Inflammation and Hras signaling control epithelial-mesenchymal transition during skin tumor progression

Genes Dev. 2013 Mar 15;27(6):670-82. doi: 10.1101/gad.210427.112.


Epithelial-mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%-30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic inflammation causes a dramatic reduction in classical papillomas and squamous cell carcinomas (SCCs), but the mice still develop highly invasive carcinomas with EMT properties, reduced levels of Hras and Egfr signaling, and frequent Ink4/Arf deletions. Deletion of Hras from the mouse germline also leads to a strong reduction in squamous tumor development, but tumors now acquire activating Kras mutations and exhibit more aggressive metastatic properties. We propose that invasive carcinomas can arise by different genetic and biological routes dependent on exposure to chronic inflammation and possibly from different target cell populations within the skin. Our data have implications for the use of inhibitors of inflammation or of Ras/Egfr pathway signaling for prevention or treatment of invasive cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology*
  • Cyclin-Dependent Kinase Inhibitor Proteins / genetics
  • Epithelial-Mesenchymal Transition
  • ErbB Receptors / metabolism
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Markers / genetics
  • Inflammation / pathology*
  • Mice
  • Mutation
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Signal Transduction*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology*


  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Genetic Markers
  • EGFR protein, mouse
  • ErbB Receptors
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)