Platelets promote growth of ovarian cancer

描述（由申请人提供）：血小板计数升高是许多癌症患者的常见发现，包括卵巢癌患者。卵巢癌合并血小板增多症患者的预后较分期相似但血小板计数正常的患者差。我们已经证明血小板在体外和小鼠卵巢癌模型中促进癌细胞的增殖；血小板计数的减少可减小卵巢癌细胞诱导小鼠原位肿瘤的大小。为了明确血小板对癌细胞生长促进作用的机制，我们在体外使用血小板阻断试剂，发现血小板的激活和TGF - 1的释放对血小板对癌细胞的增殖作用至关重要。在这个项目中，我们将研究血小板与癌细胞在体内的相互作用，使用小鼠卵巢癌模型和卵巢癌患者的组织样本。我们的假设是在血小板和癌细胞之间有一个反馈循环。癌细胞分泌ADP激活血小板，血小板分泌TGF¿1促进癌细胞增殖。具体来说

DESCRIPTION (provided by applicant): Elevated platelet counts are a common finding in many cancer patients, including patients with ovarian cancer. Patients with ovarian cancer and thrombocytosis have a worse prognosis compared to patients with similar stages of cancer and normal platelet counts. We have shown that platelets promote proliferation of cancer cells both in vitro and in the murine models of ovarian cancer; and reducing platelet counts decreased the size of orthotopic tumor induced in mice by ovarian cancer cells. To identify the mechanisms of the growth- enhancing effect of platelets on cancer cells, we used blocking reagents against platelets in vitro, and found that platelet activation and release of TGF¿1 are important for the proliferative effect of platelets on cancer cells. In this project, we will study the interaction between platelets and cancer cells in vivo, using both murine models of ovarian cancer and tissue samples obtained from patients with ovarian cancer. Our hypothesis is that there is a feedback loop between platelets and cancer cells. Cancer cells secrete ADP and activate platelets, and platelets secrete TGF¿1 that promotes proliferation in cancer cells. In the specific aim 1, we will investigate whether blocking ADP receptors on platelets would disrupt the growth promoting effect of platelets on orthotopic tumors in mice, using genetically modified mice or pharmacologic reagents. In the specific aim 2, we will target TGF¿1 secretion from platelets, TGF¿1 receptor on cancer cells, or TGF¿1 receptor signaling to evaluate the role of TGF¿1 on the platelet-cancer cell interaction. We will use platelet-specific TGF¿1 deficient mice, inhibitor RNAs, or pharmacologic reagents against TGF¿ receptor signaling to conduct these experiments. For the interaction between platelets and cancer cells to occur inside the tumors, platelets should exit circulation and enter into tumor microenvironment. We have shown the presence of platelets outside of blood vessel inside the implanted tumors in mice. In the specific aim 3, we will study the mechanisms of platelet exit from tumor microcirculation using immunofluorescence and electron microscopy on human and murine ovarian cancer tissue samples. We will identify the route of platelet extravasation, and evaluate the dependency of platelets on neutrophils for extravasation. The goal of our studies in this grant proposal is to evaluate the possibility of using anti-platelet reagents as an effective anticancer therapy.