| Co-Investigator(Kenkyū-buntansha) |
YOKOMISE Hiroyasu Kagawa University, Faculty of Medicine, Professor, 医学部, 教授 (80231728)
UENO Masaki Kagawa University, Faculty of Medicine, Associated professor, 医学部, 助教授 (30322267)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
We constructed the spontaneous metastasis model using the inoculation of tumor cell lines or tumor tissues into nude mice. The comprehensive analysis of expressions of tumor metastatic suppressor genes and angiogenesis factors revealed a reduced MRP-1/CD9 expression, a reduced KAI1/CD82 expression, and a reduced E-cadherin expression to be associated with pulmonary metastases. Regarding angiogenesis factors, a VEGF-A expression and a interleukin-8 expression were associated with intratumoral angiogenesis. In lung cancers, the HGF-cMet pathway was associated with the tumor proliferation, but not with angiogenesis (Br J Cancer 2004). The comprehensive analyses of gene expressions using cDNA microarray assays have demonstrated that the MRP-1/CD9 gene transduction suppresses the Wnt signal pathways (Oncogene 2004) and a WAVE2 expression (Oncogene 2006). Furthermore, we found the Wnt1 expression to be associated with the intratumoral VEGF-A expression, and the Wnt5a expression to be associated with the stromal VEGF-A expression (J Clin Oncol 2005). The finding that the MRP-1/CD9 transduction induces the down-regulation of VEGF-A, one of a Wnt target, suggested the possibility of the synergic effect of the combined therapy using metastatic suppressor gene therapy and angiogenesis inhibitors. Therefore, we performed experimental studies on combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors using the spontaneous metastasis model of nude mice. The adenoviral transfection of MRP-1/CD9 and KAI1/CD82 suppressed pulmonary metastases of tumors, respectively. TNP-470 and CGS27023A, angiogenesis inhibitors, also suppressed pulmonary metastases. Although TNP-470 inhibited tumor growth, but it caused weight loss as a side effect. However, we could not find any synergic effects in various types of the combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors.
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