The mechanisms of the highly metastatic property using human lung cancer sublines with highly metastatic potential established and the expolation of the molecular targets for lung cancer therapy

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A better understanding of the key factors of metastasis may be useful for designing new molecular targets of cancer therapy. In order to identify these factors, we established two highly metastatic human lung adenocarcinoma cell lines in an experimental metastasis model by repeated inoculation in nude mice and compared the expression profiles of two subpopulations of an adenocarcinoma cell line with high metastatic potential, with the parent cell line, using cDNA arrays; microarray and macroarray. The expression of 5 genes was found to be significantly enhanced or reduced in the highly metastatic subpopulations by microarray. One of the over-expressed genes that was identified encoded the β-galactoside-binding protein Galectin 3. A population (10/30) of the non-small-cell lung cancers examined was found to over-express the Galectin 3 gene at levels 3 times higher than normal epithelial cells. Galectin 3 may represent a novel target molecule in non-small-cell lung cancer therapy. The expression of matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor-1 (PAI-1), carcinoembryonic antigen (CEA) and etc. were upregulated or downregulated in the highly metastatic subpopulations. Altered expression of these genes seems topromote the highly metastatic phenotype in these function. To determine whether the change in p16INK4 methylation status and the genomic status of hBUB1, hMAD2, Insulin-like growth factor 2 receptor genes, chromosome 8p and 3p occurs during metastasis of primary lung cancers, we also analyzed the primary and metastatic tumor tissues and normal lung samples from 30 cases of advanced lung cancer with distant metastasis. The results of this study indicate that tumor cells in which the p16INK4 gene has been inactivated by hypermethylation of the promoter region could have an advantage in metastasis in non-small cell lung cancers. We will evaluate the clinical significance of MMP-2, PAI-1, CEA, Galectin 3 and identified unknown clones.