Gefitinib Decreases the Synthesis of Matrix Metalloproteinase and the Adhesion to Extracellular Matrix Proteins of Colon Cancer Cells

Background: Adhesion to extracellular matrix (ECM) proteins and degradation of basement membranes by matrix metalloproteinase (MMP) play important roles in cancer metastasis. In this study, the effects of gefitinib on the enzymatic activity of MMP and adhesion to ECM proteins in the HT29 colon cancer cell line were investigated. Materials and Methods: Microtiter plates, coated with ECM proteins, were used to investigate the adhesion of cancer cells to ECM proteins. The expression of MMPs was examined by zymography and semi- quantitative RT-PCR. Results: Gefitinib inhibited MMP-9 and MMP-2 secretion and mRNA expression in HT29 cells. Gefitinib also reduced the ability to adhere to laminin and type IV collagen. These effects were observed at such low doses that gefitinib had neither an antiproliferative effect nor the ability to induce apoptosis. Conclusion: Gefitinib decreased the production of MMPs and the adhesion to ECM proteins, important steps associated with cancer metastasis. These results suggest that gefitinib may have antimetastatic activity in colon cancer. Colorectal cancer is one of the most common types of adult malignancies in developed countries (1) and surgical excision remains the best treatment option for this cancer. However, one of the most difficult problems affecting the successful treatment of colorectal cancer is synchronous or metachronous hematogenous metastasis. Therefore, new approaches to cancer treatment and prevention of metastasis are needed. Tumor metastasis involves many steps, including adhesion of cancer cells to the extracellular matrix (ECM), cell motility and invasion. Among these, cell adhesion and degradation of ECM are the key steps in the metastatic process. Cellular adhesion is the first important step in metastasis, because cancer cells must first adhere to the ECM before they degrade ECM components. Matrix metalloproteinases (MMPs) are zinc- dependent endopeptidases that can degrade most ECM components and are thought to play a critical role in tumor invasion.