Targeting the transforming growth factor-beta signaling pathway in human cancer.

Nagaraj NS, Datta PK
Expert Opin Investig Drugs. 2010 19 (1): 77-91

PMID: 20001556 · PMCID: PMC2796203 · DOI:10.1517/13543780903382609

The transforming growth factor-ss (TGF-beta) signaling pathway plays a pivotal role in diverse cellular processes. TGF-beta switches its role from a tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers. It is widely believed that the Smad-dependent pathway is involved in TGF-beta tumor-suppressive functions, whereas activation of Smad-independent pathways, coupled with the loss of tumor-suppressor functions of TGF-beta, is important for its pro-oncogenic functions. TGF-beta signaling has been considered a useful therapeutic target. The discovery of oncogenic actions of TGF-beta has generated a great deal of enthusiasm for developing TGF-beta signaling inhibitors for the treatment of cancer. The challenge is to identify the group of patients where targeted tumors are not only refractory to TGF-beta-induced tumor suppressor functions but also responsive to the tumor-promoting effects of TGF-beta. TGF-beta pathway inhibitors, including small and large molecules, have now entered clinical trials. Preclinical studies with these inhibitors have shown promise in a variety of different tumor models. Here, we focus on the mechanisms of signaling and specific targets of the TGF-beta pathway that are critical effectors of tumor progression and invasion. This report also examines the therapeutic intervention of TGF-ss signaling in human cancers.

MeSH Terms (9)

Antineoplastic Agents Clinical Trials as Topic Drug Discovery Humans Neoplasms Oligonucleotides, Antisense Signal Transduction Small Molecule Libraries Transforming Growth Factor beta

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