The pathogenesis of mesothelioma

Our plain-English summary of The pathogenesis of mesothelioma, by M. Carbone, C.W. Bedrossian (Seminars in Diagnostic Pathology, 2006).

The study

• Authors: M. Carbone, C.W. Bedrossian
• Journal: Seminars in Diagnostic Pathology
• Published: 2006;23(1):56-60
• Type of article: Review
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Widespread asbestos exposure during the past century has been linked to the dramatic increased incidence of malignant mesothelioma (MM), a malignancy that was so rare until 1950-1960 that some pathologists questioned its existence. Although asbestos has been clearly linked to MM pathogenesis, until recently the mechanisms of asbestos carcinogenesis in humans have remained obscure. Recent results revealed that asbestos carcinogenesis in humans and in rodents is linked to the activation of the AP-1 pathway, which induces cell division, and to the secretion of TNF-alpha (and the expression of its receptor) by mesothelial cells and by nearby macrophages exposed to asbestos. In mesothelial cells, TNF-alpha signaling through NF-kappaB activation prevents apoptosis and cell death, allowing mesothelial cells to survive the genetic damage induced by asbestos and divide. In addition, mutagenic oxygen radicals released mainly by lung macrophages may contribute to asbestos carcinogenesis. Very recent results indicate that mineral fiber carcinogenesis can be influenced by genetics and microbial infections. Genetic susceptibility to the mineral fiber erionite has been demonstrated in some Turkish families and causes a MM epidemic in Cappadocia, Turkey. In these mesothelioma families, exposure to minimal amounts of erionite or asbestos appears sufficient to cause mesothelioma. Recent results (Kroczynska B, et al: Proc Natl Acad Sci USA, in press), demonstrate that SV40 and crocidolite asbestos are cocarcinogens and that, in the presence of SV40, significantly lower amounts of asbestos suffice to induce MM. These findings indicate that the risk varies among asbestos- and erionite-exposed individuals because of their genetic background or because of exposure to other carcinogens. Moreover, these data provide a rationale for the observation that only a fraction of heavily exposed asbestos workers developed mesothelioma, and novel targets for prevention and therapy.

In plain English

This article was a short review, not a new study, of research on how mesothelioma develops. The authors cited a report on South African crocidolite miners in which mesothelioma incidence was about 4.7% (20 of 423 deaths), with a mean latency of 44.9 years. They described laboratory work, partly from one author's lab, suggesting that asbestos kills many human mesothelial cells in tissue culture, but that signaling through TNF-alpha and NF-kappaB lets damaged cells survive and divide. On chrysotile, they said the literature was too contradictory, and often tied to conflicts of interest, for them to say with confidence whether it causes mesothelioma. They also reviewed other factors: the mineral fiber erionite, an inherited predisposition in some families in Cappadocia, Turkey, the virus SV40, and, rarely, radiation. Citing one author's lab, they reported that with SV40 present, lower amounts of asbestos sufficed to cause mesothelioma in experimental animals and to transform human cells in culture. The authors concluded that such interactions raise mesothelioma risk when they occur, but need not occur for mesothelioma to develop.

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 research on mesothelioma pathogenesis (no new data collected for this article)
• Who was studied: No study population of its own; the authors reviewed published human, animal and cell-culture research
• Exposure: Asbestos (amphiboles including crocidolite and amosite, chrysotile, and tremolite contamination of chrysotile), the mineral fiber erionite, SV40 virus, genetic predisposition, and radiation
• Main results:
  • In a cited report on crocidolite asbestos miners in South Africa, mesothelioma incidence was about 4.7% (20 of 423 deaths)
  • Among those 20 miners' deaths, 6 had been exposed for 12 to 95 months, 6 for 96 to 191 months, and 8 for more than 192 months
  • In those miners, the mean latency was 44.9 years from the time of exposure
  • The authors cited animal experiments indicating that mesothelioma did not develop below a dose of about 1 mg
  • In the authors' earlier tissue-culture work, high asbestos doses killed 100% of exposed human mesothelial cells in less than a week (the dose unit is garbled in the text), while similar doses caused little or no harm to human fibroblasts
  • Cited recent findings indicated that TNF-alpha signaling through NF-kappaB increases the percentage of human mesothelial cells that survive asbestos exposure
  • After reviewing the literature, one author concluded it was not possible to state with sufficient confidence whether chrysotile did or did not cause mesothelioma
  • In cited mouse experiments, about 20% of mice injected with high doses of crocidolite developed mesothelioma, compared with 100% of mice injected with erionite
  • Pedigree analysis in Cappadocian villages showed that mesothelioma predisposition was inherited in certain families
  • One author's team found no chemical or crystal-structure differences between Cappadocian erionite and erionite from elsewhere that could explain higher carcinogenicity
  • SV40 caused mesothelioma in 100% of hamsters injected in the pleural space and in 60% of those injected intracardially
  • Reported SV40 detection in mesothelioma biopsies varied: about 50% in some US studies, only 6% in others
  • Findings from one author's lab showed that in the presence of SV40 infection, lower amounts of asbestos were sufficient to cause mesothelioma in experimental animals and to transform human cells in tissue culture
• The authors' conclusion: The authors concluded that when interactions among genetics, mineral fibers and viruses such as SV40 occur, mesothelioma risk is higher, but that such interactions need not occur for mesothelioma to develop
• Limitations the authors state:
  • The authors noted that animal dose-response findings may not reflect humans, because laboratory animals are not exposed to other cocarcinogens and have short life spans
  • The authors said much of the chrysotile literature was written or sponsored by parties with strong conflicts of interest
  • The authors noted that technical differences may explain discrepancies in SV40 detection rates

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, Asbestos Exposure, Carcinogenesis, Mesothelial Cells, Macrophage, Apoptosis, Mineral Fiber, erionite.

Related studies

• Pathogenesis of malignant mesothelioma — M. Carbone, M.A. Rdzanek (2004)
• Milky spots (Taches laiteuses) as structures which trap asbestos in mesothelial layers and their significance in the pathogenesis of mesothelial neoplasia — K. Kanazawa, F.J. Roe, et al. (1979)
• Pathogenesis of experimentally induced asbestos mesothelioma in rats — L.A. Vasilieva, L.N. Pylev, et al. (1998)
• Role of fragile histidine triad protein expression in pathogenesis of malignant pleural mesothelioma — E. Tutar, H. Kiyici (2008)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice — G.S. Warshamana, D.A. Pociask, et al. (2002)

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