Targeting aberrant TGF-beta signaling in pre-clinical models of cancer.
The TGF-beta signaling pathway is central to the control of diverse biological processes including cellular proliferation, cell survival, apoptosis, extracellular matrix deposition/remodeling, migration, invasion and immune regulation/inflammation. Given the pleiotropic effects of this cytokine, it comes as no surprise that numerous pathological conditions are associated with alterations in the TGF-beta pathway, including chronic fibrosis, airway remodeling (asthma), cardiovascular disease and cancer. Thus, there are increasing efforts to develop reagents and therapeutic strategies to impair TGF-beta signaling. Here we review several classes of inhibitors, including knock-down strategies aimed at signaling components of the TGF-beta pathway, TGF-beta neutralizing antibodies, TGF-beta receptor extracellular domains that function as ligand traps and small molecule kinase inhibitors. Strategies with potential for application as anti-cancer therapeutics that have been evaluated in pre-clinical animal models will be discussed. TGF-beta action is complex, shifting from a tumor suppressor to a promoter of tumor cell invasion and metastasis in several types of cancer. This raises important issues regarding not only the status of the TGF-beta pathway in the individual patient but also the precise stage during disease progression that such inhibitors should be employed. Potential consequences of targeting the TGF-beta pathway will also be considered.
Mourskaia
Anna Alexeyevna
AA
Department of Medicine, McGill University, Montréal, Québec, Canada.
Northey
Jason Jonathan
JJ
Siegel
Peter Michael
PM
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta