TGF-ß and αvß6 integrin act in a common pathway to suppress pancreatic cancer progression.
Cancer Res
; 72(18): 4840-5, 2012 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-22787119
ABSTRACT
The TGF-ß pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-ß inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-ß in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-ß inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy. We found that αvß6 integrin acted as a key upstream activator of TGF-ß in evolving pancreatic cancers. In addition, TGF-ß or αvß6 blockade increased tumor cell proliferation and accelerated both early and later disease stages. These effects were dependent on the presence of Smad4, a central mediator of TGF-ß signaling. Therefore, our findings indicate that αvß6 and TGF-ß act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Transdução de Sinais
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Integrinas
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Fator de Crescimento Transformador beta
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Antígenos de Neoplasias
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article