Vascular endothelial-specific cadherin (VE-cadherin) is an endothelial cell-specific adhesion molecule, localized at cell-cell contact sites. It is involved in physiological and pathological angiogenesis. In this study, we showed that in vitro a soluble N-terminal fragment of VE-cadherin (EC1-3) corresponding to cadherin 1-3 ectodomains inhibited vascular endothelial growth factor-stimulated endothelial cell proliferation and capillary tube structure formation in the matrigel model. In vivo, EC1-3 was tested in a murine colon cancer model. EC1-3-expressing colon cancer C51 cells were subcutaneously grafted into nude mice, and tumor growth and angiogenesis were evaluated. At day 33, the mean volume of the tumors developed was reduced (510±104 versus 990±120 mm(3) for control). Similarly, injection of EC1-3 virus-producing cells into established C51 tumors resulted in an inhibition by 33% of tumor growth. Immunohistological staining of vessels on tumor sections showed a significantly reduced intratumoral angiogenesis. Furthermore, EC1-3 did not induce vessel injury in the lung, liver, spleen, heart and brain in the mice. These results suggest that the soluble N-terminal fragment of VE-cadherin EC1-3 could exert an antitumoral effect by targeting tumor angiogenesis, which included blocking endothelial cell proliferation and capillary tube formation with no obvious toxicity on normal organs.