Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis
Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis
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DOI：
10.1182/blood-2009-09-242065
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发表时间：
2010-06-03
期刊：
影响因子：
20.3
通讯作者：
Ryeom, Sandra
中科院分区：
文献类型：
--
作者：
Zaslavsky, Alexander;Baek, Kwan-Hyuck;Ryeom, Sandra
导致肿瘤进展的连续事件包括向血管生成表型的转变，这取决于肿瘤和基质细胞产生的阳性和阴性血管生成调节因子之间平衡的转变。尽管许多血管生成调节蛋白的生物学特性已被详细研究，但它们在病理性血管生成过程中的体内转运和递送机制尚不清楚。在这里，我们证明了最有效的血管生成抑制剂之一，血小板反应蛋白-1，在荷瘤小鼠的血小板表达上调。我们确定这种上调是巨核细胞中血小板反应蛋白-1 mRNA水平增加以及荷瘤小鼠骨髓中巨核细胞数量增加的结果。通过使用小鼠肿瘤模型和骨髓移植，我们表明，血小板源性血小板反应蛋白-1是一个关键的负调节在肿瘤血管生成的早期阶段。总的来说，我们的数据表明，血小板产生和传递内源性血管生成抑制剂血小板反应蛋白-1可能是通过抑制肿瘤血管生成来抑制肿瘤生长的关键宿主反应。此外，这项工作涉及使用血小板中的血小板反应蛋白-1水平作为肿瘤生长和消退的指标。（血。2010; 115（22）：4605-4613）
The sequential events leading to tumor progression include a switch to the angiogenic phenotype, dependent on a shift in the balance between positive and negative angiogenic regulators produced by tumor and stromal cells. Although the biologic properties of many angiogenesis regulatory proteins have been studied in detail, the mechanisms of their transport and delivery in vivo during pathologic angiogenesis are not well understood. Here, we demonstrate that expression of one of the most potent angiogenesis inhibitors, thrombospondin-1, is up-regulated in the platelets of tumor-bearing mice. We establish that this up-regulation is a consequence of both increased levels of thrombospondin-1 mRNA in megakaryocytes, as well as increased numbers of megakaryocytes in the bone marrow of tumor-bearing mice. Through the use of mouse tumor models and bone marrow transplantations, we show that platelet-derived thrombospondin-1 is a critical negative regulator during the early stages of tumor angiogenesis. Collectively, our data suggest that the production and delivery of the endogenous angiogenesis inhibitor thrombospondin-1 by platelets may be a critical host response to suppress tumor growth through inhibiting tumor angiogenesis. Further, this work implicates the use of thrombospondin-1 levels in platelets as an indicator of tumor growth and regression. (Blood. 2010; 115(22): 4605-4613)