TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer

Abstract

Lung cancer is the most frequent and one of the most deadly cancer types and is classified into small cell lung cancer and non-small cell lung cancer (NSCLC). Transforming growth factor beta (TGFb) regulates a wide array of cell functions and plays a major role in lung diseases, including NSCLC. TGFb signals through the complex of TGFb type I and type II receptors, triggering Smad and non-Smad signaling pathways such as PI3K/Akt and MEK1/ERK. We investigated the role of TGFb1 on the progression of the murine lung adenocarcinoma cell line LP07. Furthermore, we undertook a retrospective study with tissue samples from stage I and II NSCLC patients to assess the clinical pathologic role and prognostic significance of TbRI expression. We demonstrated that although lung cancer cell monolayers responded to TGFb1 anti-mitogenic effects and TGFb1 pulse (24 h treatment) delayed tumor growth at primary site; a switch towards malignant progression upon TGFb1 treatment was observed at the metastatic site. In our model, TGFb1 modulated in vitro clonogenicity, protected against stress-induced apoptosis and increased adhesion, spreading, lung retention and metastatic outgrowth. PI3K and MEK1 signaling pathways were involved in TGFb1-mediated metastasis stimulation. Several of these TGFb responses were also observed in human NSCLC cell lines. In addition, we found that a higher expression of TbRI in human lung tumors is associated with poor patient’s overall survival by univariate analysis, while multivariate analysis did not reach statistical significance. Although additional detailed analysis of the endogenous signaling in vivo and in vitro is needed, these studies may provide novel molecular targets for the treatment of lung cancer.