PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells
PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells
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DOI：
10.1038/nm.2575
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发表时间：
2012-01-01
期刊：
影响因子：
82.9
通讯作者：
Cao, Yihai
中科院分区：
文献类型：
--
作者：
Xue, Yuan;Lim, Sharon;Cao, Yihai
血小板衍生生长因子(PDGF)信号系统参与肿瘤血管生成和血管重塑。在这里，我们展示了在小鼠肿瘤模型中，PDGF-BB通过靶向表达PDGF受体-β(PDGFR-β)的基质细胞和血管周围细胞来诱导促红细胞生成素(EPO)的mRNA和蛋白表达。肿瘤来源的PDGF-BB至少部分通过调节EPO的表达来促进肿瘤的生长、血管生成和髓外造血。此外，将PDGF-BB腺病毒转移到无肿瘤的小鼠体内，既增加了EPO的产生，又增加了红细胞生成，并保护了小鼠免受辐射诱导的贫血。在分子水平上，我们发现PDGF-BB PDGFR-beta信号系统激活EPO启动子，部分是通过转录因子ATF3的转录调节作用，可能是通过它与另外两个转录因子c-jun和Sp1的结合。我们的发现表明，PDGF-BB诱导的EPO通过两种机制促进肿瘤生长：第一，通过直接诱导内皮细胞增殖、迁移、萌发和管状形成，旁分泌刺激肿瘤血管生成；第二，内分泌刺激髓外造血，增加氧气供应，预防肿瘤相关性贫血。
The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here we show in mouse tumor models that PDGF-BB induces erythropoietin (EPO) mRNA and protein expression by targeting stromal and perivascular cells that express PDGF receptor-beta (PDGFR-beta). Tumor-derived PDGF-BB promoted tumor growth, angiogenesis and extramedullary hematopoiesis at least in part through modulation of EPO expression. Moreover, adenoviral delivery of PDGF-BB to tumor-free mice increased both EPO production and erythropoiesis, as well as protecting from irradiation-induced anemia. At the molecular level, we show that the PDGF-BB PDGFR-beta signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB-induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.