Signaling in the ovarian cancer metastatic microenvironment

描述（由申请人提供）：卵巢癌是女性癌症相关死亡的第四大原因。 卵巢癌预后相对较差反映了诊断时转移的高发生率。 事实上，75%的患者被诊断患有转移性疾病，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卵巢癌的治疗提供急需的额外治疗靶点。 我们推测整合素介导的肿瘤细胞和间皮细胞之间的相互作用是卵巢癌进展的重要组成部分。 卵巢癌通过侵袭腹膜间皮转移，腹膜间皮是腹膜腔的一层间皮细胞。 我们报道了一种新的机制，调节间皮细胞入侵。 我们的数据表明，VCAM-1，这是表达的卵巢癌患者的间皮细胞优先，功能与其配体，α 4 <$1整合素（表达在卵巢癌细胞），以促进间皮细胞入侵细胞培养系统。 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并降低了肿瘤负荷。 我们的初步数据表明，溶血磷脂酸（LPA），在卵巢癌患者的腹膜腔中发现丰富的生物活性磷脂，调节间皮细胞的侵袭和间皮细胞VCAM-1的表达。 重要的是，间皮细胞长期产生LPA导致组成型VCAM-1表达，其对其他刺激（包括TNF-α，一种充分表征的VCAM-1表达调节剂）不敏感。 该提案的目标是确定调节卵巢癌患者间皮瘤VCAM-1表达的机制。 这将通过以下具体目标来实现：1）确定由调节间皮细胞中VCAM-1表达的LPA和TNF-α启动的信号传导途径; 2）确定巨噬细胞和间皮细胞对VCAM-1表达和卵巢癌进展的贡献;和3）鉴定与卵巢癌患者中间皮VCAM-1表达相关的临床参数。 了解卵巢癌患者中调节VCAM-1表达的因素将为设计新的治疗干预机会提供见解。 这些目标的成功完成，预计将提供重要的机制信息间皮细胞，发挥关键作用，卵巢癌腹膜转移。 此外，了解LPA促进VCAM-1表达的机制对于治疗以慢性VCAM-1表达为特征的其他疾病，包括自身免疫和动脉粥样硬化具有意义。 公共卫生相关性：我们提案的总体目标是了解卵巢癌患者中调节VCAM-1表达的机制。 从成功完成该提案中获得的信息将增强我们对LPA和TNF-α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理解。 此外，我们的数据有望为其他疾病（包括多发性硬化症、关节炎、哮喘、结肠炎和动脉粥样硬化）中慢性VCAM-1表达的调节机制提供见解。

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.