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 (TGFβ) regulates a wide array of cell functions and plays a major role in lung diseases, including NSCLC. TGFβ signals through the complex of TGFβ 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 TGFβ1 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 TβRI expression. We demonstrated that although lung cancer cell monolayers responded to TGFβ1 anti-mitogenic effects and TGFβ1 pulse (24 h treatment) delayed tumor growth at primary site; a switch towards malignant progression upon TGFβ1 treatment was observed at the metastatic site. In our model, TGFβ1 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 TGFβ1-mediated metastasis stimulation. Several of these TGFβ responses were also observed in human NSCLC cell lines. In addition, we found that a higher expression of TβRI 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.

TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis

“…Based on our above findings and previous reports correlating increased TGF-b expression with tumor progression and metastasis in lung ADC (Hasegawa et al 2001;Nemunaitis et al 2009;Vazquez et al 2013), we next asked whether DOCK4 mediates the prometastatic effects of TGF-b in lung ADC. To address this, we first established an experimental model for the analysis of lung ADC metastasis.…”

“…A key factor reported to drive lung ADC metastasis is the cytokine TGF-b (Lund et al 1991;Hasegawa et al 2001;Nemunaitis et al 2009;Toonkel et al 2010;Vazquez et al 2013); however, the genes and mechanisms that mediate the prometastatic effects of TGF-b remain largely unknown. Here we identify DOCK4 as a novel, key target of the TGF-b/Smad signaling pathway that promotes lung ADC metastasis by enhancing the competence of lung ADC cells to extravasate into distant organs.…”

“…The relevance of TGF-b signaling for disease progression has been particularly recognized in tumors where cancer cells retain the core TGF-b signaling components, as is often the case in breast and lung cancers (Kang et al 2003;Elliott and Blobe 2005;Massague 2008;Padua and Massague 2009). Indeed, in lung adenocarcinoma (ADC), the most common subtype of lung cancer with a high mortality rate, increased TGF-b1 expression correlates with tumor progression and poor patient survival, and various experimental model systems support a prometastatic role for TGF-b in these tumors (Lund et al 1991;Hoffman et al 2000;Hasegawa et al 2001;Gibbons et al 2009;Nemunaitis et al 2009;Toonkel et al 2010;Provencio et al 2011;Vazquez et al 2013). However, a major remaining challenge is the identification of TGF-b target genes that drive the different steps of metastasis, especially since TGF-b modulates gene expression in a highly cell-and context-specific manner (Padua and Massague 2009;Mullen et al 2011;Massague 2012).…”

Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis

“…TGF-β1 signaling is both an initiator and a driver of tissue stiffness because accumulation of collagen and other matrix proteins promotes integrin-dependent latent TGF-β1 activation and further extracellular matrix deposition (12). Enhanced stiffness is thought to promote tumor cell β 1 integrin activation, leading to more invasive tumor phenotypes and metastasis, consistent with the strong correlation of TGF-β1 signaling with poor cancer prognosis (9,13,14). For these and other reasons there has been much interest in TGF-β1 signaling as a therapeutic target (15)(16)(17).…”

The transforming growth factor beta-1 in the oncogenesis of human lung adenocarcinoma

“…Действитель-но, при НМРЛ -наиболее распространенном гисто-логическом подтипе РЛ с высоким уровнем смертно-сти -увеличение экспрессии TGF-β1 коррелирует с прогрессией опухоли и плохой выживаемостью па-циентов. Различные экспериментальные модельные системы подтверждают мнение о прометастатической роли TGF-β1 в этих опухолях [22][23][24][25]. Тем не менее одной из основных нерешенных задач остается иден-тификация генов-мишеней для TGF-β1, которые управляют различными стадиями метастазирования, тем более что TGF-β1 модулирует экспрессию генов по-разному в зависимости от типа клеток [26,27].…”