Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer.
TGFβ signaling Smads (Smad2, 3, and 4) were suspected tumor suppressors soon after their discovery. Nearly two decades of research confirmed this role and revealed other divergent and cancer-specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context-specific as exemplified by pancreatic cancer and head-and-neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head-and-neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. The differing consequences of impaired Smad signaling in human cancers and the molecular mechanisms that underpin these differences will have important implications for the design and application of novel targeted therapies.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States.
Stephen P
SP
Malkoski
Xiao-Jing
XJ
Wang
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D018450:Disease Progression; D005199:Fanconi Anemia / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D044483:Intestinal Polyposis / Q000151:congenital / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D009386:Neoplastic Syndromes, Hereditary; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism
C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta