Transforming growth factor-β and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis
Transforming growth factor-β and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis
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DOI：
10.1002/ijc.1599
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发表时间：
2002-01-10
影响因子：
6.4
通讯作者：
Reichmann, E
中科院分区：
文献类型：
--
作者：
Breier, G;Blum, S;Reichmann, E
通过毛细血管发芽或血管生成形成新的微血管是实体肿瘤生长的先决条件。在肿瘤血管生成中激活血管生成程序所需的遗传改变仍然只是模糊地知道，但占主导地位的癌蛋白可能具有比以前认识到的更大的影响。在这里，我们研究了在小鼠乳腺癌模型中致癌转化对肿瘤血管生成的影响。我们提供的证据表明，表达血管内皮生长因子（VEGF）和VEGF受体-2（Flk-1），一个信号系统集中参与肿瘤血管生成，有效地发生在由Ras转化的乳腺上皮细胞形成的肿瘤中，TGF-β 1和缺氧都是这些细胞中VEGF表达的有效诱导剂。肿瘤周边的VEGF诱导主要由TGF-β 1触发，而坏死周围区域的VEGF表达受缺氧和TGF-β 1调节。随着Ras转化的肿瘤细胞转化为迁移的成纤维细胞样细胞，其在肿瘤进展期间开始产生TGF-β，TGF-β对VEGF表达的影响在整个肿瘤组织中传播。因此，在进展的肿瘤中，TGF-β 1活化和缺氧的区域可能重叠，因此协同诱导VEGF表达和血管生成。然而，VEGF在非Ras转化的小鼠乳腺上皮细胞中的过表达不足以促进体内血管形成。基于这些发现，我们得出结论，在使正常细胞致瘤的多个突变中，致癌Ras是与肿瘤的微环境一起为肿瘤细胞侵袭和血管生成设置阶段的主要参与者。(C)2002 Wiley-Liss，Inc.
The formation of new microvasculature by capillary sprouting, or angiogenesis, is a prerequisite for solid tumor growth. The genetic alterations required to activate the angiogenic program in tumor angiogenesis are still only vaguely known, but dominantly acting oncoproteins may have a much greater impact than previously realized. Here we have studied the consequences of oncogenic transformation on tumor angiogenesis in a mouse mammary carcinoma model. We provide evidence that the expression of vascular endothelial growth factor (VEGF) and of the VEGF receptor-2 (Flk-1), a signaling system centrally involved in tumor angiogenesis, occurs efficiently in tumors formed by Ras-transformed mammary epithelial cells and that both TGF-P I and hypoxia are potent inducers of VEGF expression in these cells. VEGF induction in the tumor periphery is mainly triggered by TGF-beta1, whereas VEGF expression in perinecrotic areas is regulated by both hypoxia and TGF-beta1. As the Ras-transformed tumor cells convert into migrating, fibroblastoid cells that start to produce TGF-beta during tumor progression, the TGF-beta effect on VEGF expression becomes propagated throughout the tumor tissue. Thus, in progressed tumors, areas of TGF-beta1 activation and hypoxia may overlap and hence cooperate to induce VEGF expression and angiogenesis. Nevertheless, the overexpression of VEGF in non-Ras-transformed mouse mammary epithelial cells was not sufficient to promote vascularization in vivo. Based on these findings, we conclude that amongst the multiple mutations that render a normal cell tumorigenic, oncogenic Ras is a major player that in conjunction with the tumor's micro-environment sets the stage for tumor cell invasion and angiogenesis. (C) 2002 Wiley-Liss, Inc.