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 Based on our recent studies (published and unpublished), we have developed a unique hypothesis that the MISR2-derived subpopulation of ovarian and fallopian tube epithelial cells are epithelial stem cells and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 本研究项目是为了研究一种可能的卵巢癌前体细胞和干细胞群体，及其对 更年期对细胞发生转化的潜力的影响。我们有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源于MISR2(Mullerian 抑制性物质受体2)谱系。此外，MISR2衍生亚群的这些细胞具有 高增殖潜能和发生上皮性肿瘤的小鼠的卵巢卵泡耗尽。基于 我们最近的研究(已发表和未发表)提出了一个独特的假设，即MISR2起源于 卵巢和输卵管上皮细胞亚群为上皮性干细胞和卵巢前体 癌症。此外，这些细胞对MIS/AMH(苗勒氏抑制物质/抗-AMH)的抑制有反应。 苗勒氏激素)由卵泡的颗粒细胞产生。我们计划通过研究 含有MISR2的卵巢和输卵管上皮细胞的生长和干细胞特性，以及 在小鼠模型和人类细胞和组织中研究它们对管理信息系统因子的反应。此前，我们发现 卵泡和颗粒细胞产生对卵巢上皮细胞的生长抑制因子(S) 文化，并提供证据表明，管理信息系统是该因素的有力候选者。我们将寻求确定因素(S) 利用Transwell装置共培养卵巢和输卵管上皮细胞产生的颗粒细胞 与颗粒细胞结合，并验证是否有部分或全部的抑制活性是由管理信息系统贡献的。设计的实验 也是为了测试MIS/MISR2旁分泌/内分泌途径在维持组织动态平衡中的作用 对卵巢和输卵管环境的影响，以及对肿瘤的抑制，总结为两个主要目标。这个 第一个主要目的是鉴定MISR2阳性细胞，以确定这些细胞是否为祖细胞/干细胞样细胞， 以及卵巢癌的先兆。第二个主要目的是鉴定产生的肿瘤抑制因子(S 通过对卵泡/颗粒细胞的作用，研究其对卵巢上皮细胞在卵巢组织内稳态的调节作用。 颗粒细胞来源的管理信息系统将被测试为卵泡来源因子的有力候选者。这些实验 将使用人类卵巢癌组织、原代和已建立的细胞以及转基因突变小鼠模型来 研究分子机制及其与人卵巢组织和癌症的相关性。调查结果和结论 来自细胞和小鼠的研究模型将在人类正常组织和癌症组织中得到验证。如果成功，我们的 这项工作将解开更年期女性患卵巢癌风险高的长期谜团。 这项研究还将深入了解卵巢上皮细胞和癌症干细胞群体，并将产生 卵巢癌生物学的实质性新进展。