Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells

Our plain-English summary of Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells, by Y. Sekido (Cancer Science, 2010).

The study

• Author: Y. Sekido
• Journal: Cancer Science
• Published: 2010;101(1):1-6
• Type of article: Review
• Cited by: 71 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a tumor with poor prognosis associated with asbestos exposure. While it remains to be clarified how asbestos fibers confer genetic/epigenetic alterations and induce cellular transformation in normal mesothelial cells, the understanding of key molecular mechanisms of MM cell development, proliferation, and invasion has progressed. MM shows frequent genetic inactivation of tumor suppressor genes of p16(INK4a)/p14(ARF) and neurofibromatosis type 2 (NF2) which encodes Merlin, and epigenetic inactivation of RASSF1A. However, no frequent mutations of well-known oncogenes such as K-RAS and PIK3CA have been identified. Activation of multiple receptor tyrosine kinases including the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades are frequently observed in most MM cells. The tumor suppressive function of Merlin in MM cells is also being investigated by dissecting its possible downstream signaling cascade called the Hippo pathway. Further comprehensive delineation of dysregulated signaling cascades in MM cells will lead to identification of key addiction pathways for cell survival and proliferation of MM cells, which strongly promote establishment of a new molecular target therapy for MM.

In plain English

This article was a review by a single author, not a new study of patients or workers. It summarized published laboratory, animal and clinical research on gene changes and faulty cell signaling in malignant mesothelioma, a cancer the article describes as associated with asbestos exposure. The review stated that the link between amphibole asbestos and mesothelioma is well accepted, that crocidolite is considered the most cancer-causing type, and that whether chrysotile causes mesothelioma is still controversial. In the studies reviewed, the gene p16INK4a/p14ARF was the most frequently inactivated tumor suppressor gene, and the NF2 gene was inactivated in 40 to 50% of mesotheliomas. Growth-signal receptors such as MET and EGFR were often activated. However, in the clinical studies cited, the EGFR-blocking drug gefitinib was not active, and imatinib, which targets other receptors, showed limited efficacy. The author concluded that mesothelioma is caused by multiple genetic and epigenetic changes and that this knowledge should help develop targeted treatments. The author also wrote that the long delay between asbestos exposure and the tumor is still unexplained.

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 article summarizing published research on genetic, epigenetic and cell-signaling abnormalities in malignant mesothelioma (MM). It includes one illustrative figure of receptor testing on a single surgically removed pleural mesothelioma specimen.
• Who was studied: No study population of its own. The review covered published studies of human MM tumors, MM cell lines, mouse models of MM, and clinical trials in MM patients.
• Exposure: Asbestos in general, as background. The review describes the amphiboles (amosite, crocidolite, anthophyllite, actinolite, tremolite) and the serpentine chrysotile. It states that the amphibole association with MM is well accepted, that crocidolite is considered the most oncogenic type, and that whether chrysotile causes MM is still controversial. Erionite in Cappadocia, Turkey, is also mentioned.
• Main results:
  • Per the studies reviewed, p16INK4a/p14ARF is the most frequently inactivated tumor suppressor gene in human MM, while only 20 to 25% of MMs show a p53 mutation.
  • Per a cited study of established malignant pleural mesothelioma cell lines, 90% had a homozygous deletion of the p16INK4a/p14ARF gene locus.
  • Per cited studies, the NF2 gene, which encodes the protein Merlin, is inactivated in 40 to 50% of MMs.
  • Per cited studies, K-RAS mutation has not been reported in MM. One study found an activating N-RAS mutation in three of 38 MMs.
  • Per cited studies of MM cell lines (not patients), MET and EGFR family receptors were the most frequently activated of 42 receptor tyrosine kinases studied. In those cells, combined MET and EGFR inhibitors suppressed growth more strongly than either inhibitor alone.
  • Per the cited clinical studies, gefitinib, an EGFR inhibitor, was not active in a phase II study of 43 previously untreated MM patients, even though 97% had EGFR overexpression. Imatinib, which affects Kit and PDGF receptors, showed limited efficacy for malignant pleural mesothelioma. The article does not report a clinical trial of MET blockade.
  • Per a cited study, significantly higher lung asbestos burden was associated with promoter methylation of cell cycle control genes, including RASSF1A, in malignant pleural mesotheliomas.
• The authors' conclusion: The author concluded that MM is an aggressive malignancy caused by multiple genetic and epigenetic changes, and that knowledge of these abnormalities will help develop molecular target therapy and other treatments. The author also noted that the long latency between asbestos exposure and MM remains an enigma.
• Limitations the authors state:
  • The author states that citations for many observations had to be omitted because of restrictions on preparing review manuscripts.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Prognosis, Asbestos Exposure, Mesothelial Cells, Tumor Suppressor Gene, Merlin, EGFR.

Related studies

• Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro — M. You, J. Varona-Santos, et al. (2014)
• Cross reactivity between many anti-human antibodies for their hamster homologs provide the tools to study the signal transduction pathway activated by asbestos and SV40 in the malignant mesothelioma model — B. Kroczynska, M. Carbone (2006)
• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• Crocidolite asbestos-induced signal pathway dysregulation in mesothelial cells — H. Wang, A. Gillis, et al. (2011)
• New vistas in malignant mesothelioma: MicroRNA architecture and NRF2/MAPK signal transduction — M. Gandhi, S. Nair (2020)
• Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells — Y.J. Lee, H.Y. Jeong, et al. (2012)

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