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 gastrointestinal organs. Smad4 encodes a key intracellular messenger in the transforming 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, we show that restoration of Smad4 to human pancreatic carcinoma cells suppressed tumor formation in vivo, yet it did not restore sensitivity to TGF-beta. Rather, Smad4 restoration influenced angiogenesis, decreasing expression of vascular endothelial growth factor and increasing expression of thrombospondin-1. In contrast to the parental cell line and to control transfectants that produced rapidly growing tumors in vivo, Smad4 revertants induced small 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 mediators vascular endothelial growth factor and thrombospondin-1 as key target genes.
Schwarte-Waldhoff
I
I
Immunologisch-Molekularbiologisches Labor, Medizinische Universitätsklinik Bochum, Knappschaftskrankenhaus, Ruhr-Universität Bochum, Germany.
Volpert
O V
OV
Bouck
N P
NP
Sipos
B
B
Hahn
S A
SA
Klein-Scory
S
S
Lüttges
J
J
Klöppel
G
G
Graeven
U
U
Eilert-Micus
C
C
Hintelmann
A
A
Schmiegel
W
W
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D016147:Genes, Tumor Suppressor / Q000235:genetics; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051901:Smad4 Protein; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D019700:Thrombospondin 1; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2