The Role of the Microenvironment in Early Ovarian Cancer Metastasis

微环境在早期卵巢癌转移中的作用

• 批准号: 7740558
• 负责人: Hilary Ann Kenny
• 金额: $ 10.91万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740558
• 关键词: Abdominal Cavity; Adhesions; Adipocytes; Apoptosis; Ascites; Award; Cancer Etiology; Cancer Patient; Cell Adhesion; Cell Adhesion Molecules; Cells; Cessation of life; Characteristics; Chemicals; Cleaved cell; Collagen Type I; Conditioned Culture Media; Confocal Microscopy; Cytoskeleton; Data; Dimensions; Disease; Early treatment; Effectiveness; Electrophoresis; Energy-Generating Resources; Extracellular Matrix; Female Genital Neoplasms; Fibroblasts; Fibronectin Receptors; Fibronectins; Figs - dietary; Gelatinase A; Gene Expression; Goals; Greater sac of peritoneum; Human; Image; Immunoblot Analysis; Immunofluorescence Immunologic; In Situ Hybridization; In Vitro; Individual; Integrins; Life; Lipids; Lipolysis; Malignant Neoplasms; Malignant neoplasm of ovary; Matrix Metalloproteinases; Measures; Mediating; Mentors; Mesothelial Cell; Microarray Analysis; Microscopic; Modeling; Mus; Neoplasm Metastasis; Omentum; Operative Surgical Procedures; Ovary; Patients; Peptide Hydrolases; Peritoneum; Phase; Play; Primary Neoplasm; Proteins; Publishing; Role; Screening for cancer; Site; Specific qualifier value; Staging; Stromal Cells; Surface; Testing; Time; Tissue Inhibitor of Metalloproteinase-1; Tumor Debulking; Vitronectin; Woman; Work; adhesion receptor; advanced disease; cancer cell; cell motility; cell type; clinical application; design; effective therapy; high throughput screening; in vitro testing; in vivo; inhibitor/antagonist; intraperitoneal; mRNA Expression; migration; mortality; novel; receptor; research study; three-dimensional modeling; tumor

DESCRIPTION (provided by applicant): One of the most important characteristics of ovarian cancer (OvCa) is metastasis of cancer cells to the peritoneal cavity. The main site of OvCa metastasis is the omentum. The omental microenvironment is composed of a layer of mesothelial cells covering the underlying stroma composed of extra-cellular matrices (ECMs) and stromal cells (i.e. fibroblasts and adipocytes). Adipocytes are the main cell type (over 80%) present in omentum . OvCa metastasis requires the initial adhesion and invasion of cancer cells into the surface of the omentum. Our preliminary results show that a number of factors in the microenvironment regulate the initial steps of OvCa metastasis to the omentum including stromal cells (i.e. mesothelial cells, fibroblasts, adipocytes), different extra-cellular matrices (ECMs) (i.e. fibronectin), adhesion molecules (i.e. a5¿1-integrin), and proteases (i.e. matrix-metalloproteinase 2 [MMP-2]). However, the mechanisms involved in early OvCa cell metastasis have yet to be fully elucidated. The objectives of this project during the mentored phase are to determine the functional significance of MMP-2, to differentiate the functional roles of FN and its receptor, a5¿1-integrin, and to clarify the functional value of adipocytes as conductors of early OvCa metastasis. During the independent phase of the award, the intent is to discover new inhibitors of OvCa cell adhesion and metastasis and to further investigate and evaluate the functional significance of adipocytes as regulators of early OvCa metastasis. Our overall hypothesis is that the OvCa microenvironment plays a critical role in OvCa adhesion and invasion as the first step of metastasis. Most patients with OvCa present in an advanced stage that involves the dissemination of cancer cells throughout the peritoneum cavity. Even after aggressive surgical debulking, tumors repopulate the abdominal cavity, and treatment is hampered by a lack of understanding of OvCa metastasis. This proposal will investigate adhesion and invasion, the initial rate-limiting steps of early OvCa metastasis. To design new and effective treatments, it is important that we understand the mechanisms of OvCa cell adhesion to the omentum, prior to establishment of single metastases. In pursuit of this goal, we have designed a three dimensional model of the surface of the omentum using primary human mesothelial cells and fibroblasts with ECM. This model gives us the opportunity to study in vitro the distinct roles of each cellular and ECM component present in the OvCa microenvironment on metastasis. RELEVANCE: The potential long-term clinical application of our studies is to identify early intraperitoneal treatment that inhibits OvCa cell (primary tumor or ascites-derived) adhesion (i.e. MMP-2 selective inhibitor) to the peritoneal cavity and metastasis. The OvCa patients that will benefit from early treatment include patients with advanced disease who, at the end of surgery, were rendered macroscopically tumor free (approximately 70% of FIGO stage IIIB to IV) and have only presumed "microscopic disease", and patients with ascites whose disease is limited to the ovary (FIGO stage IC to IIIA).

描述（申请人提供）：卵巢癌（OvCa）最重要的特征之一是癌细胞转移到腹膜腔。OvCa转移的主要部位是网膜。大网膜微环境由一层间皮细胞组成，覆盖着由细胞外基质（ecm）和基质细胞（即成纤维细胞和脂肪细胞）组成的底层基质。脂肪细胞是网膜中主要的细胞类型（超过80%）。OvCa转移需要癌细胞最初粘附并浸润到网膜表面。我们的初步结果表明，微环境中的许多因素调节OvCa转移到网膜的初始步骤，包括基质细胞（如间皮细胞、成纤维细胞、脂肪细胞）、不同的细胞外基质（ecm）（如纤维连接蛋白）、粘附分子（如a5¿1-整合素）和蛋白酶（如基质金属蛋白酶2 [MMP-2]）。然而，参与早期OvCa细胞转移的机制尚未完全阐明。本项目在指导阶段的目标是确定MMP-2的功能意义，区分FN及其受体a5¿1整合素的功能作用，并阐明脂肪细胞作为OvCa早期转移的传导体的功能价值。在独立奖项阶段，目的是发现OvCa细胞粘附和转移的新抑制剂，并进一步研究和评估脂肪细胞作为OvCa早期转移调节因子的功能意义。我们的总体假设是，OvCa微环境作为OvCa转移的第一步，在OvCa的粘附和侵袭中起着关键作用。