The expression of vascular endothelial growth factor (VEGF), a highly potent angiogenic molecule, is thought to be correlated with the development of colon cancer; however, direct evidence for a role of VEGF in metastasis is lacking. This study was designed to more directly establish the role of VEGF in the growth and metastasis of human colon cancer using a genetically engineered cancer cell line. A stable VEGF gene-transfected human colon cancer cell line, LoVo, was made by genetic manipulation using eukaryotic expression constructs designed to express the complete VEGF₁₂₁ cDNA in the sense orientation. Transfected clones were screened for VEGF₁₂₁ mRNA expression by Northern blot analysis and for VEGF₁₂₁protein expression by Western blot analysis. Consequently, we obtained S17 cells that expressed a high level of both VEGF mRNA and VEGF protein. A vector-transfected clone (V7 cell) was used as a control. The experiment with the dorsal air sac method revealed that S17 cells elicited a stronger directional outgrowth of capillaries than V7 cells. S17 cells formed faster-growing tumors than did V7 cells when xenografted s.c. into nude mice, although there was no significant difference in their in vitro proliferation. Tumors derived from S17 cells had more vascularity, as assessed by counting capillary vessels after staining with factor VIII, than did tumors derived from V7 cells (P < 0.05). With regard to the metastatic potential, S17 cells exhibited a higher capacity for both hepatic metastasis after the splenic portal inoculation and peritoneal dissemination after i.p. injection than did V7 cells. However, S17 cells showed no apparent metastasis, despite their rapid growth after orthotopic implantation. In conclusion, the present study showed clearly that VEGF plays an important role in cancer growth due to stimulation of angiogenesis by accelerating cell growth after reaching the target organs.