| First Author | Malkoski SP | Year | 2012 |
| Journal | Clin Cancer Res | Volume | 18 |
| Issue | 8 | Pages | 2173-83 |
| PubMed ID | 22399565 | Mgi Jnum | J:234589 |
| Mgi Id | MGI:5790297 | Doi | 10.1158/1078-0432.CCR-11-2557 |
| Citation | Malkoski SP, et al. (2012) Loss of transforming growth factor beta type II receptor increases aggressive tumor behavior and reduces survival in lung adenocarcinoma and squamous cell carcinoma. Clin Cancer Res 18(8):2173-83 |
| abstractText | 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 TGFbeta type II receptor (TGFbetaRII) promotes lung adenocarcinoma and SCC carcinogenesis. EXPERIMENTAL DESIGN: We examined TGFbetaRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFbetaRII expression and clinicopathologic parameters. To determine whether sporadic TGFbetaRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFbetaRII deletion alone and in combination with oncogenic Kras(G12D) to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase. RESULTS: Reduced TGFbetaRII 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 TGFbetaRII deletion in mouse airway epithelia increases the size and number of Kras(G12D)-initiated adenocarcinoma and SCC. TGFbetaRII deletion increases proliferation, local inflammation, and TGFbeta ligand elaboration; TGFbetaRII knockdown in airway epithelial cells increases migration and invasion. CONCLUSIONS: Reduced TGFbetaRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGFbeta1 expression. TGFbetaRII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGFbetaRII loss plays a causal role in lung carcinogenesis. That TGFbetaRII shows haploid insufficiency suggests that a 50% TGFbetaRII protein reduction would negatively impact lung cancer prognosis. |
