Dentin Matrix Protein 1 inhibits VEGF‐induced angiogenesis and impairs tumor growth

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin‐Binding LIgand N‐linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis. Although pro‐angiogenic activities have been demonstrated for two SIBLINGs, the role of DMP1 in angiogenesis has not been addressed yet. We demonstrated that this secreted protein induced the expression of VE‐cadherin, a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate VEGFR‐2 activity, the major receptor for VEGF. DMP1 induced VE‐cadherin and p27Kip1 expression followed by cell cycle arrest in human umbilical endothelial vein cells (HUVEC) in a CD44‐dependent manner. VEGF‐induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre‐treatment of HUVEC. Indeed, subsequently to VE‐cadherin induction, DMP1 inhibited VEGFR‐2 phosphorylation and Src‐mediated signaling. In vivo, DMP1 significantly inhibited tumor‐associated angiogenesis. These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF‐induced angiogenesis.