Lung adenocarcinoma (AdC) 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 transforming growth factor β type II receptor (TGFβRII) promotes lung AdC and SCC carcinogenesis.
We examined TGFβRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFβRII expression and clinico-pathologic parameters. To determine if sporadic TGFβRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFβRII deletion alone and in combination with oncogenic KrasG12D to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase.
Reduced TGFβRII 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 TGFβRII deletion in mouse airway epithelia increases the size and number of KrasG12D-initiated AdC and SCC. TGFβRII deletion increases proliferation, local inflammation, and TGFβ ligand elaboration; TGFβRII knockdown in airway epithelial cells increases migration and invasion.
Reduced TGFβRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is at least partially mediated by increased TGFβ1 expression. TGFβRII deletion in mouse airway epithelial cells promotes AdC and SCC formation, indicating that TGFβRII loss plays a causal role in lung carcinogenesis. That TGFβRII demonstrates haploid insufficiency, suggests that a 50% TGFβRII protein reduction would negatively impact lung cancer prognosis.
Keywords: lung adenocarcinoma, lung squamous cell carcinoma, TGFβ, tumor progression, mouse model