Platelets promote growth of ovarian cancer

项目概要/摘要 在约30%的卵巢癌患者中检测到血小板计数升高， 预后我们发现卵巢癌患者的血小板增多不仅仅是晚期卵巢癌的副作用， 恶性肿瘤，但事实上，血小板促进肿瘤生长。通过减少血小板计数，我们减少了 小鼠卵巢癌模型中的原发性肿瘤。虽然以前的大多数研究都集中在 血小板在促进转移中的作用，我们发现血小板通过以下方式增加原发性肿瘤的生长： 促进癌细胞的增殖。血小板对肿瘤生长影响的基础是血小板与肿瘤细胞之间的相互作用。 血小板和癌细胞之间的联系我们发现卵巢癌细胞通过分泌ADP激活血小板， 活化的血小板分泌促进癌细胞增殖的TGFβ1。P2 Y12 ADP阻断或缺乏 血小板上的TGFβ1受体，血小板中TGFβ 1受体1的阻断或缺乏，或血小板上TGFβ1受体1（TGFβR1）的减少， 癌细胞减少了血小板对卵巢癌的促生长作用。在卵巢癌研究期间 从患者和荷瘤小鼠切除的肿瘤中，我们观察到肿瘤内的血管外血小板。我们 提出血小板对癌症的主要作用是由外渗的血小板介导的。血小板迁移 血小板在血管外的聚集并不是一个众所周知的现象，尽管事实上血小板具有 机械所需的外渗，并能够进行必要的剧烈结构变化， 嗜中性粒细胞的外渗，嗜中性粒细胞是专业的迁移细胞。我们对血小板的体内外研究 肿瘤外渗表明这一过程是一个活跃的过程，抗血小板药物可减少这一过程 （阿司匹林或替格瑞洛）。在这个提议的第一个目标中，我们将研究来自肿瘤的刺激物引发血小板活化。 外渗。我们将确定血小板跨内皮迁移的分子机制， 研究周细胞对血小板外渗的促进作用。血小板从血管中排出后， 被癌细胞和肿瘤基质激活。在本提案的第二个目标中，我们将调查 通过分析各种G蛋白偶联受体在血小板活化中的作用， 肿瘤生长中的血小板。我们将研究不同血小板G- 血小板-癌细胞相互作用的蛋白质。在第三个目标中，我们将研究我们的 在卵巢癌小鼠模型中的发现和卵巢癌患者的行为。我们已经使用 先进的成像研究，以准确和客观地量化肿瘤组织中的血小板密度。我们将 测定60例诊断为卵巢癌的患者的肿瘤标本中的血小板密度。 安德森癌症中心（从485名患者中招募到卵巢癌登月计划， 我们的机构）。我们将把肿瘤内的血小板密度与手术、化疗的反应率联系起来， 抗血管生成治疗和生存率;并确定血小板密度是否可以作为 作为对治疗的反应率的预测标志物以及作为存活率和复发率的预后标志物。

Project Summary/Abstract Elevated platelet counts are detected in about 30% of ovarian cancer patients and associated with a poor prognosis. We found that thrombocytosis in ovarian cancer is not just epiphenomena of an advanced malignancy, but in fact, platelets promote tumor growth. By reducing platelet counts, we reduced the growth of primary tumors in murine models of ovarian cancer. While most of the previous studies focused on the role of platelets in promoting metastasis, we discovered that platelets increase the growth of primary tumors by enhancing proliferation of cancer cells. The basis for the effect of platelets on tumor growth is the interactions between platelets and cancer cells. We found that ovarian cancer cells activate platelets by secreting ADP, and activated platelets secrete Tgfβ1 that promotes cancer cell proliferation. Blocking or deficiency of P2Y12 ADP receptors on platelets, blocking or deficiency of Tgfβ1 in platelets, or reducing Tgfβ1 receptor 1 (TgfβR1) on cancer cells reduced the pro-growth effects of platelets on ovarian cancer. During studies on ovarian cancer tumors resected from patients and tumor-bearing mice, we observed extravascular platelets inside tumors. We propose that the main effects of platelets on cancer are mediated by extravasated platelets. Migration of platelets outside of blood vessels is not a well-known phenomenon, despite the fact that platelets possess the molecular machinery required for extravasation, and are able to undergo drastic structural changes necessary for extravasation of neutrophils that are professional migratory cells. Our in vivo and in-vitro studies on platelet extravasation into tumors showed that this process is an active process and is reduced by antiplatelet agents (aspirin or ticagrelor). In the first aim of this proposal, we will study the stimuli from tumors that initiate platelet extravasation. We will identify the molecular mechanism of transendothelial migration of platelets, and investigate the facilitatory effects of pericytes on platelets extravasation. After exiting blood vessels, platelets become activated by cancer cells and tumor stroma. In the second aim of this proposal, we will investigate the mechanism of platelet activation in the cancer by dissecting the role of various G-protein-coupled receptors on platelets in tumor growth. We will study the redundancy, synergism, or opposing effects of different platelet G- proteins on platelet-cancer cell interactions. In the third aim, we will investigate the correlation between our findings in the murine models of ovarian cancer and the behavior of ovarian cancer in patients. We have used advanced imaging studies to accurately and objectively quantify platelet density in tumor tissues. We will determine platelet density in tumor specimens resected from 60 patients diagnosed with ovarian cancer in M.D. Anderson Cancer Center (from a pool of 485 patients recruited to the Ovarian Cancer Moon Shots program in our institution). We will correlate platelet density inside tumors with the response rate to surgery, chemotherapy, and antiangiogenic therapy and the survival rates; and determine whether platelet density can be used as a predictive marker for the response rates to therapy and as a prognostic marker for survival and recurrence rates.