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We recently characterized an anti-tumor protein termed angiocidin. Here, we report that angiocidin may inhibit angiogenesis by binding collagen and its receptors. Angiocidin bound purified type I collagen and α2β1 with high affinity. K562 cells expressing α2β1 bound and adhered to angiocidin while K562 cells which only expressed α5β1 integrin showed no binding and adhesion. Binding was specific since a neutralizing antibody against α2β1 inhibited binding but antibodies against α5β1 had no effect. Additionally, angiocidin co-localized with α2β1 on K562 α2β1 transfected cells, pancreatic cancer colo 357 cells, breast cancer MB-231 cells and human umbilical endothelial vein (HUVE) cells. In an α2β1-dependent collagen gel angiogenesis assay, angiocidin showed potent inhibitory activity. We identified a 20-amino-acid amino terminal peptide of angiocidin that bound both α2β1 and type I collagen. This peptide promoted α2β1-dependent cell adhesion and inhibited tumor growth and angiogenesis. Taken together, these results are consistent with the conclusion that the anti-tumor activity of angiocidin arises from its ability to ligate collagen and α2β1 on endothelial cells and tumor cells. Our results provide support for the concept that targeting matrix–cell interactions is a viable strategy for the development of anti-cancer therapeutics.