Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium

J Clin Invest. 2011 May;121(5):1935-45. doi: 10.1172/JCI44871. Epub 2011 Apr 1.

Abstract

Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bronchi / metabolism
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Epithelial Cells / cytology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lung / metabolism
  • Lung Neoplasms / metabolism*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Phenotype
  • Signal Transduction
  • Stem Cells / cytology*
  • Wnt Proteins / metabolism*

Substances

  • Cadherins
  • Wnt Proteins