Studies on characteristics and mechanism of radiation carcinogenesis in radiosensitive strains of mice

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The C.B-17 Scid mouse demonstrates immunodeficiency and also radio sensitivity similar to human ataxia-telangiectasia because of mutation in the DNA-PKcs gene. This strain of mice was also susceptible to radiation induction of thymic lymphomas. Therefore, characteristics of radiation carcinogenesis and molecular mechanisms were examined in this study. Scid, C.B-17 and their hybrid F1 mice were irradiated with gamma-rays and spectrum of carcinogenesis was first examined. Scid mice were extremely susceptible to the induction of thymic lymphomas by ionizing radiation, but not C.B-17 and F1 mice. Then irradiated Scid mice were transplanted with normal bone marrow cells of C.B-17 mice just after gamma-ray-irradiation to suppress induction of thymic lymphomas and thereby to examine carcinogenesis in various organs other than the thymus. This treatment completely reduced development of thymic lymphomas, but no excess of other tumors was demonstrated comparing with that in C.B-17 and F1 mice. Next, Scid mice with C3H background (C3H Scid mice) were used to examine effects of genetic background on radiosensitivity and radiation carcinogenesis. C3H Scid were demonstrated to be more radiosensitive and more susceptible to radiation induction of thymic lymphomas compared with C.B-17 Scid mice. Furthermore, presence of modifier gene was suspected Mutations of various cancer-related genes were examined with thymic lymphomas, and mutation of the Notch1 gene encoding cell surface receptor was frequently observed. Length of this gene is 45.6 kb with 34 exons. Although Genomic rearrangement was observed in about 20% of thymic lymphomas of STS and C.B-17 mice, that was more frequent in C.B-17 Scid mice. Detected rearrangements are deletion, IAP insertion and inversion. Furthermore, abnormal mRNA and protein were demonstrated in the tumors. Then, it is suggested that Notch1 gene is an oncogene, which is continuously active and may have a important role in thymic lymphomagenesis.