Ovarian Epithelial Cancer Progenitor Cell Population

摘要 这项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，以及 绝经对细胞转化潜能的影响。我们做了一个令人惊讶的 发现卵巢和输卵管上皮细胞的嵌合体亚群来自MISR2 (苗勒氏抑制性物质受体2型)谱系。此外，这些MISR2来源的细胞 亚群具有很高的增殖潜力，并在小鼠身上发展为卵巢上皮癌 耗尽了。 基于我们最近的研究(已发表和未发表)，我们提出了一个独特的假设 MISR2来源的卵巢和输卵管上皮细胞亚群是上皮干细胞和 卵巢癌的先兆。此外，这些细胞对MIS/AMH(Mullerian)的抑制有反应 抑制物质/抗苗勒氏激素)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验证这些想法 研究了它们的生长和干细胞特性，并研究了它们对两只小鼠的MI因子的反应 模型和人类细胞和组织。此前，我们发现卵巢卵泡和颗粒细胞产生一种 生长抑制因子(S)对体外培养的卵巢上皮细胞的生长抑制作用，为中药复方制剂具有较强的抗肿瘤活性提供了证据。 该因素的候选人。我们将使用Transwell来鉴定颗粒细胞产生的因子(S)。 卵巢和输卵管上皮细胞与颗粒细胞共培养装置 对部分或全部抑制活性有贡献。设计的实验也是为了测试 MIS/MISR2旁分泌/内分泌途径在维持卵巢和输卵管组织动态平衡中的作用 管状环境和在肿瘤抑制方面，概括起来有两个主要目的。第一个主要目标是 鉴定MISR2阳性细胞以确定这些细胞是否为祖细胞/干细胞样细胞和前体细胞 治疗卵巢癌。第二个主要目的是鉴定S产生的肿瘤抑制因子 探讨卵泡/颗粒细胞及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，研究分子机制及其与人类卵巢组织和癌症的相关性。 来自细胞和小鼠模型的研究结果和结论将在人类正常和 癌症组织。 如果成功，我们的工作将解开卵巢癌风险高的长期谜团 在更年期妇女中。这项研究还将深入了解卵巢上皮干细胞和癌症干细胞 并将在卵巢癌生物学方面产生实质性的新进展。

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 Based on our recent studies (published and unpublished), we have developed a unique hypothesis that the MISR2-derived subpopulation of ovarian and fallopian tube epithelial cells are epithelial stem cells and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