Abstract
The TGF-β 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-β 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-β signaling. Here we review several classes of inhibitors, including knockdown strategies aimed at signaling components of the TGF-β pathway, TGF-β neutralizing antibodies, TGF-β 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-β 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-β 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-β pathway will also be considered.
Keywords: TGF-β Pathway, antagonists, ligand-traps, knock-down strategies, kinase inhibitors, targeted therapies, pre-clinical models, cancer
Anti-Cancer Agents in Medicinal Chemistry
Title: Targeting Aberrant TGF-β Signaling in Pre-Clinical Models of Cancer
Volume: 7 Issue: 5
Author(s): Anna Alexeyevna Mourskaia, Jason Jonathan Northey and Peter Michael Siegel
Affiliation:
Keywords: TGF-β Pathway, antagonists, ligand-traps, knock-down strategies, kinase inhibitors, targeted therapies, pre-clinical models, cancer
Abstract: The TGF-β 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-β 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-β signaling. Here we review several classes of inhibitors, including knockdown strategies aimed at signaling components of the TGF-β pathway, TGF-β neutralizing antibodies, TGF-β 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-β 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-β 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-β pathway will also be considered.
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Cite this article as:
Mourskaia Alexeyevna Anna, Northey Jonathan Jason and Siegel Michael Peter, Targeting Aberrant TGF-β Signaling in Pre-Clinical Models of Cancer, Anti-Cancer Agents in Medicinal Chemistry 2007; 7 (5) . https://dx.doi.org/10.2174/187152007781668689
DOI https://dx.doi.org/10.2174/187152007781668689 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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