β-Catenin Regulates Vascular Endothelial Growth Factor Expression in Colon Cancer

To evaluate whether β-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for β-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor ( VEGF , or VEGF-A ) contains seven consensus binding sites for β-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli ( APC ) mutational status (activation of β-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene ( Min /+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear β-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated β-catenin up-regulated levels of VEGF-A mRNA and protein by 250–300%. When colon cancer cells with elevated β-catenin levels were treated with β-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between β-catenin signaling and the regulation of VEGF-A expression in colon cancer.