Platelets promote growth of ovarian cancer

血小板促进卵巢癌的生长

基本信息

批准号：
9079434
负责人：
Vahid Afshar-Kharghan
金额：
$ 33.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9079434
关键词：
ADP Receptors Adjuvant Therapy Affect Antibodies Antiplatelet Drugs Applications Grants Apyrase Aspirin Beds Biological Assay Blocking Antibodies Blood Blood Circulation Blood Platelets Blood Vessels Cancer Patient Cancerous Cell Adhesion Molecules Cell Communication Cell Proliferation Clinical Coupled Dependency Diagnostic Neoplasm Staging Electron Microscopy Extravasation Feedback Genetic Genetically Engineered Mouse Goals Growth Health Human Immunofluorescence Microscopy Implant In Vitro Infusion procedures Interleukin-6 Knowledge Lead Liver Malignant Neoplasms Malignant neoplasm of ovary Mediating Microcirculation Modeling Modification Mus Neoplasm Metastasis Outcome Ovarian Tissue Patients Pharmaceutical Preparations Platelet Activation Platelet Count measurement Process Reagent Receptor Signaling Role Route Sampling Signal Transduction Specimen Thrombopoietin Tissue Sample Tissues Wild Type Mouse base cancer cell cancer therapy in vivo inhibitor/antagonist kinase inhibitor knock-down malignant ascites mouse model neutrophil novel outcome forecast ovarian neoplasm overexpression paraform receptor research study thrombocytosis tool tumor tumor growth tumor microenvironment tumor progression

项目摘要

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.

描述（由适用提供）：在许多癌症患者（包括卵巢癌患者）中，血小板计数升高是一个普遍发现。与癌症和正常血小板相似的患者相比，患有卵巢癌和血小板病的患者的预后较差。我们已经表明，血小板在体外和卵巢癌的鼠模型中促进了癌细胞的扩散。减少血小板计数可降低卵巢癌细胞诱导的小鼠原位肿瘤的大小。为了确定血小板对癌细胞增强生长增强作用的机制，我们在体外使用了针对血小板的阻断试剂，并发现血小板激活和TGF¿1的释放对于血小板对癌细胞的增殖作用很重要。在该项目中，我们将使用卵巢癌的鼠模型和从卵巢癌患者获得的鼠类模型研究体内血小板和癌细胞之间的相互作用。我们的假设是血小板和癌细胞之间存在反馈回路。癌细胞秘密ADP并激活血小板，而血小板则促进癌细胞增殖的秘密TGF¿1。在具体中 AIM 1，我们将使用转基因的小鼠或药物试剂来调查血小板上的ADP受体是否会破坏小鼠对小鼠原位肿瘤的生长促进作用。在特定的目标2中，我们将靶向TGF¿1血小板的分泌，TGF¿1癌细胞上的受体或TGF¿1受体信号传导，以评估TGF¿1对血小板癌细胞相互作用的作用。我们将使用血小板特异性的TGF tgf虫，抑制剂RNA或针对TGF接收器信号传导的药物试剂进行这些实验。为了使血小板与癌细胞之间发生在肿瘤内部，血小板应退出循环并进入肿瘤微环境。我们已经显示了小鼠植入肿瘤内血管外的血小板存在。在特定的目标3中，我们将使用免疫荧光和电子显微镜在人和鼠类卵巢癌组织样品上研究血小板从肿瘤微循环中出口的机制。我们将确定血小板渗出的途径，并评估血小板对中性粒细胞进行渗出的依赖性。我们在这项赠款提案中进行研究的目的是评估使用抗血小板试剂作为有效的抗癌疗法的可能性。