How does malignancy subvert platelet and megakaryocytic biology?

项目摘要 传统上被认为是血液的绷带，血小板对恶性肿瘤的进展的贡献 正在成为治疗干预的一个引人注目的焦点。肿瘤细胞之间复杂的相互作用， 循环血小板在肿瘤生长和扩散中起着重要作用，越来越多的数据表明， 支持血小板活化和趋化因子释放在转移和新血管形成中的作用。 支持这一概念的证据是，诊断时血小板计数升高（血小板增多）， 恶性肿瘤是预后不良的侵袭性癌症的预兆。一个非常有趣和挑衅性的 越来越多的证据表明，肿瘤细胞劫持血小板， 一种更促恶性表型来驱动疾病进展。我们的实验室一直在帮助 建立血小板在转移和新血管形成中的促恶性作用。我们最近 发现肿瘤细胞可以指示血小板释放CCL5，这是一种已知的肿瘤细胞侵袭的驱动因素， 转移，并扩大了CCL5的作用，不仅作为转移的调节剂，而且作为中央 血小板生成的控制者。尽管取得了这一进展，肿瘤细胞如何指导巨核细胞增加 血小板生成，以及恶性肿瘤如何重编程巨核细胞和操纵血小板表型， 支持肿瘤生长和转移仍然是一个谜。由于血小板在驱动癌症方面起着核心作用， 该提案将涉及三个相互关联而又独立的具体目标，重点是细胞生物学和 肿瘤细胞劫持巨核细胞和血小板以促进癌症生长的分子途径。 具体目标1将确定趋化因子CCL5作为血小板增多症的主要驱动因素的作用， 恶性肿瘤通过上调巨核细胞成熟和前血小板产生。具体目标2将 确定恶性肿瘤如何重编程巨核细胞以产生更促恶性的血小板表型， 伴随着对新血管形成和转移必需的因子的上调。具体目标3将决定 通过阐明CCL5驱动的血小板生成和巨核细胞重编程的临床意义， 对乳腺癌患者的影响。这项工作是创新的，因为它进入了未知的领域， 采取多方面的实验方法来了解肿瘤细胞如何通过联合工作劫持血小板 血小板生成与癌症生物学的关系总的来说，我们希望这次调查能证明 恶性肿瘤可以通过操纵血小板来破坏正常血小板生物学的分子机制， 巨核细胞促进肿瘤生长和转移，为开发新型 治疗方式

Project Summary Traditionally viewed as the bandaids of the blood, the contribution of platelets to the progression of malignancy is emerging as a compelling focus for therapeutic intervention. Complex interactions between tumor cells, and circulating platelets play an important role in tumor growth and dissemination, and a growing body of data supports a role for platelet activation and release of chemokines in metastases and neovascularization. Supporting this concept is the evidence that elevated platelet counts (thrombocytosis) at time of diagnosis with malignancy is a harbinger of an aggressive cancer with a poor prognosis. One very interesting and provocative connection between cancer and platelets is the increasing evidence that tumor cells hijack platelets to promote a more pro-malignant phenotype to drive disease progression. Our laboratories have been instrumental in establishing the pro-malignant role of platelets in metastasis and neovascularization. We have recently discovered that tumor cells can instruct platelets to release CCL5, a known driver of tumor cell invasion and metastasis, and have expanded the role of CCL5 not only as a regulator of metastasis but also as a central controller of platelet production. Despite this progress, how tumor cells instruct megakaryocytes to increase platelet production, and how malignancy reprograms megakaryocytes and manipulates platelet phenotype to support tumor growth and metastasis remains an enigma. Since platelets play a central role in driving cancer, this proposal will address three interrelated while independent Specific Aims focused on the cell biological and molecular pathways by which tumor cells hijack megakaryocytes and platelets to promote cancer growth. Specific Aim 1 will determine the role of the chemokine CCL5 as a major driver of thrombocytosis in malignancy via upregulation of megakaryocyte maturation and proplatelet production. Specific Aim 2 will determine how malignancy reprograms megakaryocytes to produce a more pro-malignant platelet phenotype, with upregulation of factors essential to neovascularization and metastasis. Specific Aim 3 will determine the clinical significance of CCL5 driven platelet production and megakaryocyte reprogramming by elucidating the impact of each in breast cancer patients. This work is innovative because it enters unchartered territory and takes a multifaceted experimental approach to understanding how tumor cells hijack platelets by uniting work on platelet production with cancer biology. Taken together, we expect that this investigation will demonstrate the molecular mechanisms by which malignancy can subvert normal platelet biology by manipulating the megakaryocyte to promote cancer growth and metastasis, and lay the foundation for the development of novel therapeutic modalities.