Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases

Our plain-English summary of Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases, by P. Harvey, I.M. Clark, M.C. Jaurand, et al (British Journal of Cancer, 2000).

The study

• Authors: P. Harvey, I.M. Clark, M.C. Jaurand, R.M. Warn, D.R. Edwards
• Journal: British Journal of Cancer
• Published: 2000;83(9):1147-53
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional factor involved both in development and tissue repair, as well as pathological processes such as cancer and metastasis. It has been identified in vivo in many types of tumours together with its tyrosine kinase receptor, Met. We show here that exogenous HGF/SF acts as a strong chemoattractant for human mesothelioma cell lines. The factor also enhanced cell adhesion to and invasion into Matrigel. The mesothelioma cell lines synthesized a panel of matrix metalloproteinases critical for tumour progression such as MMP-1, 2, 3, 9 and membrane-bound MT1-MMP. HGF/SF stimulated the expression of MMP-1, 9 and MT1-MMP and had a slight effect on expression of the MMP inhibitor TIMP-1 but not TIMP-2. However, there was no simple correlation between the levels of MMPs and TIMPs of the cell lines and their different invasion properties or between HGF/SF stimulatory effects on MMP expression and invasion. In addition, effects of protease inhibitors on invasion suggested that serine proteases were also expressed in human mesothelioma cell lines and were involved in HGF/SF-induced invasion. The results show a predominant role for HGF/SF in mesothelioma cell invasion, stimulating simultaneously adhesion, motility, invasion and regulation of MMP and TIMP levels.

Copyright 2000 Cancer Research Campaign.

In plain English

This was a laboratory study of three human mesothelioma cell lines grown in culture: BT (epithelioid type), BR (fibroblastoid type) and TA (mixed type). It did not study asbestos exposure or patients. The authors added hepatocyte growth factor/scatter factor (HGF/SF) and measured how the cells moved, how they attached to Matrigel, and how they invaded through it. Matrigel is a reconstituted basement membrane, a laboratory model of the tissue layer that cells must cross to invade. HGF/SF increased movement in all three lines, five-fold in TA cells. It also increased attachment and invasion. BT cells did not invade on their own but became weakly invasive with the factor after 48 hours. All lines made several tissue-digesting enzymes (MMPs) and their inhibitors (TIMPs). HGF/SF raised some of these, for example MMP-1 four- to five-fold in BT cells. However, enzyme levels did not simply match how invasive the cells were. In TA cells, the serine protease inhibitor aprotinin reduced invasion more than an MMP inhibitor did. The authors concluded that HGF/SF had a major stimulatory effect on mesothelioma cell adhesion and invasion.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiments on cultured human mesothelioma cell lines
• Who was studied: Three human mesothelioma cell lines: BT (epithelioid), BR (fibroblastoid) and TA (mixed phenotype); work done at the University of East Anglia, Norwich, UK, and INSERM, Créteil, France; dates of the experiments not stated
• Exposure: No asbestos exposure was studied. The cells were treated with recombinant human HGF/SF at a range of concentrations (for example 10 ng per ml in the adhesion and invasion assays). Some experiments added a neutralizing anti-HGF/SF antibody, suramin, the MMP inhibitor CT1746 or the serine proteinase inhibitor aprotinin.
• Main results:
  • HGF/SF increased motility of the mixed-phenotype TA cell line five-fold, with a weaker but significant effect in the fibroblastoid BR cells. Motility of the epithelial BT cells rose over the whole range of concentrations, but these cells needed a longer time to migrate.
  • In TA cells, neutralizing anti-HGF/SF antibodies strongly reduced the HGF/SF-induced motility; the discussion reports a 4-fold reduction in migration.
  • Pre-treatment with HGF/SF for 24 hours enhanced adhesion to Matrigel in all three cell lines, particularly in TA and BR cells.
  • BR and TA cells were highly invasive in Matrigel. BT cells did not invade even in 48-hour assays. HGF/SF markedly stimulated invasion in all lines, most strongly in TA cells, and BT cells became weakly invasive with the factor after 48 hours.
  • TA cell invasion was reduced by proteinase inhibitors in a dose-dependent manner; the serine protease inhibitor aprotinin was more efficient than the MMP inhibitor CT1746.
  • HGF/SF increased MMP-9 by 50–60% in BT cells and 70–90% in TA cells. It had no effect on MMP-9 in BR cells and no effect on MMP-2 in any cell line.
  • BT cells secreted more MMP-1 than the other two lines, and HGF/SF increased it 4–5-fold. By ELISA, MMP-1 in BT cells was 26.2 ng per mg protein without HGF/SF and 101.0 at 1 ng per ml HGF/SF. MMP-1 was lowest in TA cells but was stimulated by HGF/SF. HGF/SF had no effect on MMP-1 in BR cells.
  • HGF/SF increased MT1-MMP by 50–90% in BT and TA cells but not in BR cells. MMP-3 was detected only in TA cells and was not appreciably stimulated by HGF/SF.
  • TIMP-1 levels were higher in BR and TA cells than in BT cells and were slightly enhanced by HGF/SF. TIMP-2 seemed equal across the three lines and was not affected by the factor.
  • The 10-fold increase in TA cell invasion could not be correlated with up-regulation of any particular MMP.
• The authors' conclusion: The authors concluded that HGF/SF had a major stimulatory effect on adhesion and invasion of the mesothelioma cell lines. They also concluded that the relationships between cell behaviour and MMP/TIMP expression profiles were complex and disparate, and that serine proteases may be involved in HGF/SF-induced invasion.
• Limitations the authors state:
  • The authors could not block TA cell invasion using a range of concentrations and combinations of protease inhibitors; high concentrations of MMP inhibitors reduced it only slightly.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Metastasis.

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