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。卵巢癌的预后相对较差，反映了诊断时转移的高发生率。事实上，75%的患者被诊断为转移性疾病，其5年生存率为20-25%。高死亡率在很大程度上是由于对转移性癌症缺乏有效的治疗选择。确定调控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。我们假设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。卵巢癌通过侵袭间皮细胞转移，间皮细胞是排列在腹膜腔内的一层间皮细胞。我们报道了一种调节间皮细胞侵袭的新机制。我们的数据表明，优先在卵巢癌患者间皮上表达的VCAM-1与其配体a4¿1整合素（在卵巢癌细胞上表达）一起作用，促进细胞培养系统中间皮的侵袭。重要的是，在卵巢癌腹膜转移小鼠模型中，抑制VCAM-1功能可提高生存率并降低肿瘤负荷。我们的初步数据表明，溶血磷脂酸（LPA）是一种生物活性磷脂，在卵巢癌患者的腹膜腔中大量发现，可调节间皮浸润和间皮VCAM-1的表达。重要的是，间皮细胞慢性产生LPA会导致VCAM-1的组成性表达，而这种表达对其他刺激（包括TNF-a，一种具有良好特征的VCAM-1表达调节剂）是不耐受的。本研究的目的是确定卵巢癌患者间皮中VCAM-1表达的调控机制。这将实现以下具体目标：1)确定由LPA和TNF-a启动的调节间皮细胞VCAM-1表达的信号通路；2)明确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表达的因素将为治疗干预的设计提供新的机会。这些目标的成功完成有望为间皮细胞提供重要的机制信息，间皮细胞在卵巢癌腹膜转移中起关键作用。此外，了解LPA促进VCAM-1表达的机制对其他以慢性VCAM-1表达为特征的疾病的治疗也有意义，包括自身免疫和动脉粥样硬化。

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.