Mechanism of fiber carcinogenesis: from reactive radical species to silencing of the beta igH3 gene

Our plain-English summary of Mechanism of fiber carcinogenesis: from reactive radical species to silencing of the beta igH3 gene, by T.K. Hei, A. Xu, S.X. Huang, et al (Inhalation Toxicology, 2006).

The study

• Authors: T.K. Hei, A. Xu, S.X. Huang, Y. Zhao
• Journal: Inhalation Toxicology
• Published: 2006;18(12):985-90
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Although the U.S. Environmental Protection Agency has restricted the industrial use of regulated forms of asbestos in the United States since the early 1970s, environmental exposure to asbestos remains a health concern in the United States and is a significant health issue among developing countries. Exposure to asbestos is associated with chronic pulmonary diseases and cancer of the lung, pleura, and peritoneum. The mechanism of fiber carcinogenesis is far from clear and is likely to be complex, depending on fiber dimensions, surface properties, and physical durability. The induction of reactive oxygen and nitrogen species upon phagocytosis of fibers plays an important role in fiber genotoxicity. The beta igH3, a secreted protein induced by the transforming growth factor-beta and essential for cell adhesion, is downregulated in asbestos-induced tumorigenic human bronchial epithelial cells. Ectopic expression of the beta igH3 gene abrogates the tumorigenic phenotype and suggests that the gene plays a causal role in fiber carcinogenesis. A better understanding of the carcinogenic mechanism of asbestos and other mineral fibers will provide useful information on interventional and preventive measures for asbestos-mediated diseases such as human pleural and peritoneal mesotheliomas.

In plain English

This article, from a Columbia University laboratory, reviewed proposed ways asbestos fibers may cause cancer and described the group's experiments in cells and mice. It did not study people. The authors listed five possible mechanisms, including reactive oxygen and nitrogen species and loss or silencing of tumor suppressor genes. In human–hamster hybrid cells exposed to crocidolite, L-NMMA, a blocker of the enzyme that makes nitric oxide, cut the mutation yield more than threefold. An inactive form of the blocker had little or no effect. Chrysotile-induced tumor-forming BEP2D cells (immortalized human bronchial cells) lost that ability when fused with nontumorigenic control BEP2D cells: none of 10 fused clones formed tumors in nude mice. Earlier work by the group had found βigH3 gene expression reduced more than seven- to eight-fold in these tumor cells. When the gene was re-expressed, 5 of 10 and 6 of 10 mice formed small tumor nodules at 4 weeks, versus 10 of 10 given unmodified tumor cells. The authors concluded that no single pathway accounts for all known effects of asbestos.

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: Review-style article on mechanisms of fiber carcinogenesis that also presents laboratory experiments (cell culture and mouse tumor tests) from the authors' group
• Who was studied: No human subjects. Human–hamster hybrid (AL) cells; human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells and their asbestos-induced tumorigenic derivatives (TB2A); athymic nude mice (10 per group in the gene re-expression test)
• Exposure: Crocidolite fibers at 4 µg/cm2 for 24 h in AL cells, with or without L-NMMA or D-NMMA (15 µM); chrysotile at 4 µg/cm2 for a single 7-day treatment to produce tumorigenic BEP2D cells
• Main results:
  • In AL cells exposed to crocidolite, L-NMMA (15 µM) suppressed the asbestos-induced mutation yield by more than threefold
  • D-NMMA, an inactive form that does not inhibit nitric oxide synthase, had little or no effect on fiber-induced mutation in AL cells
  • When chrysotile-induced tumorigenic BEP2D cells were fused with nontumorigenic control BEP2D cells, none of 10 independent fusion clones formed tumors in nude mice
  • Earlier cDNA microarray work by the group (cited as Zhao et al., 2002) found βigH3 gene expression downregulated by more than seven- to eight-fold in the asbestos-induced tumorigenic cells
  • In nude mice, 0/10 injected with parental BEP2D cells developed tumors after more than 20 weeks
  • 10/10 mice injected with TB2A or TB2A-pRc/CMV2 tumor cells developed growing tumors at 4 weeks, with average volumes of 544.9 mm3 and 495.9 mm3, respectively
  • After the βigH3 gene was re-expressed, 5/10 mice given clone 5 cells and 6/10 given clone 11 cells formed small tumor nodules at 4 weeks, with an average volume of 62.8 mm3. This was significantly smaller than with parental TB2A cells (p less than .01)
• The authors' conclusion: The authors concluded that the carcinogenic mechanism of asbestos is complex and that no single listed pathway accounts for all known effects of asbestos fibers. They stated that their re-expression results provide unequivocal evidence of a role for the βigH3 gene in fiber carcinogenesis.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Environmental Exposure, Pleura, Peritoneum, Fiber Dimensions, Phagocytosis, Genotoxicity, Transforming Growth Factor-beta (TGF-β).

Related studies

• Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles — A. Valavanidis, T. Vlachogianni, et al. (2009)
• Relationship of fiber surface iron and active oxygen species to expression of procollagen, PDGF-A, and TGF-beta(1) in tracheal explants exposed to amosite asbestos — J. Dai, A. Churg (2001)
• Asbestos-derived reactive oxygen species activate TGF-beta1 — D.A. Pociask, P.J. Sime, et al. (2004)
• Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis — I. Emerit (1994)
• Transforming growth factor-β-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway — G. Wen, M. Hong, et al. (2011)
• Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms — A. Valavanidis, T. Vlachogianni, et al. (2013)

Browse more research in Inhalation Toxicology, or return to medical research.