Luo Yu-Wei, Fang Yang, Zeng Hui-Xian, Ji Yu-Chen, Wu Meng-Zhi, Li Hui, Chen Jie-Ying, Zheng Li-Min, Fang Jian-Hong, Zhuang Shi-Mei
MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, P. R. China.
Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
Cancer Res. 2025 Jan 2;85(1):69-83. doi: 10.1158/0008-5472.CAN-24-2324.
Emerging evidence suggests that TGFβ1 can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the antiangiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiologic angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the antiangiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating antiangiogenic factor thrombospondin 1 (TSP1) in endothelial cells (EC) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced miR145 expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma displayed increased miR145 and decreased SMAD3 and TSP1 compared with ECs from adjacent nontumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in hepatocellular carcinoma tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis. Significance: Suppression of angiogenesis by TGFβ1 is mediated by TSP1 upregulation in endothelial cells and abrogated by HIF1α-miR145 activity in the hypoxic tumor microenvironment, providing potential targets to remodel the tumor vasculature.
新出现的证据表明，转化生长因子β1（TGFβ1）可抑制血管生成，这与肿瘤微环境中活跃的血管生成和高丰度的TGFβ1并存相矛盾。在此，我们研究了肿瘤如何克服TGFβ1的抗血管生成作用。TGFβ1处理抑制了鸡胚绒毛尿囊膜和斑马鱼模型中的生理性血管生成，但不影响小鼠肝癌异种移植瘤中的血管生成。通过缺氧诱导因子1α（HIF1α）抑制剂可恢复TGFβ1对小鼠异种移植瘤血管生成的抑制作用。相反，HIF1α稳定剂可消除斑马鱼中的血管生成，表明缺氧可能减弱TGFβ1的抗血管生成作用。在常氧条件下，TGFβ1通过TGFβⅠ型受体（TGFβR1）-SMAD2/3信号通路上调内皮细胞（EC）中的抗血管生成因子血小板反应蛋白1（TSP1）来抑制血管生成。在缺氧微环境中，HIF1α诱导miR145表达；miR145通过结合并抑制SMAD2/3表达，进而降低EC中TSP1水平，消除了TGFβ1对血管生成的抑制作用。与来自相邻非肿瘤肝脏的EC相比，从人肝细胞癌中分离出的原代EC显示miR145增加，SMAD3和TSP1减少。EC中SMAD3或TSP1的减少与肝细胞癌组织中血管生成增加有关。总的来说，本研究确定EC中的TGFβ1-TGFβR1-SMAD2/3-TSP1信号通路抑制血管生成。这种抑制作用可被缺氧-HIF1α-miR145轴规避，阐明了缺氧促进血管生成的机制。意义：TGFβ1对血管生成的抑制作用是由内皮细胞中TSP1上调介导的，并在缺氧肿瘤微环境中被HIF1α-miR145活性消除，为重塑肿瘤血管提供了潜在靶点。
