Platelets promote growth of ovarian cancer

项目摘要/摘要 在大约30%的卵巢癌患者中检测到血小板计数升高，并与不良 预后。我们发现卵巢癌中的血小板增多症不仅仅是晚期卵巢癌的并发症。 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 卵巢癌小鼠模型中的原发肿瘤。虽然以前的大多数研究都集中在细胞因子的作用 血小板在促进转移中的作用，我们发现血小板通过以下途径促进原发肿瘤的生长 促进癌细胞的增殖。血小板对肿瘤生长影响的基础是相互作用 在血小板和癌细胞之间。我们发现卵巢癌细胞通过分泌ADP激活血小板，并且 活化的血小板分泌转化生长因子β1，促进癌细胞增殖。P2Y12 ADP的封闭或缺失 血小板上的受体，阻断或缺乏转化生长因子β1，或减少转化生长因子β1受体1(转化生长因子βR1)。 癌细胞减少了血小板对卵巢癌的促生长作用。在对卵巢癌的研究中 手术切除肿瘤患者和荷瘤小鼠，观察肿瘤内血管外血小板的变化。我们 认为血小板在癌症中的主要作用是通过外渗的血小板介导的。血小板的迁移 血管外并不是一个众所周知的现象，尽管事实上血小板拥有这种分子 外渗所需的机械，并能够经历必要的剧烈结构变化 中性粒细胞是专业的迁移细胞，其外渗。我们对血小板的体内外研究 肿瘤的渗入表明，这一过程是一个活跃的过程，并被抗血小板药物减少。 (阿司匹林或替卡格雷)。在这个提议的第一个目标中，我们将研究来自启动血小板的肿瘤的刺激。 渗出。我们将确定血小板跨内皮细胞迁移的分子机制，并 研究周细胞对血小板外渗的促进作用。在离开血管后，血小板 被癌细胞和肿瘤间质激活。在这项建议的第二个目标中，我们将调查 通过解剖多种G蛋白偶联受体在肿瘤中的作用来探讨肿瘤中血小板活化的机制 血小板在肿瘤生长中的作用我们将研究不同的血小板G-2的冗余性、协同或相反作用。 蛋白质对血小板-癌细胞相互作用的影响。在第三个目标中，我们将调查我们的 在小鼠卵巢癌模型中的发现和卵巢癌患者的行为。我们已经使用了 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。我们会 检测60例临床诊断为卵巢癌患者的肿瘤标本中的血小板密度。 安德森癌症中心(从485名卵巢癌登月计划招募的患者中挑选出来) 我们的机构)。我们将把肿瘤内的血小板密度与手术、化疗、 以及抗血管生成治疗和存活率；并确定血小板密度是否可以作为 作为治疗应答率的预测标志，以及作为生存和复发率的预后标志。

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.