| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
The effect of hyperthermia on the production of membrane type-1 matrix metalloproteinase (MT1-MMP) which closely correlated with tumor invasiveness was examined. Heat shock at 42℃ for 3h suppressed the gene expression and production of MT1-MMP in cultured human fibrosarcoma HT-1080 cells and human squamous carcinoma A431 cells, and thereby resulted in the inhibition of progelatinase A/proMMP-2 activation. The heat shock simultaneously increased the release of tissue inhibitor of metalloproteinases-2(TIMP-2) from cell surface of HT-1080 cells. In an effort to clarify the heat shock-mediated transduction pathways, an intracellular 3', 5'-cyclic AMP(cAMP) was found to be transiently augmented in the heat shocked HT-1080 cells. When HT-1080 cells were treated with cAMP elevating reagents, forskolin and dibutyryl cAMP, instead of heat shock, the production and gene expression of MT1-MMP, the release of TIMP-2, and the activation of proMMP-2 were also suppressed. Furthermore, in vitro tumor invasion assay in a Matrigel model indicated that the transiently increased cAMP by forskolin as well as heat shock interfered with the invasive activity of HT-1080 cells. Therefore, the transient increase in intracellular cAMP by heat shock is an essential event which interferes with the tumor invasion. In addition, the heat shock suppressed the production of vascular endothelial cell growth factor (VEGF) which closely participates in the promotion of angiogenesis in tumor tissues. Therefore, these results indicated that hyperthermia actually has a novel anti-invasive effect along with the known mechanism of inhibiting tumor growth.
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