Transforming growth factor‐β and Ras regulate the VEGF/VEGF‐receptor system during tumor angiogenesis

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Abstract
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‐β1 and hypoxia are potent inducers of VEGF expression in these cells. VEGF induction in the tumor periphery is mainly triggered by TGF‐β1, whereas VEGF expression in perinecrotic areas is regulated by both hypoxia and TGF‐β1. As the Ras‐transformed tumor cells convert into migrating, fibroblastoid cells that start to produce TGF‐β during tumor progression, the TGF‐β effect on VEGF expression becomes propagated throughout the tumor tissue. Thus, in progressed tumors, areas of TGF‐β1 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.