Abrogation of c-kit/Steel factor-dependent tumorigenesis by kinase defective mutants of the c-kit receptor: c-kit kinase defective mutants as candidate tools for cancer gene therapy.
The growth and survival of many types of cancer cells are known to be supported by specific growth factor/cytokine systems. Among these, the activation of c-kit receptor and its ligand steel factor participates in several types of human carcinogenesis. W mutations of laboratory mouse strains are loss of functional mutations of the c-kit receptor. To examine the validity of these mutants in investigating c-kit-mediated carcinogenesis and in the treatment of c-kit-dependent tumors, we introduced various W mutations (W, Wv, and W42) into a transgenic mouse strain carrying human papillomavirus oncogenes, in which c-kit/Steel-mediated tumorigenesis occurs with a very high incidence. In all transgenic strains carrying a W mutation, the c-kit deficiency affected the tumorgenic process to various degrees. Tumor development was markedly suppressed in transgenic strains carrying kinase defective mutations (Wv and W42) in a heterozygous condition. In null-type (W) heterozygous transgenic mice, tumorigenesis was suppressed at a lower level. Moreover, minimal focal legions or, in some cases, no focal legions were found in the testes of W/Wv heterozygous transgenic mice, showing a close relationship between tumor cell growth and the degree of c-kit inactivation. These results indicated that c-kit activity is a pivotal determinant of testicular tumor development and that the kinase defective mutants of c-kit are valuable for treating c-kit-dependent cancer, as well as for clarifying the c-kit-mediated carcinogenesis.
Li
Q
Q
Research Institute for Microbial Diseases, Osaka University, Japan.
Kondoh
G
G
Inafuku
S
S
Nishimune
Y
Y
Hakura
A
A
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion; D019089:Stem Cell Factor / Q000502:physiology*; D013736:Testicular Neoplasms / Q000235:genetics / Q000517:prevention & control*
D009363:Neoplasm Proteins; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit