ALK1 as an emerging target for antiangiogenic therapy of cancer

Members of the TGF-beta family act on many, if not all, cell types within the body, producing diverse and complex cellular outcomes. Activation of the endothelial cell-restricted TGF-beta type I receptor ALK1 results from the binding of several different ligands of the TGF-beta family, including bone morphogenetic protein (BMP) 9, BMP10, and TGF-beta. Mounting genetic, pharmacologic, and histopathologic evidence supports a critical role for ALK1 signaling in regulation of both developmental and pathologic blood vessel formation. However, the precise function of TGF-beta family signaling in endothelial cells is difficult to predict and appears highly context dependent because of the multitude of ligands and receptors influencing the final outcome. Pharmacologic inhibitors of ALK1 have recently been developed and will allow for more accurate studies of ALK1 function in vivo, as well as for assessment of ALK1 as a target for suppression of angiogenesis during tumor development. Herein, we will summarize the current view of ALK1 regulation of endothelial cell phenotype in vitro and in vivo as well as provide an outlook for the ongoing clinical trials of ALK1 inhibitors in malignant disease. (Blood.2011;117(26):6999-7006)