HGF/Met Signaling Is a Key Player in Malignant Mesothelioma Carcinogenesis

Our plain-English summary of HGF/Met Signaling Is a Key Player in Malignant Mesothelioma Carcinogenesis, by G. Gaudino, H. Yang, M. Carbone (Biomedicines, 2014).

The study

• Authors: G. Gaudino, H. Yang, M. Carbone
• Journal: Biomedicines
• Published: 2014;2(4):327-344
• Type of article: Review
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a highly aggressive cancer related to asbestos or erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF) and its tyrosine kinase receptor Met regulate cell growth, survival, motility/migration, and invasion. HGF and Met are expressed in MM cells, suggesting that the HGF/Met signaling plays a role in development and progression of this tumor, by autocrine and/or paracrine mechanisms. Upregulation and ligand-independent activation of Met, which is under suppressive control of miR-34 family members, correlate with enhanced invasion, migration and metastatic potential in several cancers, including MM. Moreover, Simian Virus 40 (SV40) Tag expression also induces a HGF autocrine circuit in an Rb-dependent manner in human mesothelial cells (HM) and possibly other cell types, enhancing cell adhesion, invasion and angiogenesis. The resulting activation of Met causes HM transformation and cell cycle progression, and contributes to virus particle assembling and infection of adjacent cells. The constitutive activation of Met, frequently occurring in MM, has been successfully targeted in preclinical models of MM. In conclusion, Met expression, activation state, subcellular localization and also HGF co-receptors expression, such as CD44, have clinical relevance for novel targeted therapies in a cancer for which no effective treatment is currently available.

In plain English

This article was a review, not a new study. The authors summarized published laboratory and animal research, including some of their own earlier work, on how a growth factor called HGF and its receptor Met may be involved in the development of malignant mesothelioma. The review did not enroll new patients or workers. It described earlier reports that HGF and Met are highly expressed in most mesothelioma cells and tissues. It also cited the authors' earlier laboratory work. That work reported that a signaling protein called Akt was responsible for resistance to cell death in human mesothelial cells and mesothelioma cells after amosite asbestos exposure. It reported that exposure to either crocidolite or chrysotile fibers led to a change in cell form called epithelial-mesenchymal transition. It also reported that the virus SV40 switched on an HGF signaling loop in mesothelial cells. The review described Met-blocking agents tested in cell and animal models. The authors concluded that HGF and Met are key players in mesothelioma development and that targeted therapy is promising. They also stated that the evidence supporting this as a treatment target is still limited.

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 and animal research, including the authors' own earlier work
• Who was studied: No newly enrolled study population. The review covered published research on mesothelioma cell lines, cells from pleural fluids of patients, human mesothelial cells, tumor specimens and animal models.
• Exposure: Mineral fibers in laboratory studies: amosite, crocidolite and chrysotile asbestos, and erionite. Simian Virus 40 (SV40) was discussed as a potential cofactor.
• Main results:
  • The review reported, citing earlier studies, that HGF and Met are highly expressed in most malignant mesothelioma cells and tissues.
  • Citing the authors' earlier work, the review stated that Akt signaling was responsible for resistance to cell death in human mesothelial cells and mesothelioma cells after amosite asbestos exposure.
  • Citing the authors' earlier work, the review stated that exposure of human mesothelial cells to either crocidolite or chrysotile fibers resulted in epithelial-mesenchymal transition, with E-cadherin downregulation.
  • Citing the authors' earlier work, the review stated that continuous chrysotile exposure could transform human mesothelial cells in the laboratory (in vitro), though with limited transforming potential compared with crocidolite.
  • Citing the authors' earlier work, the review stated that the SV40 large T antigen (Tag) induces an HGF autocrine circuit in human mesothelial cells.
  • Citing an earlier study, the review reported that NK4, an HGF fragment that blocks Met, significantly inhibited tumor growth in a mouse xenograft model of mesothelioma.
• The authors' conclusion: The authors concluded that HGF and Met are key players in mesothelioma carcinogenesis and tumor progression. They described targeted therapy against HGF, Met and their downstream pathways as promising.
• Limitations the authors state:
  • The authors stated that the evidence supporting HGF/Met signaling as a therapeutic target for mesothelioma is still limited and needs further preclinical and clinical validation.
  • The authors stated there is no evidence yet that CSPG4 cooperates with Met in the way its homolog CD44 does.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Carcinogenesis, erionite, SV40, Mesothelial Cells, Angiogenesis.

Related studies

• Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling — F. Qi, G. Okimoto, et al. (2013)
• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling — F. Novelli, Y. Yoshikawa, et al. (2024)
• Mesothelioma epidemiology, carcinogenesis, and pathogenesis — H. Yang, J.R. Testa, et al. (2008)
• Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma — M. Carbone, H. Yang (2012)
• Arsenic, asbestos and radon: emerging players in lung tumorigenesis — R. Hubaux, D.D. Becker-Santos, et al. (2012)
• Asbestos: a hidden player behind the cholangiocarcinoma increase? Findings from a case-control analysis — G. Brandi, S. Di Girolamo, et al. (2013)

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