| Co-Investigator(Kenkyū-buntansha) |
MITSUDOMI Tetsuya Aichi Cancer Center, 胸部外科, 部長 (70209807)
NAKAMORI Shoji Osaka University, 医学部・第2外科, 助手 (70294080)
TAKI Toshihiko Tazuke Kofukai Medical Research Institute, 医学研究所・第5研究部, 主幹 (60135605)
中村 吉昭 財団法人 田附興風会, 医学研究所第2研究部, 研究員 (50281605)
|
|---|
| Budget Amount *help |
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 1999: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 1998: ¥7,800,000 (Direct Cost: ¥7,800,000)
|
|---|
| Research Abstract |
Among the transmembrane 4 superfamily (TM4SF), which includes at least 19 members that are expressed on various tissues, MRP-1/CD9 and KAI1/CD82 are noted for their involvement in tumor progression and metastasis. MPR-1/CD9 is associated with other TM4SF members, CD81 and ME491/CD63. In addition, CD81 and KAI1/CD82 formed multimolecular membrane complexes by associating with each other and with integrin α3 α4 α6 and β6. This is true of MRP-1/CD9. Therefore, TM4SF members may act in large multicomponent complexes, and serve as receptor-associated ion channels or may act to transduce of signals across the plasma membrane and to regulate cell activation, development, proliferation, and motility. Moreover, we can predict the prognosis of patients with lung cancers, breast cancers, esophageal cancers and pancreas cancers more precisely by evaluating the expression of both MRP-1/CD9 and KAI1/CD82. Considering the progression of malignant tumors, the reduction in KAI1/CD82 might precede the r
… More
eduction in MRP-1/CD9. The tumor suppressor genes, p53 or RB had been mutated or deleted during the early stage of these tumors and thus the KAI1/CD82 gene might be in decline. During the last stage, the levels of MRP-1/CD9 might be diminishing due to methylation of the promoter and therefore the normal functions of MRP-1/CD9 could be lost. Thus, the malignant cells could finally acquire metastatic potential. Therefore, combination therapy involving the adenovirus-mediated transfer of the genes encoding MRP-1/CD9 and KAI1/CD82 was used to treat the metastases from the mouse melanoma BL6 cell line in Balb/c nude mice. The intravenous injection of an adenovirus vector (rAd-MRP-1/CD9) expressing MRP-1/CD9 resulted in an 75% reduction in the number of pulmonary metastases. In contrast, intravenous injection of an adenovirus vector (rAd-KAI1/CD82) expressing KAI1/CD82 resulted in a 70% reduction. Furthermore, the delivery of both MRP-1/CD9 plus KAI1/CD82 resulted in the strongest suppression against pulmonary metastasis (92%). Moreover, the overall survival of mice treated with both rAd-MRP-1/CD9 and rAd-KAI1/CD82 was much longer than any of the other groups (p<0.0001). These results support the expression of MRP-1/CD9 and KAI1/CD82 through gene transfer as a therapeutic strategy for preventing metastases and for prolonging survival, and support the feasibility of gene transfer in a clinically relevant setting. Less
|
