Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors

Background: The extracellular matrix metalloproteases (MMPs) produced by tumour and stromal cells are believed to play a key role in tumour cell invasion and metastasis. Malignant mesothelioma is a highly aggressive tumour. Previous studies have shown that malignant mesothelioma cells express MMP-1, -2, -3, -7 and -9. However, the regulation of MMP expression in malignant mesothelioma cells has not been thoroughly investigated. Methods: The effects of a number of growth factors on the secretion of MMP-2, -3 and -9 in malignant mesothelioma cells were studied by substrate zymography. The expression of relevant growth factor receptors in malignant mesothelioma cells was also examined using RT-PCR. Results: The exposure of malignant mesothelioma cells to different growth factors including epidermal growth factor (EGF), transforming growth factor-alpha, amphiregulin, heparin binding EGF, beta-cellulin (BTC), stem cell factor, insulin-like growth factors I and II, acidic and basic fibroblast growth factors, and hepatocyte growth factor increased secretion of MMP-9 and/or MMP-3. EGF receptor ligands BTC and EGF had the most potent effect on MMP-9 and MMP-3 production, respectively. Production of MMP-2 was not affected by any growth factors used in this study. We have also demonstrated mRNA expression of different growth factor receptors in malignant mesothelioma cells, and found that the tyrosine kinase inhibitor genistein inhibited the increased production of MMPs resulting from stimulation with different growth factors. Conclusion: This study shows, for the first time, the broad extent of regulation of MMPs by various growth factors in malignant mesothelioma cells.