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

Abstract

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.

• Authors: Damia Tormo, Aleix Ferrer, Evelyn Gaffal, Jörg Wenzel, Etiena Basner-Tschakarjan, Julia Steitz, Lukas C Heukamp, Ines Gütgemann, Reinhard Buettner, Marcos Malumbres, Mariano Barbacid, Glenn Merlino, Thomas Tüting
• Journal: The American journal of pathology (Am J Pathol) Vol. 169 Issue 2 Pg. 665-72 (Aug 2006) ISSN: 0002-9440 [Print] United States
• PMID: 16877364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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)