Colorectal carcinoma cell production of transforming growth factor beta decreases expression of endothelial cell vascular endothelial growth factor receptor 2

Abstract

Vascular endothelial growth factor (VEGF) signaling is a target for antiangiogenic cancer therapy. The authors have previously observed that up to 40% of vessels in colorectal carcinoma (CRC) tumors are negative for VEGF receptor 2 (VEGFR2) expression. Differential activity of transforming growth factor beta (TGF-β) is a potential contributor to this receptor heterogeneity because TGF-β contributes to both angiogenesis and CRC tumor progression. The authors analyzed VEGFR2 expression by Western blotting, and TGF-β expression in endothelial and CRC cell lines, respectively. In addition, they immunostained endothelial cells in CRC xenografts to find an association between VEGFR2 and TGF-β levels or activity. In bovine aortic endothelial cells (BAECs), TGF-β1 significantly repressed VEGFR2 protein in a time-dependent and dose-dependent fashion (P < .05). Serum-free conditioned media from various malignant human CRC cell lines (HCT116, 379.2, Dks8, and DLD1) induced down-regulation of VEGFR2 in BAECs. This effect was proportional to the total levels of TGF-β1 and TGF-β2 and was blocked by SB-431542 and SD-208, TGF-β receptor I inhibitors. Immunofluorescence staining of subcutaneous mouse xenografts of HCT116, 379.2, Dks8, and SW480 cells revealed vessels with an inverse relationship between TGF-β activity and VEGFR2 expression. Oxygen and bone morphogenetic protein 9 levels were shown to modulate TGF-β-induced VEGFR2 down-regulation. In combination with other factors, TGF-β may contribute to the vascular heterogeneity in human colorectal tumors.