Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation

Am J Pathol. 2006 Aug;169(2):665-72. doi: 10.2353/ajpath.2006.060017.


Currently, novel mouse models of melanoma are being generated that recapitulate the histopathology and molecular pathogenesis observed in human disease. Impaired cell-cycle control, which is a hallmark of both familial and sporadic melanoma, promotes slowly growing carcinogen-induced melanomas in the skin of mice carrying a mutated cyclin-dependent kinase 4 (CDK4(R24C)). Deregulated receptor tyrosine kinase signaling, which is another important feature of human melanoma, leads to spontaneous development of metastatic melanoma after a long latency period in mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF mice). Here we report that treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate induced metastatic melanomas in all HGF/SF mice on the C57BL/6 background, which histologically resemble human melanoma. Importantly, mutant CDK4 dramatically increased the number and the growth kinetics of carcinogen-induced primary melanomas in the skin and promoted the growth of spontaneous metastases in lymph nodes and lungs in all HGF/SF mice within the first 3 months of life. Apart from very few skin papillomas, we did not observe tumors of other histology in carcinogen-treated HGF/SF x CDK4(R24C) mice. This new experimental mouse model can now be exploited to study further the biology of melanoma and evaluate new treatment modalities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Carcinogens
  • Cyclin-Dependent Kinase 4 / genetics*
  • Disease Models, Animal
  • Gene Expression
  • Hepatocyte Growth Factor / genetics*
  • Humans
  • Lung / pathology
  • Lymph Nodes / pathology
  • Melanoma, Experimental / chemically induced*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutant Proteins / genetics
  • Mutation / genetics*
  • Neoplasm Invasiveness / pathology*
  • Neoplasm Metastasis / pathology*
  • Skin Neoplasms / pathology*


  • Carcinogens
  • Mutant Proteins
  • Hepatocyte Growth Factor
  • Cyclin-Dependent Kinase 4