian epithelial cells in culture, and provided evidence that MIS is a strong candidate for the factor. We will seek to identify the factor(s) produced by granulosa cells using a transwell device for co-culturing of ovarian and fallopian tube epithelial cells with granulosa cells, and to verify if MIS contributes to part or all of the inhibitory activity. Experiments designed are also to test the roles of the MIS/MISR2 paracrine/endocrine pathway in maintaining the tissues homeostasis of the ovarian and fallopian tube environment, and in tumor suppression, as summarized in two main aims. The first major aim is to characterize the MISR2-positive cells to determine if these cells are progenitor/stem cell like, and precursors for ovarian cancer. The second major aim is to identify the tumor suppressing factor(s) produced by follicles/granulosa cells and to study its regulation of ovarian epithelial cells in ovarian tissue homeostasis. Granulosa cell-derived MIS will be tested as a strong candidate of the follicle-derived factor. The experiments will use human ovarian cancer tissues, primary and established cells, and transgenic mutant mouse models to study molecular mechanisms and relevance to human ovarian tissue and cancer. The findings and conclusions from the study of cell and mouse models will be verified in human normal and cancer tissues. If successful, our work will solve the long-standing puzzle for the reason why ovarian cancer risk is high in menopausal women. The research will also gain insight into an ovarian epithelial and cancer stem cell population, and will yield a substantial new advance in ovarian cancer biology.

项目摘要 该研究项目是研究假定的卵巢癌祖细胞和干细胞种群，以及影响 更年期关于细胞经历转化的可能性的可能性。我们做了一个令人惊讶的发现 卵巢和输卵管上皮细胞的镶嵌亚群来自Misr2（Mullerian 抑制性物质受体2）谱系。此外，这些由MISR2衍生的亚群的细胞具有 卵巢卵泡耗尽的小鼠的高增殖潜力并发展出上皮肿瘤。基于 我们最近的研究（发表和未发表），我们提出了一个独特的假设，即MISR2衍生 卵巢和输卵管上皮细胞的亚群是上皮干细胞和卵巢的前体 癌症。此外，这些细胞对MIS/AMH的抑制有反应（Mullerian抑制性物质/抗 - 由卵巢卵泡的颗粒细胞产生的mullerian激素）。我们计划通过研究 含MISR2的卵巢和输卵管上皮细胞的生长和干细胞特性，也是 在小鼠模型以及人类细胞和组织中研究它们对MIS因子的反应。以前，我们发现 卵巢卵泡和颗粒细胞对卵巢上皮细胞产生生长抑制因子 文化，并提供了MIS是该因素的有力候选者的证据。我们将寻求确定因素 由颗粒细胞使用Transwell设备共同培养卵巢和输卵管上皮细胞，生产 使用颗粒细胞，并验证MIS是否有助于部分或所有抑制活性。设计实验 还要测试MIS/MISR2旁分泌/内分泌途径在保持组织稳态中的作用 卵巢和输卵管环境以及肿瘤抑制作用，如两个主要目的所述。这 第一个主要目的是表征MISR2阳性细胞，以确定这些细胞是否是祖/干细胞， 和卵巢癌的前体。第二个主要目的是确定产生的肿瘤抑制因子 通过卵泡/颗粒细胞，研究其调节卵巢组织稳态中卵巢上皮细胞的调节。 颗粒细胞衍生的MIS将被视为卵泡衍生因子的有力候选者。实验 将使用人类卵巢癌组织，原发性和已建立的细胞以及转基因突变小鼠模型 研究分子机制以及与人卵巢组织和癌症的相关性。发现和结论 从细胞和小鼠模型的研究中，将在人正常和癌症组织中验证。如果成功，我们的 工作将解决长期的难题，原因是绝经女性卵巢癌风险很高的原因。 这项研究还将深入了解卵巢上皮和癌症干细胞的群体，并产生 卵巢癌生物学的新进步。