Ovarian Epithelial Cancer Progenitor Cell Population

卵巢上皮癌祖细胞群

基本信息

批准号：
10524246
负责人：
XiangXi Mike Xu
金额：
$ 4.65万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10524246
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

项目摘要

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 Based on our recent studies (published and unpublished), we have developed a unique hypothesis that the MISR2-derived subpopulation of ovarian and fallopian tube epithelial cells are epithelial stem cells and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

抽象的该研究项目是研究假定的卵巢癌祖细胞和干细胞种群，以及更年期对细胞经历转化的潜力的影响。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型）谱系。此外，这些细胞的MISR2衍生细胞亚种群具有很高的增殖潜力，并在小鼠中发展出卵巢卵泡的上皮肿瘤耗尽。根据我们最近的研究（发表和未发表），我们开发了一个独特的假设，卵巢和输卵管上皮细胞的MISR2衍生亚群是上皮干细胞，卵巢癌的前体。另外，这些细胞对MIS/AMH的抑制作用（Mullerian）由卵巢卵泡的颗粒细胞产生的抑制性物质/抗肿瘤激素。我们计划通过研究含MISR2的卵巢和输卵管上皮细胞来测试这些想法为了它们的生长和干细胞特性，还研究了它们对MIS因子的反应模型，人类细胞和组织。以前，我们发现卵巢卵泡和颗粒细胞产生A 生长抑制因子对培养中卵巢上皮细胞的生长抑制因子，并提供了MIS是强大的证据该因素的候选人。我们将寻求使用Transwell确定颗粒细胞产生的因子与颗粒细胞共同培养卵巢和输卵管上皮细胞的装置，并验证是否误以为有助于部分或所有抑制活性。设计的实验也是测试 MIS/MISR2旁分泌/内分泌途径在维持卵巢和输卵管的组织稳态方面管子环境和肿瘤抑制作用，如两个主要目的所述。第一个主要目的是表征MISR2阳性细胞以确定这些细胞是否为祖细胞/干细胞，前体和前体用于卵巢癌。第二个主要目的是确定由卵泡/颗粒细胞，研究其对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相关的相关性。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，我们的工作将解决长期的难题，原因是卵巢癌风险很高的原因在更年期的妇女中。该研究还将深入了解卵巢上皮和癌症干细胞人口，并将在卵巢癌生物学中产生重大的新进步。