title: Loss of transforming growth factor beta type II receptor increases aggressive tumor behavior and reduces survival in lung adenocarcinoma and squamous cell carcinoma.
abstract: OBJECTIVE
  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 TGFβ type II receptor (TGFβRII) promotes lung adenocarcinoma and SCC carcinogenesis.
  
  
  METHODS
  We examined TGFβRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFβRII expression and clinicopathologic parameters. To determine whether sporadic TGFβRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFβRII deletion alone and in combination with oncogenic Kras(G12D) to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase.
  
  
  RESULTS
  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 Kras(G12D)-initiated adenocarcinoma and SCC. TGFβRII deletion increases proliferation, local inflammation, and TGFβ ligand elaboration; TGFβRII knockdown in airway epithelial cells increases migration and invasion.
  
  
  CONCLUSIONS
  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 adenocarcinoma and SCC formation, indicating that TGFβRII loss plays a causal role in lung carcinogenesis. That TGFβRII shows haploid insufficiency suggests that a 50% TGFβRII protein reduction would negatively impact lung cancer prognosis.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Pathology, Colorado School of Public Health, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Malkoski
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Haeger
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cleaver
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Rodriguez
authors.forename: Howard
authors.initials: H
authors.lastname: Li
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Lu
authors.forename: William J
authors.initials: WJ
authors.lastname: Feser
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Daniel
authors.initials: D
authors.lastname: Merrick
authors.forename: Jessyka G
authors.initials: JG
authors.lastname: Lighthall
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.forename: Wilbur
authors.initials: W
authors.lastname: Franklin
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II