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నైరూప్య

New Strategies to Target the TGF Smad Signaling Pathway in Cancer

Byung-Gyu Kim and James J Driscoll

The Transforming Growth Factor (TGF)-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a ubiquitous, multifunctional cytokine secreted by nearly all cell types that binds transmembrane TGF-β type I and II receptors to activate downstream pathways through intercellular SMAD transcriptional effectors. Deregulated inter-and intracellular TGF-β signaling contributes to cancer initiation and progression. In healthy cells and early stage cancers, TGF-β arrests epithelial growth and functions as a tumor suppressor. Later, after cancers have progressed, the cytostatic effects of TGF-β are circumvented, and TGF-β signaling exerts tumor promoting activities. TGF-β has been shown to induce epithelial-to-mesenchymal transition, stimulate angiogenesis, and contribute to immune evasion [1-3]. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Thus, based upon a wealth of preclinical and translational studies, the TGF-β signaling pathway has emerged as a highly attractive, actionable target that can be pharmacologically modulated to reduce tumor growth and improve the outcomes of cancer patients. Here, we comment on recent exciting and highly promising strategies that have been employed to target the TGF-β signaling pathway.