AN IN-VIVO MODEL FOR RECEPTOR TYROSINE KINASE AUTOCRINE PARACRINE ACTIVATION - AUTO-STIMULATED KIT RECEPTOR ACTS AS A TUMOR-PROMOTING FACTOR IN PAPILLOMAVIRUS-INDUCED TUMORIGENESIS/

Constitutive overactivation of growth factor receptors through autocri nelparacrine mechanisms occurs frequently in cancer cells and are thou ght to play a critical role in carcinogenesis. In the present report, we propose a refined in vivo model which explains the significance of these mechanisms in tumour development. We have previously established transgenic mouse lines containing human papillomavirus type 16 (HPV16 ) E6E7 oncogenes, in male mice of which a Leydig cell tumor developes with a very high incidence, Not only HPV transgene but also the c-kit proto-oncogene receptor tyrosine kinase and its ligand Steel Factor (S LF) were coexpressed in all tumors analysed. This coexpression of c-ki t/SLF was also found in two other Leydig cell tumor lines. Moreover, t he proliferation of transgenic tumor cells was attenuated by treatment with a c-kit neutralizing antibody in vitro, strongly suggesting that tumorigenesis is closely related to stimulation of receptors through ligand induction, To confirm the significance of these findings, a def ective mutation of the SLF gene in a laboratory mouse, the Steel-Dicke y (Sld) mutation, was introduced into a line of transgenic mice showin g 100% incidence of the tumor. In Sl(d)-E6E7 transgenic mice, tumorige nesis was initiated but numbers of tumor cells were markedly reduced c ompared with transgenic mice carrying both wild type SLP allele, showi ng that c-kit activation through the induction of SLF is essential for testicular tumorigenesis, especially in tumour promotion. This transg enic mice system should be a useful in vivo model for clarifying the i mplication of growth factor autostimulation in carcinogenesis.