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Most cancers are characterized by excessive transforming growth factor-β production by tumors, which can promote tumor growth and mediate epithelial-to-mesenchymal transition. Transforming growth factor-β also has the ability to overproduce extracellular matrix components in response to injury and other stimuli. There are many strategies undergoing current evaluation for inhibiting the deleterious biological effects of transforming growth factor-β by disrupting its signaling at various levels. The current review focuses on the recent advances made in this area, and the potential of these strategies in the clinical treatment of cancer and fibrosis.Four main strategies used most recently for disrupting transforming growth factor-β signaling are brought into focus in this review: inhibition or sequestration of the transforming growth factor-β protein ligands, inhibition of transforming growth factor-β receptor kinase activity, inhibition of SMAD signaling downstream of transforming growth factor-β kinase activity and restoration of antitumor immunity upon transforming growth factor-β inhibition. Various techniques currently used to employ these four strategies are discuussed.Several lines of evidence suggest that altered transforming growth factor-β signaling contributes to tumor progression and metastasis as well as development of fibrosis. Accumulating data from preclinical and clinical studies indicate that antagonizing aberrant transforming growth factor-β signaling is a promising novel therapeutic approach in cancer and fibrotic disorders.