Abstract
The transforming growth factor (TGF-β) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-β signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-β pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however in tumor cells, TGF-β looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-β signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.
Highlights
Our understanding of molecular mechanisms that underlie cancer development and progression has increased, cancer remains a significant health concern in many developed countries
We review different molecular and cellular mechanisms that lead to impairment of Transforming Growth Factor-β (TGF-β) signaling in various solid tumors and hematological malignancies
TGF-β as a proto-oncogene is important in stromalepithelial cross-talk, as was shown for the first time in mouse experiments, where deletion of the TβRII in stromal fibroblasts resulted in transformation of adjacent epithelia of prostate and forestomach
Summary
Our understanding of molecular mechanisms that underlie cancer development and progression has increased, cancer remains a significant health concern in many developed countries. TGF-β as a proto-oncogene is important in stromalepithelial cross-talk, as was shown for the first time in mouse experiments, where deletion of the TβRII in stromal fibroblasts resulted in transformation of adjacent epithelia of prostate and forestomach In this model, hepatocyte growth factor (HGF) was upregulated and complementary activation of the HGF receptor MET was detected in tissues where TβRII had been ablated, which implicates this paracrine signaling network as a potential mechanism for regulation of carcinoma development [126]. When compared to other types of cancer, such as breast and colon, down-regulation of TβRs is found more often than mutations in SMADs. Kim et al compared protein levels of TβRI and TβRII in benign and malignant prostate tissues and observed that loss of receptors expression correlated with more advanced tumor [173]. This effect can be abrogated by inhibitors of TβRI kinase domain (reviewed in [281])
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