| Co-Investigator(Kenkyū-buntansha) |
SATOMURA Kazuhito The University of Tokushima, School of Dentistry Research Associate, 歯学部, 助手 (80243715)
HAYASHI Eiji The University of Tokushima, School of Dentistry Assistant Professor, 歯学部・附属病院, 講師 (50173000)
KAMATA Nobuyuki The University of Tokushima, School of Dentistry Associate Professor, 歯学部, 助教授 (70242211)
TAKECHI Masaaki The University of Tokushima, School of Dentistry Research Associate, 歯学部, 助手 (00304535)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1999: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Research Abstract |
The loss of E-cadherin expression has been shown to correlate to the invasion and metastasis of many types of carcinomas. We estab Iished E-cadherin positive(HOC719-PE)and negative(HOC719-NE)clones from an oral squamous cell carcinoma(SCC). HOC719-PE cells showed epithelial morphology with E-cadherin expression in the cell membrane, whereas HOC719-NE cells demonstrated fibro blastic morphology without E-cadherin expression. In invasion assay and three dimensional culture, HOC719-NE showed much higher invasivce ability than HOC719-PE cells. These cells expressed similar levels of mRNAs for a- and b-catenin. However, HOC719-NE cells, but not HOC719-PE cells, showed strong expression of snail, a transcription factor implicated in the di erentiation of epithelial cells into mesenchymal phenotype. This reverse expression of snail and E-cadherin was further observed in other SCC cells including HOC313, and TSU cells that we previously reported to show no expression of E-cadherin protein. The
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se results indicated that the expression of snail has a key role for the acquisition of more invasive and metastatic phenotypes of SCC and the clones we reported here will be useful tools for understanding the mechanism of the transition from epithelial to mesenchymal SCC cells.
Angiogenesis refers to neovascularization from the existing vascular system. The importance of angiogenesis in cancer growth and metastasis has been described. It is thought that inhibition of angiogenesis will result in the inhibition of cancer growth and metastasis. On the basis of these concepts, many anti-angiogenic agents have been investigated and new chemotherapies using anti-angiogenic agents are promising. In this study, we showed the angiogenic activities of conditioned media derived from oral squamous cell carcinoma(SCC)cells and expression of several growth factors which are known to induce the angiogenesis in these cells. Then, we examined the effects of TNP-470, one of the most promising anti-angiogenic agents, on the growth of oral SCCs in severe combined immunodefi cient(SCID)mice and inculture.
The growth of oral SCC cells, HSC-2, inoculated subcutaneously in SCID mice was inhibited in a dose dependent manner by the treat ment with TNP-470. A reduction of microvessels surrounding cancer tissue treated with TNP-470 was observed by immunohistochemistry. Significant side effects were not observed except for the transient weight loss during the period of treatment with high dose(50mg/kg)of TNP-470. TNP-470 inhibited the growth of all of the 22 kinds of cells including 7 oral SCC cells, and 12 other cancer cells, fibroblasts, normal epithelial keratinocytes and endothelial cells. However, the sensitivity of endothelial cells to TNP-470 was more than 1000 times higher than those of all other cells. G _1arrest on cell cycle was induced both in endothelial cells and oral SCC cells by the treatment with TNP-470, although 1000 times more concentration was needed for SCC cells compared with endothelial cells. Binding assay using[^3H]-TNP-470 revealed that there were no significant differences of numbers or affinities of receptors for TNP-470 between endothelial cells and othercells. Similar levels of the gene expression of methionine aminopeptidase 2(MetAP-2), which TNP-470 has been reported to bind, was seen in the endothelial cells and other cells.
These results indicated that the treatment with anti-angiogenic agents such as TNP-470 may be effective as a new therapy for oral cancer and suggested that the specific infibition of endothelial cells by TNP-470 may be not due to the higher receptor number and affinity for TNP-470, but due to the existence of specific target molecules of TNP-470. Less
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