Platelets support tumor growth by promoting angiogenesis (Searching for the angiogenic switch)

我们之前报道过，包括趋化因子在内的细胞因子或辐照等生物应激源可以通过激活基质金属蛋白酶-9，动员和分化包括巨核细胞在内的造血祖细胞来促进Kit配体的加工。为了了解血小板在支持肿瘤生长中的作用，我们首先研究了这些细胞在巨核细胞活性趋化因子如基质细胞衍生因子-1 （SDF-1）的影响下如何增加。2004年，我们发表了趋化因子介导的巨核细胞祖细胞与骨髓内皮细胞的相互作用促进了tpo不依赖的血小板产生。我们报道了巨核细胞活性趋化因子，包括SDF-1和成纤维细胞生长因子-4 (FGF-4)，可以恢复TPO-/-小鼠的血小板生成。FGF-4和SDF-1增强黏附分子介导的CXCR4+巨核细胞祖细胞向内皮的定位，促进成熟和血小板释放。在生理条件下，更环境的“血管生态位”或对巨核细胞运动的干扰会抑制血小板生成。骨髓抑制后，SDF-1和FGF-4可减少血小板减少。这些数据表明，TPO支持祖细胞扩增，而趋化因子介导的祖细胞与BM血管生态位的相互作用允许祖细胞迁移到一个微环境中，这对巨核细胞成熟和血小板产生具有指导意义。祖活性趋化因子提供了一个新的策略，以恢复造血在临床设置。其他人和我们已经证明脑转移源性造血细胞有助于肿瘤血管生成和生长。由于vegf激活的血小板释放血管生成因子，我们假设血小板生成促进肿瘤血管生成和生长。我们证明了血栓细胞对肿瘤血管生成和生长至关重要，因为在血小板生成小鼠（TPO-/和TPO受体-/-）中肿瘤生长和血管生成严重受损。我们现在有数据显示，TPO小鼠的新血管生成受损，导致形成有缺陷的、无组织的渗漏血管。我们的数据不仅确定了血小板促进肿瘤生长的新机制，更重要的是挑战了在癌症患者中使用非必需血小板输注，因为输注血小板可能促进肿瘤生长。少

We reported previously, that cytokines including chemokines or biological stressors like irradiation can promotes the processing of Kit ligand through activation of matrix metalloproteinase-9, mobilization and differentiation of hematopoietic progenitor cells including megakaryocytes. To understand the involvement of platelets in supporting tumor growth we first examined how these cells ncrease under the influence of megakaryocytic-active chemokines such as stromal-cell derived factor-1 (SDF-1). In 2004, we published that chemokine-mediated interactions of megakaryocyte progenitors with bone marrow (BM) endothelial cells promote TPO-independent platelet production. We reported that megakaryocyte-active chemokines, including SDF-1 and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in TPO-/-mice. FGF-4 and SDF-1 enhanced adhesion molecule-mediated localization of CXCR4+ megakaryocyte progenitors to endothelium, promoting maturation and platelet release. Disruption of BM micr … More oenvironmental "vascular niche" or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggested that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the BM vascular niche allows progenitors to relocate to a microenvironment that is instructive for megakaryocyte maturation and platelet production. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.Others and we have shown that BM-derived hematopoietic cells contribute to tumor angiogenesis and growth. As VEGF-activated platelets release angiogenic factors we hypothesized that thrombopoiesis promotes tumor angiogenesis and growth. We demonstrated that thrombocytes are essential for tumor angiogenesis and growth as tumor growth and angiogenesis was profoundly impaired in thrombocytopoietic mice (TPO-/-and TPO receptor-/-). We now have data showing that neo-angiogenesis is impaired in TPO mice resulting in the formation of defective, disorganized leaky vessels. Our data not only identify a novel mechanism how platelets promote tumor growth, but more importantly challenge the use of non-essential platelet transfusion in cancer patients as transfused platelet might promote tumor growth. Less