Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Blood. 2010 Jun 3;115(22):4605-13. doi: 10.1182/blood-2009-09-242065. Epub 2010 Jan 19.
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.
导致肿瘤进展的连续事件包括向血管生成表型的转变，这依赖于肿瘤和基质细胞产生的正性和负性血管生成调节剂之间平衡的改变。虽然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运输和递释机制尚不清楚。在这里，我们证明了一种最有效的血管生成抑制剂——血小板反应蛋白-1在荷瘤小鼠的血小板中表达上调。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，我们表明血小板衍生的血小板反应蛋白-1是肿瘤血管生成早期的一个关键负性调节因子。总的来说，我们的数据表明，血小板产生和递释内源性血管生成抑制剂血小板反应蛋白-1可能是宿主抑制肿瘤生长的关键反应，通过抑制肿瘤血管生成。此外，这项工作表明血小板中血小板反应蛋白-1水平可作为肿瘤生长和消退的指标。
