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Abstract
The dual effects of TGF-β signaling on tumor initiation and progression are cell-specific and yet to be determined under distinct contexts. A
number of genetically manipulated mouse models with alterations in the TGF-β pathway
genes, particularly the pivotal Smad4, revealed that these genes play crucial functions in
maintaining tissue homeostasis and suppressing tumorigenesis. Loss of Smad4 plays a causal
role in initiating squamous cell carcinomas of skin and upper digestive tract as well as adenocarcinomas of gastrointestinal tract. However, for some cancers like pancreatic and
cholangiocellular carcinomas, Smad4 deficiency does not initiate the tumorigenesis but acts
as a promoter to accelerate or synergize the development and progression of cancers that
are started by other oncogenic pathways. Intriguingly, emerging evidences from mouse
models have highlighted the important roles of non-cell autonomous effects of
Smad4-mediated TGF-β signaling in the inhibition of oncogenesis. All these data have greatly
deepened our understanding of molecular mechanisms of cell-autonomous and non-cell
autonomous effect of Smad4-mediated TGF-β signaling in suppressing carcinogenesis, which
may facilitate the development of successful therapies targeting TGF-β signaling for the
treatment of human cancers.
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