Tumor Endothelial Cells Express Epidermal Growth Factor Receptor (EGFR) but not ErbB3 and Are Responsive to EGF and to EGFR Kinase Inhibitors

Abstract

Epidermal growth factor (EGF) receptor family members are expressed by tumor cells and contribute to tumor progression. The expression and activity of EGF receptors in endothelial cells are less well characterized. Analysis of tumor-derived endothelial cells showed that they express EGFR, ErbB2, and ErbB4, whereas their normal counterparts express ErbB2, ErbB3, and ErbB4. The gain in expression of EGFR and the loss of ErbB3 expression in tumor vasculature was also observed in vivo. As a consequence of their expressing EGFR, tumor endothelial cells responded to EGF and other EGF family members by activating both EGFR and ErbB2, by activating the downstream mitogen-activated protein kinase pathway, and by enhanced proliferation. On the other hand, normal endothelial cells did not respond to EGF but instead were responsive to neuregulin (NRG), a ligand for ErbB3 and ErbB4. NRG activated ErbB3 in normal endothelial cells and inhibited growth of these cells. In contrast, tumor endothelial cells, which do not express ErbB3, were not growth inhibited by NRG. Furthermore, due to their expression of EGFR, tumor endothelial cells, unlike normal endothelial cells, are direct targets for EGFR kinase inhibitors. These low-molecular-weight compounds block EGF-induced EGFR activation and proliferation of tumor endothelial cells. These results suggest that a gain of EGF-induced endothelial cell proliferation, and loss of NRG-induced growth inhibition in tumor endothelial cells constitutes a switch that promotes tumor angiogenesis. In addition, these results suggest that EGFR kinase inhibitors may be effective for antiangiogenesis therapy by specifically targeting the tumor, but not the normal, vasculature. (Cancer Res 2006; 66(4): 2173-80)

Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro

“…These comparative studies, which focused solely on differences in canonical biochemical signaling pathways, revealed that tumor CE cells exhibit altered growth factor signaling arising from differential expression of important growth factor receptors (30,32). Here, we show that tumor CE cells also exhibit aberrant Rho-mediated mechanosensitivity to physical cues from the ECM that are equally important for control of vascular development, and thus, these findings may have important implications for abnormal tumor angiogenesis.…”

Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells

“…Tumor endothelial cells express EGFR and are responsive to pro-angiogenic stimuli mediated by EGF. 25 Here, we report that EGF induces Bcl-x L expression in primary endothelial cells, and has a potent angiogenic effect in vitro. Endothelial cells transduced with shRNA-Bcl-x L were significantly less responsive to the pro-angiogenic signal mediated by EGF than endothelial cells transduced with an empty vector control lentivirus.…”

Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation

“…EGFR has been shown to be expressed in tumor endothelial cells, while undetectable in their normal counterparts, and plays a role in their proliferative phenotype (66). In addition, MT1-MMP is also expressed in angiogenic endothelial cells and is well known to be an important regulator of angiogenesis (3,(11)(12)(13)67).…”