title: 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.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology, University of Bonn, Sigmund Freud Str. 25, 53105 Bonn, Germany.
authors.forename: Damia
authors.initials: D
authors.lastname: Tormo
authors.forename: Aleix
authors.initials: A
authors.lastname: Ferrer
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.forename: Jörg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: Julia
authors.initials: J
authors.lastname: Steitz
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Ines
authors.initials: I
authors.lastname: Gütgemann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008546:Melanoma, Experimental / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D012878:Skin Neoplasms / Q000473:pathology*
chemical_list: D002273:Carcinogens; D050505:Mutant Proteins; D017228:Hepatocyte Growth Factor; D051358:Cyclin-Dependent Kinase 4