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

Abstract

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-α, amphiregulin, heparin binding EGF, β-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.

EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways

“…Consistent with other reports in various other cell lines (Charoenrat et al 2000, Liu & Klominek 2003, Nutt et al 2003, our results showed that EGF stimulates secretion of proMMP-9 but not of proMMP-2 (Fig. 3A).…”

“…In contrast, IL-10 (Roth & Fisher 1999) and transforming growth factor b (Meisser et al 1999) are known to inhibit trophoblastic MMP-9 secretion. Epidermal growth factor (EGF)-induced MMP-9 secretion, believed to facilitate tumour invasion and metastasis, has been demonstrated in various tumour cells (Ellerbroek et al 1998, Charoenrat et al 2000, Cox et al 2000, Liu & Klominek 2003, Nutt et al 2003. Although it has been shown that EGF stimulates trophoblast invasion , the influence of the growth factor on MMP-9 secretion by extravillous trophoblasts has not yet been reported.…”

TRAIL induces MMP-9 expression via ERK activation in human astrocytoma cells

“…Although MMP-2 and MMP-9 have similar substrate specificities, their expression patterns displayed different responses to TRAIL. Consistent with previous reports, growth factor induced expression of MMP-9, but not that of MMP-2 in bladder cancer and malignant mesothelioma cells [32,33]. Different MMP genes have been postulated to be differentially regulated since MMP genes have diverse promoter elements [34].…”

Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study

“…To date, many angiogenic factors, such as the hepatocyte growth factor (HGF), the fibroblast growth factor family members (FGF), the vascular endothelial growth factor (VEGF), or the platelet-derived growth factor (PDGF), have been identified and shown to be produced by a variety of different tumor cells, including those of MM (14)(15)(16)(17). Functionally active growth factors induce mesothelioma cell migration and matrix metalloproteinase (MMP) production (14,18). MMPs belong to the group of extracellular matrix degradation enzymes.…”