Loss of transforming growth factor beta type II receptor increases aggressive tumor behavior and reduces survival in lung adenocarcinoma and squamous cell carcinoma.

ABSTRACT: PURPOSE:Lung adenocarcinoma and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes. This study was designed to determine whether reduced expression of TGF? type II receptor (TGF?RII) promotes lung adenocarcinoma and SCC carcinogenesis. EXPERIMENTAL DESIGN:We examined TGF?RII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGF?RII expression and clinicopathologic parameters. To determine whether sporadic TGF?RII deletion in airway epithelial cells induces NSCLC formation, we targeted TGF?RII deletion alone and in combination with oncogenic Kras(G12D) to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase. RESULTS:Reduced TGF?RII expression in human NSCLC is associated with male gender, smoking, SCC histology, reduced differentiation, increased tumor stage, increased nodal metastasis, and reduced survival. Homozygous or heterozygous TGF?RII deletion in mouse airway epithelia increases the size and number of Kras(G12D)-initiated adenocarcinoma and SCC. TGF?RII deletion increases proliferation, local inflammation, and TGF? ligand elaboration; TGF?RII knockdown in airway epithelial cells increases migration and invasion. CONCLUSIONS:Reduced TGF?RII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGF?1 expression. TGF?RII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGF?RII loss plays a causal role in lung carcinogenesis. That TGF?RII shows haploid insufficiency suggests that a 50% TGF?RII protein reduction would negatively impact lung cancer prognosis.

SUBMITTER: Malkoski SP 

PROVIDER: S-EPMC3328594 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature