Molecular mechanisms of micrometastasis of oral cancer and inhibition of metastasis by molecular target therapy

口腔癌微转移的分子机制及分子靶向治疗抑制转移

基本信息

批准号：
14207091
负责人：
HAMAKAWA Hiroyuki
金额：
$ 27.54万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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

在这项研究中，我们试图阐明口腔癌微含量的分子机制，以阻止靶向与微量含量相关的分子的转移。首先，我们建立了两个人口腔鳞状细胞癌（OSCC）细胞系和两个人类唾液腺癌细胞系，它们稳定地表达绿色荧光蛋白（GFP），并且具有不同的转移潜力。 GFP强度的测量使得正确，容易地评估体外浸润性和体内淋巴结微量和远处转移是可能的。某些分子，例如血管内皮生长因子（VEGF），趋化因子受体CXCR4，上皮生长因子受体（EGFR），基质金属蛋白酶（MMP）和细胞因子IL-8被鉴定为基因表达人类OSCC细胞和OSCC的OSCC的候选基因相关的候选基因和OSCC的候选基因。对CXCR4，VEGF，EGFR和IL-8的进一步研究表明，更多的CXCR4和EGFR调节OSCC细胞的侵入性和迁移以及VEGF调控OSCC肿瘤的血管生成。在体内肿瘤模型中，使用Anymic Nude小鼠原位接种了OSCC细胞，CXCR4或EGFR功能的阻断以及血管生成的抑制剂明显抑制了肿瘤的淋巴结转移。此外，放射疗法的组合增强了其抑制作用。另一方面，对人类唾液腺癌细胞转移机制的研究表明，缺氧诱导因子-1（HIF-1）与人类唾液腺癌的转移相关。在低氧条件下，HIF-1表达在人类唾液腺癌细胞中增加，具有转移性潜力和肝细胞生长因子（HGF）接收器/C-MET表达也有所增加。但是，在没有转移性潜在的HIF-1和C-MET的情况下，在低氧条件下不会增加。除这些结果外，这项研究还确定了许多与口腔癌转移相关的其他新型基因。较少的