Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways

Our plain-English summary of Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways, by N.H. Heintz, Y.M. Janssen-Heininger, B.T. Mossman (American Journal of Respiratory Cell and Molecular Biology, 2010).

The study

• Authors: N.H. Heintz, Y.M. Janssen-Heininger, B.T. Mossman
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2010;42(2):133-9
• Type of article: Review
• Cited by: 131 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Fifteen years have passed since we published findings in the AJRCMB demonstrating that induction of early response fos/jun proto-oncogenes in rodent tracheal and mesothelial cells correlates with fibrous geometry and pathogenicity of asbestos. Our study was the first to suggest that the aberrant induction of signaling responses by crocidolite asbestos and erionite, a fibrous zeolite mineral associated with the development of malignant mesotheliomas (MMs) in areas of Turkey, led to altered gene expression. New data questioned the widely held belief at that time that the carcinogenic effects of asbestos in the development of lung cancer and MM were due to genotoxic or mutagenic effects. Later studies by our group revealed that proto-oncogene expression and several of the signaling pathways activated by asbestos were redox dependent, explaining why antioxidants and antioxidant enzymes were elevated in lung and pleura after exposure to asbestos and how they alleviated many of the phenotypic and functional effects of asbestos in vitro or after inhalation. Since these original studies, our efforts have expanded to understand the interface between asbestos-induced redox-dependent signal transduction cascades, the relationship between these pathways and cell fate, and the role of asbestos and cell interactions in development of asbestos-associated diseases. Of considerable significance is the fact that the signal transduction pathways activated by asbestos are also important in survival and chemoresistance of MMs and lung cancers. An understanding of the pathogenic features of asbestos fibers and dysregulation of signaling pathways allows strategies for the prevention and therapy of asbestos-related diseases.

In plain English

This article was a review, not a new study. The authors, from the University of Vermont, looked back on fifteen years of laboratory research, much of it from their own group, on how asbestos fibers set off chemical signaling inside lung cells and mesothelial cells (cells lining the chest). They described their earlier finding that the ability of fibers to switch on two proto-oncogenes, c-fos and c-jun, correlated with the fibers' carcinogenic potential. Riebeckite particles, which have the same chemical composition as crocidolite asbestos, were less potent. They described work showing that chrysotile and crocidolite, but not the nonfibrous analogs antigorite and riebeckite, activated a growth-factor receptor (EGFR) in mesothelial cells. Asbestos also activated another factor, NF-kB, in cultured cells and in rat lungs after inhalation. They reviewed drug trials by others, including a phase II trial in 63 patients with mesothelioma in which erlotinib alone was ineffective in terms of median overall survival. The authors concluded that these pathways are often up-regulated in malignant mesotheliomas, contributing to tumor development and chemotherapy resistance, and that other treatment targets should be explored.

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 laboratory (cell culture and rodent) research, largely by the authors' own group, plus cited clinical trials
• Who was studied: No study population of its own; the review covered in vitro studies of rodent and human mesothelial, tracheal and lung epithelial cells and mesothelioma cells, rodent inhalation studies, and clinical trials in patients with mesothelioma and non-small cell lung cancer
• Exposure: Mainly crocidolite and chrysotile asbestos (also amosite and erionite discussed), compared with nonfibrous analogs (riebeckite, antigorite) and nonfibrous particles (platy talc, fine titanium dioxide, glass beads)
• Main results:
  • In the authors' earlier AJRCMB study, the ability of asbestos fibers to induce c-fos and c-jun correlated with the carcinogenic potential of fibers; riebeckite particles were less potent than crocidolite
  • In earlier work described in the review, persistent induction of proto-oncogenes was dose related, occurred at subcytotoxic concentrations, and was most striking with crocidolite compared with chrysotile
  • In the authors' earlier work, chrysotile and crocidolite, but not their nonfibrous analogs antigorite and riebeckite, activated the EGFR in mesothelial cells
  • In a gene-profiling study of human mesothelial cells described in the review, asbestos fibers changed expression of several AP-1-regulated and other genes, while nonfibrous materials caused no or transient expression of a few genes
  • In a phase II trial by others cited in the review, erlotinib alone was ineffective in terms of median overall survival in 63 patients with mesothelioma, despite overexpression of EGFR in 75% of tumors
  • In a cited phase II study of erlotinib plus bevacizumab in previously treated mesothelioma patients, no evidence of a favorable radiographic response was observed
• The authors' conclusion: The authors concluded that signaling and survival pathways initiated by asbestos in mesothelial and lung epithelial cells are often up-regulated in malignant mesotheliomas, where they contribute to tumor development, homeostasis and resistance to chemotherapy. They added that no single modality therapy has proven effective and that other targets should be explored.
• Limitations the authors state:
  • The authors stated that understanding is still lacking of the precise cellular targets perturbed by different asbestos fiber types and of how signaling information dictates outcomes in different cell types

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: Lung Cancer, Mesothelioma, Mesothelial Cells, Crocidolite, erionite, Zeolite, Malignant Mesothelioma, Carcinogenic.

Related studies

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• Cell signaling pathways elicited by asbestos — B.T. Mossman, S. Faux, et al. (1997)
• Oxidants and signaling by mitogen-activated protein kinases in lung epithelium — B.T. Mossman, K.M. Lounsbury, et al. (2006)
• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma — M. Carbone, H. Yang (2012)
• An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury — A. Shukla, T.F. Barrett, et al. (2011)

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