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

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

In combination with other factors, TGF‐β may contribute to the vascular heterogeneity in human colorectal tumors. Cancer 2011;. © 2011 American Cancer Society.