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 TGFß type II receptor (TGFßRII) promotes lung adenocarcinoma and SCC carcinogenesis. EXPERIMENTAL DESIGN: We examined TGFßRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFßRII expression and clinicopathologic parameters. To determine whether sporadic TGFßRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFßRII deletion alone and in combination with oncogenic Kras(G12D) to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase. RESULTS: Reduced TGFßRII 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 TGFßRII deletion in mouse airway epithelia increases the size and number of Kras(G12D)-initiated adenocarcinoma and SCC. TGFßRII deletion increases proliferation, local inflammation, and TGFß ligand elaboration; TGFßRII knockdown in airway epithelial cells increases migration and invasion. CONCLUSIONS: Reduced TGFßRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGFß1 expression. TGFßRII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGFßRII loss plays a causal role in lung carcinogenesis. That TGFßRII shows haploid insufficiency suggests that a 50% TGFßRII protein reduction would negatively impact lung cancer prognosis.