Thrombospondin-4 mediates TGF-β-induced angiogenesis.
Thrombospondin-4 mediates TGF-β-induced angiogenesis.
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DOI：
10.1038/onc.2017.140
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发表时间：
2017-09-07
期刊：
影响因子：
8
通讯作者：
Stenina-Adognravi O
中科院分区：
文献类型：
--
作者：
Muppala S;Xiao R;Krukovets I;Verbovetsky D;Yendamuri R;Habib N;Raman P;Plow E;Stenina-Adognravi O
转化生长因子-β是一种多功能细胞因子，影响多种细胞类型，参与组织重塑过程。由于其多种功能和细胞特异性效应，转化生长因子-β信号转导的结果是过程和阶段依赖的，并且转化生长因子-β在疾病进展过程中发挥不同的、有时相反的作用并不少见，取决于不同的阶段和与该阶段相关的病理变化。转化生长因子-β的细胞特异性和过程特异性作用的机制尚不清楚。我们描述了一种新的途径，它介导了转化生长因子-β1对血管生成的诱导。我们发现，在内皮细胞(EC)TSP-4中，分泌的细胞外基质(ECM)蛋白在转化生长因子-β1的响应下上调，并介导转化生长因子-β1对血管生成的影响。TSP-4的上调不需要合成新的蛋白质，也不是由TSP-4的分泌减少引起的，而是通过激活Smad3来介导的。利用Thbs4−/−小鼠和TSP-4shRNA，我们发现TSP-4对培养的EC和体内血管生成有促进血管生成的作用。我们观察到注射转化生长因子-β1的动物肿瘤质量和血管生成标志物水平增加~3倍，而Thbs4−/−动物没有这种作用。注射转化生长因子-β1信号转导抑制剂SB431542也可减轻肿瘤重量和肿瘤血管生成。我们在体内血管生成模型和培养的内皮细胞文献中的结果表明，TSP-4介导转化生长因子-β上调血管生成1.促血管生成的TSP-4的上调和TSP-4对EC的选择性作用可能有助于转化生长因子-β在抑制癌细胞增殖的情况下刺激肿瘤生长。
TGF-β is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-β signaling are process-and stage-dependent, and it is not uncommon that TGF-β exerts distinct and sometimes opposing effects on a disease progression depending on the stage and on the pathological changes associated with the stage. The mechanisms underlying cell- and process-specific effects of TGF-β are poorly understood. We are describing a novel pathway that mediates induction of angiogenesis in response to TGF-β1. We found that in endothelial cells (EC) TSP-4, a secreted extracellular matrix (ECM) protein is upregulated in response to TGF-β1 and mediates the effects of TGF-β1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of new protein, is not caused by decreased secretion of TSP-4, and is mediated by activation of SMAD3. Using Thbs4−/− mice and TSP-4 shRNA, we found that TSP-4 mediated pro-angiogenic functions on cultured EC and angiogenesis in vivo in response to TGF-β1. We observed ~ 3-fold increases in tumor mass and levels of angiogenesis markers in animals injected with TGF-β1, and these effects did not occur in Thbs4−/− animals. Injections of an inhibitor of TGF-β1 signaling SB431542 also decreased the weights of tumors and cancer angiogenesis. Our results from in vivo angiogenesis models and cultured EC document that TSP-4 mediates upregulation of angiogenesis by TGF-β1. Upregulation of pro-angiogenic TSP-4 and selective effects of TSP-4 on EC may contribute to stimulation of tumor growth by TGF-β despite the inhibition of cancer cell proliferation.
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