Role of the Mullerian Tract in Ovarian Cancer Development

苗勒管在卵巢癌发展中的作用

• 批准号: 8396652
• 负责人: Louis Dubeau
• 金额: $ 5.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396652
• 关键词: Accounting; Adult; Age; Biology; Cancer Detection; Cancerous; Carcinoma; Cells; Development; Diagnostic Neoplasm Staging; Disease; Distant; Endocervix; Endometrial; Endometrium; Endosalpingiosis; Epithelial Cells; Epithelium; Estrus; Fallopian Tube Neoplasms; Female; Gene Expression Profile; Genes; Goals; Health; Human; Human Characteristics; Invasive Lesion; Knock-out; Knowledge; Laboratories; LacZ Genes; Lesion; Location; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Menstrual cycle; Mesothelial Cell; Metaplasia; Molecular Profiling; Morbidity - disease rate; Mucinous; Mullerian-inhibiting substance receptor; Mus; Mutation; Nature; Neoplastic Cell Transformation; Operative Surgical Procedures; Organ; Ovarian; Ovarian Carcinoma; Ovarian Granulosa Cell; Ovarian Serous Adenocarcinoma; Ovarian Surface Epithelial-Stromal Tumor; Ovary; Peritoneal; Phase; Predisposition; Reporter; Role; Screening for cancer; Serous; Serous Cystadenoma; Site; Specimen; Staging; Staining method; Stains; Structure; Structure of paramesonephric duct; Surface; Technology; Testing; Time; Tissues; Transgenes; Transgenic Mice; Uterine Neoplasms; Woman; base; beta-Galactosidase; fimbria; granulosa cell; knockout gene; mortality; mouse model; mutant; novel strategies; ovarian neoplasm; programs; promoter; prophylactic; receptor; recombinase; reproductive; response; theories; tumor

DESCRIPTION (provided by applicant): All cancer screening tests that have had a significant impact on disease morbidity and mortality are aimed not at detecting early stage cancers, but pre-cancerous or pre-invasive lesions. Searching for the precursor lesion of ovarian epithelial tumors implies knowledge of their actual site of origin. Although the currently favored theory states that ovarian epithelial tumors arise from the mesothelial cell layer that lines the ovarian surface (ovarian coelomic epithelium), this theory does not account for the well-known fact that these tumors show features of tissues embryologically derived from the mullerian ducts and for the fact that preneoplastic lesions found in surgical specimens of women undergoing prophylactic surgeries for familial ovarian cancer predisposition are most often located in the fimbriae of the fallopian tubes. This proposal is based on Dr. Dubeau's longstanding hypothesis that ovarian carcinomas do not arise from the ovarian coelomic epithelium, but from tissues that are embryologically derived from the mullerian ducts. Aim #1 will use transgenic mouse models to directly determine the exact contribution of the mullerian ducts to the adult female reproductive tract and test the hypothesis that the ovarian surface epithelium is not of mullerian origin while specific para-ovarian and para-uterine structures such as rete ovarii and others have such an origin. The possibility that portions of the coelomic epithelium can re-program their differentiation state to become mullerian-like, which is an important component of the hypothesis that ovarian tumors are of coelomic origin, will also be investigated. Aim #2 will take advantage of a mouse model recently developed in Dr. Dubeau's laboratory that suggests that inactivation of Brca1 in ovarian granulosa cells stimulate neoplastic transformation in tissues that are embryologically derived from the mullerian ducts. We will use technologies similar to those used in aim #1 to determine whether the tumors that develop in these mice are of mullerian or coelomic origin. We will also knockout the p53 and Brca1 genes either in derivatives of the mullerian ducts or in coelomic epithelium and will cross the resulting mouse lines with our line carrying a knockout of Brca1 in granulosa cells. We anticipate that the tumors that will develop in these double mutants will have increased malignant potential and we will test the hypothesis that tumors in mice in which the additional mutations are targeted to the mullerian tract will most closely resemble human tumors morphologically and immunohistochemically. We will determine which portions of either the normal mullerian tract or coelomic cavity shows the most resemblance to those tumors based on their overall gene expression profile and the manner in which they respond to different phases of the estrus cycle, the equivalent of the human menstrual cycle. We will also test the hypothesis that tumors located in the para-uterine region are molecularly similar to those arising in the oviductal/ovarian region but that their anatomical location determines the likelihood that they will be cystic, which is a frequent characteristic of human ovarian tumors. PUBLIC HEALTH RELEVANCE: This project is focused on the identification of the exact site of origin of ovarian cancers, which are the most lethal cancers of the female reproductive tract, and on better understanding the biology of the tissues where they originate. Our long-term goal is to use this information to develop novel approaches for the detection of these cancers before they acquire the ability to infiltrate surrounding tissues and spread to distant organs. This, in turn, should have a major impact on the morbidity and mortality associated with this disease.

描述（由申请人提供）：所有对疾病发病率和死亡率产生重大影响的癌症筛查测试的目的不是检测早期癌症，而是癌症前或侵入性病变。寻找卵巢上皮肿瘤的前体病变意味着对其实际原产地的了解。尽管目前有利的理论指出，卵巢上皮肿瘤是由在卵巢表面（卵巢卵巢上皮上皮）排列的间皮细胞层引起的，但该理论并未说明这些肿瘤的著名事实，即这些肿瘤表现出胚胎学特征在穆勒式风管中衍生出的组织的特征，该事实是在穆尔氏症中发现的，并且在较低的妇女中发现了较低的妇女，并在这种事实中发现了这种肿瘤的陈述。家族性卵巢癌易感性最常位于输卵管的纤维中。该提议基于杜波博士的长期假设，即卵巢癌不是源自卵巢卵巢上皮，而是源自胚胎源自mullerian管道的组织。 AIM＃1将使用转基因小鼠模型直接确定Mullerian管道对成年女性生殖道的确切贡献，并测试卵巢表面上皮不是穆勒的假说，而特定的Para-ovarian和Para-para-Utererine结构（例如Rete ovarii and over ovarii and ofere ovarii and of overe and又有这样的造型。腔内上皮部分的某些可能性可以重新编程的分化状态变成类似穆勒的状态，这是卵巢肿瘤是卵巢起源的假设的重要组成部分。 AIM＃2将利用杜波博士实验室中最近开发的小鼠模型，该模型表明，卵巢颗粒细胞中BRCA1的失活刺激源自穆勒型管道的组织中的肿瘤转化。我们将使用类似于AIM＃1中使用的技术来确定这些小鼠中发育的肿瘤是否是穆勒元或卵巢起源的。我们还将在Mullerian管道的衍生物或Coelomic上皮衍生物中敲除P53和BRCA1基因，并将横穿所得小鼠线与我们的系在颗粒细胞中的BRCA1敲除。我们预计，这些双重突变体中将发育的肿瘤将具有增加的恶性潜力，我们将测试以下假设：在穆勒群中，靶向其他突变的小鼠肿瘤在形态和免疫组化上最与人类肿瘤最类似于人类肿瘤。我们将根据其总体基因表达谱以及它们对Estrus循环的不同阶段的响应（人类月经循环的等效性）的方式来确定正常的穆勒群或腔腔的哪些部分与这些肿瘤最相似。我们还将检验以下假设：位于帕拉河区域中的肿瘤与卵巢/卵巢区域中产生的肿瘤非常相似，但是它们的解剖位置决定了它们是囊性的可能性，这是人类卵巢肿瘤的常见特征。公共卫生相关性：该项目的重点是识别卵巢癌的确切原产地，这是女性生殖道的最致命的癌症，并更好地理解其起源组织的生物学。我们的长期目标是利用这些信息来开发这些新方法来检测这些癌症，然后才能获得周围组织并扩散到远处器官的能力。反过来，这应该对与这种疾病相关的发病率和死亡率产生重大影响。