Ovarian Epithelial Cancer Progenitor Cell Population

卵巢上皮癌祖细胞群

• 批准号: 9918266
• 负责人: XiangXi Mike Xu
• 金额: $ 35.11万
• 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/9918266
• 关键词: AMHR2 gene; Antral; Basic Science; Biology; Birth; Cancer Biology; Candidate Disease Gene; Carcinoma; Cell Culture Techniques; Cell model; Cells; Coculture Techniques; Development; Devices; Embryo; Embryonic Development; Endocrine; Environment; Epithelial; Epithelial Cells; Epithelial ovarian cancer; Epithelium; 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 Based on our recent studies (published and unpublished), we have developed a unique hypothesis that the MISR2-derived subpopulation of ovarian and fallopian tube epithelial cells are epithelial stem cells and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.

摘要 本研究项目是研究一个假定的卵巢癌祖细胞和干细胞群， 更年期对细胞转化潜力的影响。我们做出了一个令人惊讶的 发现卵巢和输卵管上皮细胞的镶嵌亚群源自MISR 2 （苗勒管抑制物质受体2型）谱系。此外，这些MISR 2衍生的细胞 亚群具有高增殖潜力，并在小鼠中发展上皮肿瘤， 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MISR 2衍生亚群是上皮干细胞， 卵巢癌的早期症状此外，这些细胞对MIS/AMH（Mullerian）的抑制有反应 抑制物质/抗苗勒管激素）。 我们计划通过研究含有MISR 2的卵巢和输卵管上皮细胞来验证这些想法 它们的生长和干细胞特性，并研究它们对MIS因子的反应， 模型和人体细胞和组织。以前，我们发现卵巢卵泡和颗粒细胞产生一种 生长抑制因子（s）对卵巢上皮细胞的培养，并提供证据表明，MIS是一个强大的 候选人的因素。我们将使用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， 有助于部分或全部的抑制活性。设计的实验也是为了测试 MIS/MISR 2旁分泌/内分泌通路在维持卵巢和输卵管组织稳态中的作用 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MISR 2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 治疗卵巢癌第二个主要目的是鉴定由肿瘤细胞产生的肿瘤抑制因子。 卵泡/颗粒细胞，并研究其在卵巢组织稳态中对卵巢上皮细胞的调节作用。 将颗粒细胞衍生的MIS作为卵泡衍生因子的强有力候选物进行测试。 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细胞。 突变小鼠模型，以研究分子机制和人类卵巢组织和癌症的相关性。 细胞和小鼠模型研究的发现和结论将在人类正常和 癌组织 如果成功的话，我们的工作将解决长期存在的关于卵巢癌风险高的原因的困惑 绝经期妇女。这项研究还将深入了解卵巢上皮细胞和癌症干细胞 人口，并将产生卵巢癌生物学的重大新进展。