Signaling in the ovarian cancer metastatic microenvironment

卵巢癌转移微环境中的信号传导

• 批准号: 8527932
• 负责人: Jill Slack-Davis
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527932
• 关键词: Accounting; Address; Animal Model; Arrestins; Arthritis; Asthma; Atherosclerosis; Autoimmunity; Cancer Etiology; Cancer Patient; Cell Communication; Cell Culture System; Cell Line; Cells; Cessation of life; Chi-Square Tests; Chronic; Clinical; Colitis; Cox Proportional Hazards Models; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; Disease Resistance; Disseminated Malignant Neoplasm; Exposure to; Flow Cytometry; Genetic Transcription; Goals; Greater sac of peritoneum; Incidence; Integrins; Invaded; Lead; Ligands; Lipids; Lysophosphatidic Acid Receptors; Lysophospholipids; Malignant neoplasm of ovary; Mediating; Mesothelial Cell; Mesothelium; Modeling; Molecular; Multiple Sclerosis; Mus; Natural Immunity; Neoplasm Metastasis; Ovarian Carcinoma; Pathway interactions; Patients; Peritoneal; Phospholipids; Phosphoric Monoester Hydrolases; Platinum; Play; Production; Recurrence; Refractory; Regulation; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Staging; Stimulus; TNF gene; Testing; Therapeutic Intervention; Time; Tumor Burden; Tumor Debulking; Tumor Necrosis Factor Receptor; Tumor stage; Vascular Cell Adhesion Molecule-1; Woman; Xenograft Model; adaptive immunity; cancer cell; chemotherapy; defined contribution; design; effective therapy; improved; insight; lysophosphatidic acid; macrophage; metastatic process; mortality; mouse model; neoplastic cell; novel; outcome forecast; public health relevance; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Ovarian cancer is the fourth leading cause of cancer-related death among women. The relatively poor prognosis for ovarian cancer reflects the high incidence of metastasis at diagnosis. Indeed, 75% of patients are diagnosed with metastatic disease, which has a 5-year survival of 20-25%. The high mortality rate is due in large part to the lack of effective treatment options for metastatic cancer. Identifying the mechanisms that regulate ovarian cancer metastasis will provide much needed additional therapeutic targets for the treatment of ovarian cancer. We hypothesize that the integrin mediated interaction between the tumor cells and mesothelium is an important component of ovarian cancer progression. Ovarian carcinomas metastasize by invading through the mesothelium, a layer of mesothelial cells that line the peritoneal cavity. We reported a novel mechanism for the regulation of mesothelial invasion. Our data demonstrate that VCAM-1, which is expressed preferentially on the mesothelium of ovarian cancer patients, functions together with its ligand, a4¿1 integrin (expressed on ovarian cancer cells), to promote mesothelial invasion in cell culture systems. Importantly, inhibition of VCAM-1 function increased survival and decreased tumor burden in a mouse model of ovarian cancer peritoneal metastasis. Our preliminary data demonstrate that lysophosphatidic acid (LPA), a bioactive phospholipid found in abundance in the peritoneal cavity of ovarian cancer patients, regulates mesothelial invasion and mesothelial VCAM-1 expression. Importantly, chronic production of LPA by mesothelial cells results in constitutive VCAM-1 expression that is refractory to other stimuli, including TNF-a, a well- characterized regulator of VCAM-1 expression. The goal of this proposal is to determine the mechanisms that regulate VCAM-1 expression on the mesothelium of ovarian cancer patients. This will be accomplished with the following specific aims: 1) determine the signaling pathways initiated by LPA and TNF-a that regulate VCAM-1 expression in mesothelial cells; 2) define the contribution of macrophages and mesothelial cells to VCAM-1 expression and ovarian cancer progression; and 3) identify the clinical parameters that correlate with mesothelial VCAM-1 expression in ovarian cancer patients. Understanding the factors that regulate VCAM-1 expression in ovarian cancer patients will provide insights into the design of new opportunities for therapeutic intervention. Successful completion of these aims is expected to provide important mechanistic information about mesothelial cells, which play a critical role in ovarian cancer peritoneal metastasis. Additionally, understanding the mechanisms by which LPA promotes VCAM-1 expression has implications for the treatment of other diseases characterized by chronic VCAM-1 expression, including autoimmunity and atherosclerosis. PUBLIC HEALTH RELEVANCE: The overall goal of our proposal is to understand the mechanisms that regulate VCAM-1 expression in ovarian cancer patients. Information obtained from the successful completion of this proposal will enhance our understanding of the role of LPA and TNF-a signaling pathways in the regulation of VCAM-1 expression, the contribution of macrophages to VCAM-1 expression, and the clinical parameters associated with expression. In addition, our data is expected to provide insight toward the mechanisms that regulate chronic VCAM-1 expression in other conditions including multiple sclerosis, arthritis, asthma, colitis, and atherosclerosis.

描述（由适用提供）：卵巢癌是女性与癌症相关死亡的第四个主要原因。卵巢癌的相对预后不良反映了诊断时转移的高入射。实际上，有75％的患者被诊断出患有转移性疾病，其5年生存率为20-25％。高死亡率在很大程度上是由于缺乏转移性癌症的有效治疗选择。确定调节卵巢癌转移的机制将为治疗卵巢癌提供急需的其他治疗靶标。我们假设整联蛋白介导的肿瘤细胞与间皮之间的相互作用是卵巢癌进展的重要组成部分。卵巢癌通过通过间皮细胞侵入腹膜腔的间皮细胞来转移。我们报道了一种调节间皮入侵的新机制。我们的数据表明，在卵巢癌患者的间皮上更优选地表达的VCAM-1及其配体A4€1整联蛋白（在卵巢癌细胞中表达）起作用，以促进细胞培养系统中的间皮性侵袭。重要的是，在卵巢癌腹膜转移的小鼠模型中，VCAM-1功能的抑制增加了存活率和肿瘤燃烧的减少。我们的初步数据表明，在卵巢癌患者的腹膜腔中发现了一种在抽象中发现的生物活性磷脂酸（LPA），可调节间皮性侵袭和间皮VCAM-1表达。重要的是，间皮细胞慢性产生LPA会导致构成型VCAM-1表达，这是对其他刺激的难治性的，包括TNF-A，包括VCAM-1表达的特征良好的调节剂TNF-A。该提案的目的是确定调节卵巢癌患者间皮上VCAM-1表达的机制。这将通过以下特定目的来完成：1）确定由LPA和TNF-A引发的信号传导途径调节间皮细胞中VCAM-1表达的表达； 2）定义巨噬细胞和间皮细胞对VCAM-1表达和卵巢癌进展的贡献； 3）确定与卵巢癌患者中与间皮VCAM-1表达相关的临床参数。了解调节卵巢癌患者VCAM-1表达的因素将为您提供有关治疗干预新机会的见解。这些目标的成功完成有望提供有关间皮细胞的重要机械信息，这些信息在卵巢癌腹膜转移中起着至关重要的作用。此外，了解LPA促进VCAM-1表达的机制对治疗以慢性VCAM-1表达（包括自身免疫性和动脉粥样硬化）为特征的其他疾病具有影响。 公共卫生相关性：我们提案的总体目标是了解调节卵巢癌患者VCAM-1表达的机制。从该提案的成功完成中获得的信息将增强我们对LPA和TNF-A信号通路在VCAM-1表达调节中的作用，巨噬细胞对VCAM-1表达的贡献以及与表达相关的临床参数的贡献。此外，我们的数据有望提供对调节慢性VCAM-1表达在其他条件（包括多发性硬化症，关节炎，哮喘，结肠炎和动脉粥样硬化）的机制的见解。