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Expression profiling and interferon-beta regulation of liver metastases in colorectal cancer cells.
Liver metastasis is the major cause of death among colorectal cancer patients. Many gene products have been associated with the colon cancer cells' ability to metastasize to the liver, including carcinoembryonic antigen (CEA) and mucins. In this study we examined changes in expression of 384 genes in a model of human colorectal cancer metastasis in nude mice. Using DNA microarrays, we compared expression between MIP-101 cells, a poorly metastatic human colon cancer cell line, with an interferon-beta (IFN-beta) resistant subline of MIP-101 (beta-MIP) that is metastatic to the liver. Treatment of beta-MIP cells with increasing concentrations of IFN-beta caused a reversion to the non-metastatic phenotype. The array data showed down-regulation of genes involved in apoptosis in beta-MIP cells and their return to the MIP-101 pattern upon IFN-beta treatment. Cluster analysis also showed involvement of genes belonging to cell cycle, angiogenesis and invasion pathways. Selected genes were chosen to validate the microarray data by semi-quantitative RT-PCR. Association between gene expression pattern and metastatic phenotype was verified by intra-splenic injection in nude mice. The number of genes examined in this study was small, but carefully selected. Significant changes associated with cell growth and survival were observed, which gave the metastatic cells an advantage to grow in the liver. This information may help identifying new markers for colorectal cancer prognosis as well as aid the development of new therapeutic approaches.
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