Ovarian Epithelial Cancer Progenitor Cell Population

卵巢上皮癌祖细胞群

• 批准号: 10391479
• 负责人: XiangXi Mike Xu
• 金额: $ 34.41万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391479
• 关键词: AMHR2 gene; Antral; Basic Science; Biology; Birth; Cancer Biology; Candidate Disease Gene; Carcinoma; Cell model; Cells; Coculture Techniques; Development; Devices; Embryo; Embryonic Development; Endocrine; Environment; Epithelial; Epithelial Cells; Epithelial ovarian cancer; Event; Female; Gene Chips; Germ Cells; Goals; Growth; Homeostasis; Human; Implant; Investigation; LGR5 gene; Lesion; MT3 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Menopause; Methods; Modeling; Molecular; Mosaicism; Mus; Mutation; Organ; Ovarian; Ovarian Follicle; Ovarian Granulosa Cell; Ovarian Serous Adenocarcinoma; Ovarian Tissue; Ovarian aging; Ovary; Ovulation; Pathway interactions; Pharmaceutical Preparations; Physiology; Play; Population; Production; Property; Proteomics; Publishing; Regulation; Reproductive History; Research; Research Project Grants; Role; Serous; Study models; Surface; TP53 gene; Testing; Testis; Tissues; Transgenic Organisms; Tumor Suppression; Tumor-Derived; Variant; White Spots; Woman; Work; base; cancer risk; cancer stem cell; cell population study; clinical application; design; epithelial stem cell; experimental study; fimbria; granulosa cell; human tissue; insight; male; mouse model; mullerian-inhibiting hormone; mutant mouse model; ovarian neoplasm; paracrine; progenitor; receptor; reproductive; response; screening; stem cell model; stem cell population; stem cells; stem-like cell; tumor

ABSTRACT 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 Based on our recent studies (published and unpublished), we have developed a unique hypothesis that the MISR2-derived subpopulation of ovarian and fallopian tube epithelial cells are epithelial stem cells and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.

抽象的 该研究项目旨在研究假定的卵巢癌祖细胞和干细胞群，以及 更年期对细胞转化潜力的影响。我们做出了令人惊讶的 发现卵巢和输卵管上皮细胞的镶嵌亚群源自 MISR2 （苗勒管抑制物质受体2型）谱系。此外，这些 MISR2 衍生的细胞 亚群具有很高的增殖潜力，并在小鼠卵巢卵泡中形成上皮肿瘤 耗尽了。 根据我们最近的研究（已发表和未发表），我们提出了一个独特的假设： 卵巢和输卵管上皮细胞的 MISR2 衍生亚群是上皮干细胞 卵巢癌的前兆。此外，这些细胞对 MIS/AMH（苗勒氏管）的抑制有反应 抑制物质/抗缪勒氏管激素）由卵泡颗粒细胞产生。 我们计划通过研究含有 MISR2 的卵巢和输卵管上皮细胞来检验这些想法 在两种小鼠中研究它们的生长和干细胞特性，并研究它们对 MIS 因子的反应 模型以及人体细胞和组织。此前，我们发现卵泡和颗粒细胞产生一种 培养物中卵巢上皮细胞的生长抑制因子，并提供了 MIS 是一种强有力的证据 该因子的候选者。我们将寻求使用 Transwell 来鉴定颗粒细胞产生的因子 用于卵巢和输卵管上皮细胞与颗粒细胞共培养的装置，并验证 MIS 是否有效 有助于部分或全部抑制活性。设计的实验也是为了测试 MIS/MISR2旁分泌/内分泌途径维持卵巢和输卵管组织稳态 管环境和肿瘤抑制，概括为两个主要目标。第一个主要目标是 表征 MISR2 阳性细胞，以确定这些细胞是否是祖细胞/干细胞样细胞和前体细胞 用于卵巢癌。第二个主要目标是鉴定由 卵泡/颗粒细胞并研究其对卵巢上皮细胞在卵巢组织稳态中的调节作用。 颗粒细胞衍生的 MIS 将作为滤泡衍生因子的有力候选者进行测试。 实验将使用人类卵巢癌组织、原代细胞和已建立的细胞以及转基因细胞 突变小鼠模型用于研究分子机制及其与人类卵巢组织和癌症的相关性。 细胞和小鼠模型研究的结果和结论将在人类正常和 癌组织。 如果成功，我们的工作将解决长期以来困扰卵巢癌风险高的难题 在更年期妇女中。该研究还将深入了解卵巢上皮细胞和癌症干细胞 人口，并将在卵巢癌生物学方面取得重大新进展。