Loss of Transforming Growth Factor Beta Type II Receptor Increases Aggressive Tumor Behavior and Reduces Survival in Lung Adenocarcinoma and Squamous Cell Carcinoma

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 beta type II receptor (TGF beta RII) promotes lung adenocarcinoma and SCC carcinogenesis. Experimental Design: We examined TGF beta RII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGF beta RII expression and clinicopathologic parameters. To determine whether sporadic TGF beta RII deletion in airway epithelial cells induces NSCLC formation, we targeted TGF beta 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 beta 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 beta RII deletion in mouse airway epithelia increases the size and number of Kras(G12D)-initiated adenocarcinoma and SCC. TGF beta RII deletion increases proliferation, local inflammation, and TGF beta ligand elaboration; TGF beta RII knockdown in airway epithelial cells increases migration and invasion. Conclusions: Reduced TGF beta RII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGF beta 1 expression. TGF beta RII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGF beta RII loss plays a causal role in lung carcinogenesis. That TGF beta RII shows haploid insufficiency suggests that a 50% TGF beta RII protein reduction would negatively impact lung cancer prognosis. Clin Cancer Res; 18(8); 2173-83. (C) 2012 AACR.