2004 Fiscal Year Final Research Report Summary
Molecular mechanisms of micrometastasis of oral cancer and inhibition of metastasis by molecular target therapy
| Project/Area Number |
14207091
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Surgical dentistry
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| Research Institution | Ehime University |
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Principal Investigator |
HAMAKAWA Hiroyuki Ehime University, School of Medicine, Professor, 医学部, 教授 (20127905)
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| Co-Investigator(Kenkyū-buntansha) |
SHINTANI Satoru Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (80294429)
NAKASHIRO Koichi Ehime University, Hospital, lecturer, 医学部附属病院, 講師 (90314880)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Oral cancer / Metastasis / Molecular target therapy / EGFR / CXCR4 / VEGF / HIF-1 / c-Met |
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| Research Abstract |
In this study, we have attempted to clarify molecular mechanisms of micrometastasis of oral cancer in order to block metastasis targeting molecules related to micrometastasis. At first, we established two human oral squamous cell carcinoma (OSCC) cell lines and two human salivary gland cancer cell lines, which stably express green fluorescent protein (GFP) and have different potential of metastasis. Measurements of GFP strength make it possible to evaluate the in vitro invasiveness and in vivo lymph node micrometastasis and distant metastasis of tumor correctly and easily. Some molecules such as vascular endothelial growth factor (VEGF), chemokine receptor CXCR4, epithelial growth factor receptor (EGFR), matrix metalloproteinases (MMPs) and cytokine IL-8 were identified as candidate genes related to metastasis of OSCC by gene expression profile of human OSCC cell lines and OSCC tissues using human genome wide microarray. Further investigation of CXCR4,VEGF, EGFR and IL-8 revealed that
… More
CXCR4 and EGFR regulated the invasiveness and migration of OSCC cells respectively and VEGF regulated angiogenesis of OSCC tumor. In in vivo tumor model using athymic nude mice orthotopically inoculated with OSCC cells, the blockade of function of CXCR4 or EGFR and the inhibitors of angiogenesis markedly suppressed lymph node metastasis of tumor. Moreover, combination of radiotherapy enhanced their inhibitory effects. On the other hand, investigation of the mechanisms of metastasis in human salivary gland cancer cells suggested that hypoxia-inducible factor-1 (HIF-1) correlated with metastasis of human salivary gland cancer. Under hypoxic condition HIF-1 expression increased in human salivary gland cancer cells which have metastatic potential and hepatocyte growth factor (HGF) receptor/c-Met expression also increased. But in those which have no metastatic potential HIF-1 and c-Met did not increase under hypoxic condition. In addition to these results, many other novel genes related to metastasis of oral cancer were identified by this study. Less
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