Hepatocyte growth factor/scatter factor stimulates chemotaxis and growth of malignant mesothelioma cells through c-met receptor

Abstract

Hepatocyte growth factor (HGF) and its receptor c‐met are present in several human tissues but their expression in mesothelial cells has not been examined. In this study, we have investigated the expression of HGF and c‐met in normal human mesothelial cells and 11 human malignant mesothelioma cell lines. Using RT‐PCR and Western blotting we found that HGF is produced by 3/11 mesothelioma cell lines whereas c‐met is expressed in 11/11 mesothelioma cell lines. In addition, c‐met expression was also found in 6/6 cell samples obtained from pleural fluids of patients with mesothelioma. In contrast, neither normal cultured mesothelial cells nor mesothelial cells obtained directly from patients without mesothelioma expressed HGF nor c‐met. We have also analysed the biological function of HGF and c‐met in mesothelioma cell lines. Recombinant human (rh) HGF stimulated both directional (chemotactic) and random (chemokinetic) motility in all mesothelioma cell lines tested. Furthermore, mesothelioma serum free conditioned medium containing HGF stimulated mesothelioma cell migration. This effect could be blocked in the presence of neutralizing anti‐HGF monoclonal antibodies (MAbs) in the assay. Addition of HGF to mesothelioma cells cultured on collagen type IV was associated with induction of bipolar shape and protrusion of prominent pseudopodia. We have also found that rhHGF was mitogenic for mesothelioma cells. Our findings suggest that expression of HGF/c‐met is involved not only in mesothelioma progression but also in its growth and migration and that c‐met expression found in mesothelioma cells taken directly from patients may be of diagnostic importance. Int. J. Cancer76:240–249, 1998.© 1998 Wiley‐Liss, Inc.

SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma

“…Several studies investigated the potential involvement of other growth factors, like platelet-derived growth factor A and B (13), insulin-like growth factor-1 (14), transforming growth factor ␤, fibroblast growth factor-2 (15), and hepatocyte growth factor (HGF) (16)(17)(18)(19) in the onset of MM. High levels of HGF, in particular, were detected in pleural effusion from patients with MM (20).…”

Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

“…Moreover, as recently shown, the requirement of CD44 for hepatocyte growth factor (HGF)/c-Met signalling has been recently demonstrated (Orian-Rousseau et al, 2002). Interestingly, HGF/c-Met has been considered as an autocrine loop in the control of MM cell proliferation (Harvey et al, 1996;Klominek et al, 1998). Hence, NF2 appears to be possibly associated with pathways regulating proliferation of MM cells.…”

AXL regulates mesothelioma proliferation and invasiveness

“…These studies suggest that epidermal growth factor receptor activation might play an early role in asbestos-induced mesothelial mitogenicity and carcinogenesis. The RTK protein, MET, and its ligand (hepatocyte growth factor) are co-overexpressed in mesothelioma compared with nonneoplastic mesothelial cells (Klominek et al, 1998;Tolnay et al, 1998), and MET activation results in increased mesothelioma cell proliferation (Klominek et al, 1998). PHA-665752, a specific small-molecular inhibitor of MET, caused mesothelioma cell cycle arrest and inhibited phosphorylation of MET, p70S6K, AKT and MAPK (Mukohara et al, 2005).…”