Antibody against vascular endothelial growth factor (VEGF) inhibits angiogenic switch and liver metastasis in orthotopic xenograft model with site-dependent expression of VEGF

We previously reported that upregulation of angiogenesis, i.e. angiogenic switch (AS), may occur simultaneously to initiation of invasion in the early development of human colon cancer. We also showed that mRNA upregulation of the gene of vascular endothelial growth factor (VEGF) occurs immediately prior to metastasis in human colon cancer in an orthotopic nude mouse model of colon cancer liver metastasis. In this paper, we studied whether the antibody against VEGF inhibits AS and liver metastasis in an orthotopic xenograft model with site-dependent expression of VEGF. We examined levels of vessel density, VEGF mRNA by in situ hybridization (ISH) method and liver metastasis in pre-AS (on days 8 and 11) and post-AS (on days 15 and 18) treatment groups. The mean vessel density and the intensity of VEGF mRNA by ISH in the pre-AS treatment group were significantly lower than those for the post-AS treatment and the control group. Liver metastases were completely inhibited (0/10) in the pre-AS treatment, while they occurred in 4 out of 10 and 5 out of 10 mice in the post-AS treatment and the control groups, respectively (p<0.01). These results suggest that VEGF antibody treatment performed before AS could efficiently inhibit AS and liver metastasis, which may indicate that VEGF antibody has another potential as a drug for chemoprevention of colon cancer.