The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy

Our plain-English summary of The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy, by S. Toyokuni (Pathology International, 2016).

The study

• Author: S. Toyokuni
• Journal: Pathology International
• Published: 2016;66(5):245-59
• Type of article: Review
• Cited by: 81 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Helmut Sies established the concept of oxidative stress in 1985. However, it took some time to introduce this concept into pathology, where investigators count on formalin-fixed paraffin-embedded tissue sections. I sought out antigens for this purpose based on an oxidative stress-induced rat renal carcinogenesis model, which revealed that 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins are ideal. These two monoclonal antibodies successfully revealed the involvement of oxidative stress in numerous human diseases, including carcinogenesis and atherosclerosis. Shigeru Okada established the aforementioned ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model, which thus far has answered many questions regarding the presence of target genes in oxidative stress-induced carcinogenesis and the sites that are susceptible to oxidative stress in the genome. Particularly, the similarity of genomic alterations between Fe-NTA-induced renal cancer and human cancers suggests that excess iron plays a role also in human carcinogenesis. Furthermore, excess iron is a major pathology in asbestos-induced mesothelioma, including chrysotile. Despite an analogy to asbestos, multi-wall carbon nanotubes were distinct in that diameter is another responsible factor for mesothelial carcinogenesis. Recently, non-thermal plasma emerged as a candidate for medical intervention for wounds and cancers via manipulating oxidative stress. Counteracting excess iron is a promising preventive strategy for major diseases.

© 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

In plain English

This was a review in which the author described three decades of the author's involvement in oxidative stress research, including work with collaborators and by others. It summarized earlier studies rather than reporting a new one. The author described producing two monoclonal antibodies to detect oxidative damage in preserved tissue, using a rat kidney cancer model caused by an iron compound. In the asbestos section, the author summarized rat experiments in which chrysotile, crocidolite and amosite were injected into the abdominal cavity. Chrysotile was the earliest to induce malignant mesothelioma, followed by crocidolite and amosite, and almost all rats eventually developed it. Most tumors showed homozygous deletion of the p15/p16 tumor suppressor genes. The author suggested that chrysotile's uptake of hemoglobin, which is rich in iron, appears important. Multi-wall carbon nanotubes 50 nm in diameter showed potent carcinogenicity in rats, while tangled 15 nm nanotubes caused no mesothelial carcinogenesis. The author noted that the injection model skips the respiratory system. The author concluded by proposing appropriate blood donation or phlebotomy as cancer prevention for middle-aged people, especially men.

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 article (narrative review of previously published research on oxidative stress, iron and cancer by the author, the author's group and collaborators, including asbestos and carbon nanotube animal experiments)
• Who was studied: Rats used in the author's group's earlier experiments, including intraperitoneal asbestos injection experiments (numbers of animals not given in this review)
• Exposure: Intraperitoneal injection of 10 mg of chrysotile, crocidolite or amosite in rats; also multi-wall carbon nanotubes of different diameters; and ferric nitrilotriacetate (Fe-NTA), an iron compound, in a rat kidney cancer model
• Main results:
  • The author and collaborators produced two monoclonal antibodies to detect oxidative stress in formalin-fixed paraffin-embedded tissue specimens
  • In rats, intraperitoneal injection was the most sensitive route compared with intrapleural or intrapulmonary injection
  • In rats given intraperitoneal asbestos, chrysotile was the earliest to induce malignant mesothelioma, followed by crocidolite and amosite
  • Almost all of the rats eventually developed malignant mesothelioma
  • In rats, repeated administration of NTA (an iron chelator that promotes the Fenton reaction) promoted mesothelial carcinogenesis in all cases, which the author took as suggesting involvement of excess iron
  • Most asbestos-induced malignant mesotheliomas in rats showed homozygous deletion of the p15/p16 tumor suppressor genes (95% in Table 3)
  • In Table 3, the sarcomatoid subtype was common (50%) in asbestos-induced mesothelioma in rats
  • The author considered hemolytic activity and adsorption of hemoglobin by chrysotile, which contains no iron itself, to appear important
  • In animal experiments with iron reduction, the share of mesothelioma histology shifted toward the type with a better prognosis (epithelioid rather than sarcomatoid)
  • In a prospective rat study, rats with high serum CTGF (connective tissue growth factor) developed malignant mesothelioma earlier than rats with low serum CTGF; the difference was statistically significant
  • In rats, multi-wall carbon nanotubes 50 nm in diameter showed potent carcinogenicity
  • Tangled multi-wall carbon nanotubes 15 nm in diameter showed little mesothelial cytotoxicity and no mesothelial carcinogenesis
• The authors' conclusion: The author believed that iron addiction and resistance to ferroptosis (an iron-dependent form of cell death) are major components of cancer, and proposed appropriate blood donation or phlebotomy as cancer prevention for middle-aged people, especially men
• Limitations the authors state:
  • The intraperitoneal injection model skips the respiratory system
  • For non-thermal plasma therapy, the apparatus has not yet been standardized

Topics

Medical terms in this study, explained in our Lexicon: Oxidative Stress, Pathology, Carcinogenesis, Monoclonal, Mesothelioma, Chrysotile.

Related studies

• Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention — S. Toyokuni (2019)
• Free radical activity of industrial fibers: role of iron in oxidative stress and activation of transcription factors — P.S. Gilmour, D.M. Brown, et al. (1997)
• Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy — L. Shi, F. Ito, et al. (2017)
• Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis — L. Jiang, S.H. Chew, et al. (2016)
• 8-hydroxy-2' -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis — A. Valavanidis, T. Vlachogianni, et al. (2009)
• Effect of mineral particles containing iron on primary cultures of rabbit tracheal epithelial cells: possible implication of oxidative stress — C. Guilianelli, A. Baeza-Squiban, et al. (1993)

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