Targeting the transforming growth factor-beta signaling pathway in human cancer.
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.
Nagaraj
Nagathihalli S
NS
Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Department of Surgery, Nashville, TN 37232, USA.
Datta
Pran K
PK
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D054852:Small Molecule Libraries; D016212:Transforming Growth Factor beta