MOLECULAR-BIOLOGICAL APPROACHES TO CARCINOGENESIS AND METASTASIS OF HEAD AND NECK CANCER AND THEIR APPLICATIONS TO IMMUNO-GENETIC THERAPY

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1) Beta-catenin accumulation and the mutation of the beta-catenin gene head and neck cancers were evaluated. Twelve out of 49 (24.5%) cases exhibited beta-catenin accumulation in our histochemical study. The 5 year survival rate was 0% in the beta-catenin accumulation group, compared to 50% in the non-accumulation group, (p<0.01). This finding strongly suggests that beta-catenin may play an important role in the carcinogenesis or progression of head and neck cancer. One of the 15 cases exhibited an APC missense mutation that led to the replacement of amino acids ; this case died in 12 months. Regarding the beta-catein mutation, non of the 31 samples exhibited a gene mutation in beta-catenin exon 3. Thus, the rate of APC and beta-catenin mutation in head and neck cancer may be very low.2) Vascular endothelial growth factor (VEGF) gene was transfected to the head and neck cancer cell line which lacked the VEGF gene and the effect of gene induction was examined in vitro and in vivo. The m … More axillary cancer cell line which was not expressing VEGF, OKK-LN was established and VEGF gene expressing vector was transfected to OKK-LN cell line and OKK-LN/pCIneo-VEGF which producing VEGF was established. This cell line extensively produced VEGF compared with the control cell line, OKK-LN/pCIneo transfected with pCIneo plasmid alone. Both cell lines were transplanted into 6 week-Balb/c nu/nu mice by subcutaneous injection to right lateral abdomen. Tumor volume of the VEGF-transfected group significantly increased in approximately three times compared with the control group after 35 days of transplantation. The survival of the VEGF-transfected group was shortened by 9 days on an average. The effect on the proliferation of VEGF-producing tumor by TNP-470, Fumagilin analogue, which nonspecifically inhibits angiogenesis was examined. Tumor volume of TNP-470 administered group was significantly reduced to one-third compared with non-administered group after 35 and 42 days of the transplantation. The survival of TNP-470 administered group was significantly prolonged. In conclusion, the production of VEGF may facilitate tumor proliferation, influence the survival, and contribute to the malignancy and the suppression of VEGF may be one of the promising strategies against head and neck cancers.3) We examined the expression of survivin and the two splicing variants in various cancer cells and normal adult tissues. Two splicing variants were detected in various types of cancer cells as well as survivin. By stimulating peripheral blood lymphocytes with survivin-pulsed antigen-presenting cells, CTLs were successfully induced in vitro from HLA-A24-positive cancer patients. These data suggest that survivin may be a potent T-cell epitope eliciting CTL response against survivin, which is expressed in many kinds of cancer cells. Less