The role of the HGF/Met axis in mesothelioma

Our plain-English summary of The role of the HGF/Met axis in mesothelioma, by T. Thayaparan, J.F. Spicer, J. Maher (Biochemical Society Transactions, 2016).

The study

• Authors: T. Thayaparan, J.F. Spicer, J. Maher
• Journal: Biochemical Society Transactions
• Published: 2016;44(2):363-70
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is an asbestos-related cancer that occurs most commonly in the pleural space and is incurable. Increasing evidence suggests that aberrant receptor tyrosine kinase (RTK)-directed signalling plays a key role in the pathogenesis of this cancer. In the majority of mesotheliomas, up-regulated expression or signalling by Met, the receptor for hepatocyte growth factor (HGF) can be demonstrated. Following binding of ligand, Met relays signals that promote cell survival, proliferation, movement, invasiveness, branching morphogenesis and angiogenesis. Here we describe the HGF/Met axis and review the mechanisms that lead to the aberrant activation of this signalling system in mesothelioma. We also describe the cross-talk that occurs between HGF/Met and a number of other receptors, ligands and co-receptor systems. The prevalent occurrence of HGF/Met dysregulation in patients with mesothelioma sets the scene for the investigation of pharmaceutical inhibitors of this axis. In light of the inter-relationship between HGF/Met and other ligand receptor, combinatorial targeting strategies may provide opportunities for therapeutic advancement in this challenging tumour.

© 2016 Authors; published by Portland Press Limited.

In plain English

This article is a review, not a new study. The authors, from King's College London and London hospitals, described a signalling system made up of hepatocyte growth factor (HGF) and its receptor, Met. They reviewed published research on how this system is disrupted in malignant mesothelioma, mostly malignant pleural mesothelioma. In one study they cited, 33 of 39 pleural mesothelioma tumours stained positive for HGF. Four series of 35 to 157 tumours found Met in 74% to 82% of tumours. Mutations in the MET gene itself were estimated to occur in about 3% of tumours. In other cited studies, crocidolite asbestos raised Met in mouse mesothelial cells and raised HGF in lung and pleural washing fluid of rats. In cell-line studies, blocking Met and the EGF receptor together suppressed cell growth more than blocking either alone. The authors noted uncertainties, including increasing evidence that tivantinib and other Met inhibitors have significant off-target effects on other kinases. They concluded that HGF/Met disruption is common in mesothelioma and that combined targeting approaches may prove more effective.

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: Narrative review of published laboratory, animal and clinical research; no new data collected
• Who was studied: No new patients or subjects. The review covered published studies of malignant mesothelioma tumours (mostly malignant pleural mesothelioma), pleural effusions, mesothelioma cell lines, and mouse and rat models.
• Exposure: Not an exposure study; the topic is HGF/Met cell signalling. The review describes cited studies in which murine mesothelial cells, and rats by intratracheal instillation, were exposed to crocidolite asbestos.
• Main results:
  • In a cited study by Tolnay et al., 33 of 39 malignant pleural mesothelioma tumours stained positive for HGF. Only one in eight sarcomatoid tumours was positive.
  • In four cited series of malignant pleural mesothelioma tumours, Met expression was found in 74% (n = 39), 80% (n = 35), 82% (n = 66) and 76% (n = 157) of tumours.
  • Somatic mutation of the MET gene was estimated to be detectable in approximately 3% of malignant pleural mesothelioma tumours.
  • In a cited rat study, crocidolite asbestos delivered by intratracheal instillation was followed by proliferation of bronchoalveolar epithelium and pleural mesothelial cells. HGF and keratinocyte growth factor levels rose in bronchoalveolar and pleural lavage fluid.
  • In one cited series, high plasma membrane expression of Met was associated with improved outcome. The study's authors noted that this finding requires independent validation.
  • In cited studies using mesothelioma cell lines, combined inhibition of Met and the EGF receptor suppressed cell growth, migration and invasion more than targeting either receptor alone.
  • At the time of writing, a Phase 2 trial of the Met inhibitor tivantinib was ongoing in mesothelioma patients who had failed prior therapies. Monoclonal antibodies against HGF or Met were not being evaluated in mesothelioma.
• The authors' conclusion: The authors concluded that dysregulation of the HGF/Met axis is prevalent in malignant mesothelioma. Because of cooperative signalling with other receptor systems, they concluded that combinatorial targeting approaches may prove more effective.
• Limitations the authors state:
  • The authors stated that it remains uncertain whether the T1010I polymorphism has clinical relevance in mesothelioma.
  • The authors stated that results of Met inhibitor trials, including the tivantinib trial, must be interpreted in light of increasing evidence that these drugs have significant off-target effects on other kinases.
  • The authors noted that the cell-line situations in which Met inhibitors suppressed growth occur in only a minority of mesotheliomas, and that the situation in the body is more complex.

Topics

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

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

Related studies

• Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma — E. Tolnay, C. Kuhnen, et al. (1998)
• Perifosine as a potential novel anti-cancer agent inhibits EGFR/MET-AKT axis in malignant pleural mesothelioma — G. Pinton, A.G. Manente, et al. (2012)
• Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy — X.B. Deng, L. Xiao, et al. (2015)
• Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy — M. Brevet, S. Shimizu, et al. (2011)
• Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma — W.B. Ou, C. Hubert, et al. (2011)
• PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma — R. Kanteti, J.J. Riehm, et al. (2016)

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