Targeting transforming growth factor-beta signaling.
OBJECTIVE
Most cancers are characterized by excessive transforming growth factor-beta production by tumors, which can promote tumor growth and mediate epithelial-to-mesenchymal transition. Transforming growth factor-beta 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-beta 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.


RESULTS
Four main strategies used most recently for disrupting transforming growth factor-beta signaling are brought into focus in this review: inhibition or sequestration of the transforming growth factor-beta protein ligands, inhibition of transforming growth factor-beta receptor kinase activity, inhibition of SMAD signaling downstream of transforming growth factor-beta kinase activity and restoration of antitumor immunity upon transforming growth factor-beta inhibition. Various techniques currently used to employ these four strategies are discussed.


CONCLUSIONS
Several lines of evidence suggest that altered transforming growth factor-beta 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-beta signaling is a promising novel therapeutic approach in cancer and fibrotic disorders.
Pennison
Michael
M
Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Pasche
Boris
B
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D008024:Ligands; D016212:Transforming Growth Factor beta