100th Anniversary of Nagoya J Med Sci: Comments to the Highly Cited Articles
Nagoya J. Med. Sci. 85. 13–15, 2023
doi:10.18999/nagjms.85.1.13

Commentary on “Mechanisms of asbestos-inducedcarcinogenesis” published in 2009
Shinya Toyokuni
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine,Nagoya, Japan

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Toyokuni S. Mechanisms of asbestos-induced carcinogenesis. Nagoya J Med Sci. 2009;71(1–2):
1–10.
Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM
and the development of animal models, the carcinogenic mechanisms of the disease remain
unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-inducedDMM, which may be summarized as follows: (1) the “oxidative stress theory” is based on thefact that phagocytic cells that engulf asbestos fibers produce large amounts of free radicals dueto their inability to digest the fibers, and epidemiological studies indicating that iron-containing
asbestos fibers appear more carcinogenic; (2) the “chromosome tangling theory” postulates thatasbestos fibers damage chromosomes when cells divide; and (3) the “theory of adsorption ofmany specific proteins as well as carcinogenic molecules” states that asbestos fibers in vivo
concentrate proteins or chemicals including the components of cigarette smoke. Elucidationof the major mechanisms underlying DMM would be helpful for the development of novel
strategies to prevent DMM induction in people who have already been exposed to asbestos.
Keywords: Asbestos, Mesothelioma, Iron, Oxidative stress
Asbestos is a natural fibrous mineral, which has been used abundantly for various industrial
purposes especially in the last century. It is unfortunate that this material has been used till 2006
in Japan and is still in use in many developing countries due to the economical merits though
International Agency for Research on Cancer (IARC) in World Health Organization announced
that all the asbestos is a definite carcinogen to humans in 1987. Chrysotile, crocidolite andamosite are the major three asbestos mined, manufactured and used.1 I am excited to know that
this review article on the mechanism of asbestos-induced carcinogenesis published in the Nagoya
Journal of Medical Science in 20092 attracted the interests of many researchers with high citation.
Received: July 14, 2022; accepted: July 14, 2022
Corresponding Author: Shinya Toyokuni, MD, PhD
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine,
65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Phone: +81-52-744-2086; Fax: +81-52-744-2091; E-mail: toyokuni@med.nagoya-u.ac.jp
13Shinya Toyokuni

Of note, mesothelial cells are the major target cells in asbestos-induced carcinogenesis. In thisreview article, I for the first time summarized the carcinogenic mechanism into three distinct
processes: 1) scavenging of asbestos fibers by macrophages, leading to persistent free radicalgeneration (frustrated phagocytosis), 2) unexpected intense phagocytic activity of mesothelial cells,and 3) adsorption of specific proteins on asbestos surface (Ex. hemoglobin and histone). Notably
a combination of the 2nd and the 3rd mechanisms I proposed can explain the specific mutagenic
activity of asbestos in mesothelial cells via providing oxidative damage through the attractionof iron-loaded asbestos to chromosomal histones. In this review article,2 I also suggested themechanisms why chrysotile, white asbestos with no iron in itself, can induce similar oxidative
DNA damage, where high hemolytic activity via chrysotile was the key phenomenon.

Fig. 1Current understanding of asbestos-induced mesothelial carcinogenesis

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Shinya Toyokuni

More than 10 years after the publication, there have been great advancements in theunderstanding of molecular mechanisms. We have revealed that chrysotile-induced malignant
mesothelioma in rats shows excess iron pathology with homozygous deletion of p16Ink4a tumor
suppressor gene,3 which we believe is the evidence of iron-induced carcinogenesis.4 Carbon nanotubes are an essential material for modern electronic technologies, such as semiconductors andlithium batteries. Multiwalled carbon nanotube of ~50 nm diameter shows the similar pathologic
processes to those of asbestos,5 which has to be carefully handled as assigned Group 2B by
IARC. Iron removal either by iron chelating agents or phlebotomy could work as cancer prevention of asbestos-induced mesothelial carcinogenesis at least in the preclinical animal models.4
Recently, further advances have been achieved on this topic. It is well established that
exosomes, containing various intracellular molecules, are used for multicellular communications
in vivo. Our laboratory recently found a link between exosome production and iron metabolism. Specifically, CD63, a representative exosome marker, is regulated posttrancriptionally via
iron-regulatory protein/iron-responsive element system, which is specific for iron metabolism.6
Furthermore, macrophages exposed to the asbestos of diameter and/or length which they cannot
cope with die in the form of ferroptosis. In those situations, iron-loaded ferritin is released asexosomes from the dying macrophages representing ferroptosis. Notably, these exosomes arereceived by mesothelial cells where oxidative DNA damage, such as DNA double-strand breaks
and 8-hydroxy-2’-deoxyguanosine, is induced7. This is a novel indirect mechanism of asbestosinduced mesothelial carcinogenesis (Fig. 1). In this way, this review article worked as a detonator
for further elucidation of asbestos-induced mesothelial carcinogenesis.

REFERENCES
1IARC W. Asbestos (chrysotile, amosite, crocidolite, tremolite, actinolite, and anthophyllite). IARC Monographs on the Evaluation of Carcinogenic. Risks to Humans. A Review of Human Carcinogens; Part C:
Arsenic, Metals, Fibres, and Dusts. Volume 100C. Lyon, France 2012. p 219–309.
2 Toyokuni S. Mechanisms of asbestos-induced carcinogenesis. Nagoya J Med Sci. 2009;71:1–10.
3 Jiang L, Akatsuka S, Nagai H et al. Iron overload signature in chrysotile-induced malignant mesothelioma.
J Pathol. 2012;228:366–377. doi:10.1002/path.4075.
4 Toyokuni S. Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis:
Toward the era of mesothelioma prevention. Free Radic Biol Med. 2019;133:206–215. doi:10.1016/j.
freeradbiomed.2018.10.401.
5 Nagai H, Okazaki Y, Chew S et al. Diameter and rigidity of multiwalled carbon nanotubes are critical factors
in mesothelial injury and carcinogenesis. Proc Natl Acad Sci U S A. 2011;108:E1330-E1338. doi:10.1073/
pnas.1110013108.
6 Yanatori I, Richardson DR, Dhekne HS, Toyokuni S, Kishi F. CD63 is regulated by iron via the IREIRP system and is important for ferritin secretion by extracellular vesicles. Blood. 2021;138:1490–1503.
doi:10.1182/blood.2021010995.
7 Ito F, Kato K, Yanatori I, Murohara T, Toyokuni S. Ferroptosis-dependent extracellular vesicles frommacrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin. Redox Biol.
2021;47:102174. doi:10.1016/j.redox.2021.102174.
References End

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