Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis

Smad4/DPC4 (deleted in pancreatic carcinoma, locus 4) is a tumor suppressor gene lost at high frequency in cancers of the pancreas and other gastroint estinal organs. Smad4 encodes a key intracellular messenger in the transfor ming growth factor beta (TGF-beta) signaling cascade. TGF-beta is a potent inhibitor of the growth of epithelial cells; thus, it has been assumed that loss of Smad4 during tumor progression relieves this inhibition. Herein, w e show that restoration of Smad4 to human pancreatic carcinoma cells suppre ssed tumor formation in vivo, yet it did not restore sensitivity to TGF-bet a. Rather, Smad4 restoration influenced angiogenesis, decreasing expression of vascular endothelial growth factor and increasing expression of thrombo spondin-1, In contrast to the parental cell line and to control transfectan ts that produced rapidly growing tumors in vivo, Smad4 revertants induced s mall nonprogressive tumors with reduced Vascular density. These data define the control of an angiogenic switch as an alternative, previously unknown mechanism of tumor suppression for Smad4 and identify the angiogenic mediat ors vascular endothelial growth factor and thrombospondin-1 as key target g enes.