ABROGATION OF C-KIT STEEL-FACTOR-DEPENDENT TUMORIGENESIS BY KINASE DEFECTIVE-MUTANTS OF THE C-KIT RECEPTOR - C-KIT KINASE DEFECTIVE-MUTANTSAS 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 m ouse strains are loss of functional mutations of the c-kit receptor. T o examine the validity of these mutants in investigating c-kit-mediate d carcinogenesis and in the treatment of c-kit-dependent tumors, we in troduced various W mutations (W, W-v, and W-42) into a transgenic mous e strain carrying human papillomavirus oncogenes, in which c-kit/Steel -mediated tumorigenesis occurs with a very high incidence. In all tran sgenic strains carrying a W mutation, the c-kit deficiency affected th e tumorgenic process to various degrees. Tumor development was markedl y suppressed in transgenic strains carrying kinase defective mutations (W-v and W-42) in a heterozygous condition. In null-type (W) heterozy gous transgenic mice, tumorigenesis was suppressed at a lower level, M oreover, minimal focal legions or, in some cases, no focal legions wer e found in the testes of W/W-v 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 defec tive mutants of c-kit are valuable for treating c-kit-dependent cancer , as well as for clarifying the c-kit-mediated carcinogenesis.