Platelets promote growth of ovarian cancer

血小板促进卵巢癌的生长

• 批准号: 10296684
• 负责人: Vahid Afshar-Kharghan
• 金额: $ 47.94万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296684
• 关键词: ADP Receptors; Affect; Agonist; Alpha Granule; Angiogenesis Inhibitors; Anoikis; Antiplatelet Drugs; Area; Aspirin; Behavior; Blood Platelets; Blood Vessels; Cancer Center; Cancer Patient; Cell Adhesion Molecules; Cell Communication; Cell Proliferation; Cells; Chemotactic Factors; Clinical Data; Consequentialism; Data; Diagnosis; Disease; Doctor of Medicine; Epithelial; Event; Extravasation; Fibroblasts; Funding; G-Protein-Coupled Receptors; GTP-Binding Proteins; Growth; In Vitro; Inflammation; Institution; Integrins; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mesenchymal; Molecular; Moon; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Patient Recruitments; Patients; Pericytes; Platelet Activation; Platelet Count measurement; Predictive Value; Primary Neoplasm; Process; Prognosis; Prognostic Marker; Reagent; Recurrence; Reporting; Resected; Resistance; Role; Signal Transduction; Specimen; Stimulus; Stromal Cell-Derived Factor 1; Surface; Survival Rate; Tissue Sample; Tumor Tissue; Tumor-Derived; base; cancer cell; cancer survival; chemotherapy; circulating cancer cell; clinically relevant; density; imaging study; in vivo; migration; mouse model; neutrophil; new therapeutic target; ovarian neoplasm; podoplanin; predictive marker; prognostic value; programs; receptor; response; response biomarker; synergism; thrombocytosis; treatment response; tumor; tumor growth

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.

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，并且与较差有关 预后。我们发现，卵巢癌中的血小板病不仅是晚期的Epiphenomena 恶性肿瘤，但实际上，血小板会促进肿瘤的生长。通过减少血小板计数，我们降低了 卵巢癌鼠模型中的原发性肿瘤。虽然以前的大多数研究都集中在 促进转移的血小板，我们发现血小板通过 增强癌细胞的增殖。血小板对肿瘤生长的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 活化的血小板秘密TGFβ1促进癌细胞增殖。阻塞或缺乏P2Y12 ADP 血小板上的受体，血小板中TGFβ1的阻塞或缺乏，或者在降低TGFβ1受体1（TGFβR1）上的受体 癌细胞降低了血小板对卵巢癌的促增长作用。在研究卵巢癌期间 从患者和肿瘤小鼠中矫正的肿瘤，我们观察到肿瘤内血管外血小板。我们 提议血小板对癌症的主要影响是由外部血小板介导的。血小板的迁移 在血管之外不是一个众所周知的现象，是否具有分子 渗出所需的机械，并且能够经历急剧的结构变化 中性粒细胞是专业迁徙细胞的渗出。我们关于血小板的体内和体外研究 渗入肿瘤表明该过程是一个活跃过程，并被抗血小板剂减少 （阿司匹林或ticagrelor）。在该提案的第一个目的中，我们将研究启动血小板的肿瘤的刺激 奢侈。我们将确定血小板的跨内皮迁移的分子机制， 研究周细胞对血小板渗出的促进作用。退出血管后，血小板 被癌细胞和肿瘤基质激活。在该提案的第二个目标中，我们将调查 通过解剖各种G蛋白偶联受体在癌症中血小板激活的机制 肿瘤生长的血小板。我们将研究不同血小板g-的冗余，协同作用或相反的作用 血小板癌细胞相互作用的蛋白质。在第三个目标中，我们将研究我们的相关性 卵巢癌的鼠模型和患者卵巢癌的行为中的发现。我们已经使用过 高级成像研究以准确，客观地量化肿瘤组织中的血小板密度。我们将 确定从医学博士诊断为卵巢癌的60例患者切除的肿瘤规格中的血小板密度。 安德森癌症中心（来自485名患者的池 我们的机构）。我们将使肿瘤内的血小板密度与手术，化学疗法，化学疗法相关联 和抗血管生成疗法和存活率；并确定是否可以将血小板密度用作 预测治疗的反应率和作为生存和复发率的预后标记。