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Mesothelioma: HELP
Articles by Shinya Toyokuni
Based on 38 articles published since 2010
(Why 38 articles?)
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Between 2010 and 2020, S. Toyokuni wrote the following 38 articles about Mesothelioma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention. 2019

Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Sydney Medical School, The University of Sydney, NSW, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Free Radic Biol Med · Pubmed #30312759.

ABSTRACT: Cancer is the primary cause of human mortality in most countries. This tendency has increased as various medical therapeutics have advanced, which suggests that we cannot escape carcinogenesis, although the final outcome may be modified by exposomes and statistics. Cancer is classified by its cellular differentiation. Mesothelial cells are distinct in that they line somatic cavities, facilitating the smooth movement of organs, but are not exposed to the external environment. Malignant mesothelioma, or simply mesothelioma, develops either in the pleural, peritoneal or pericardial cavities, or in the tunica vaginalis testes. Mesothelioma has been a relatively rare cancer but is socially important due to its association with asbestos exposure, caused by modern industrial development. The major pathogenic mechanisms include oxidative stress either via catalytic reactions against the asbestos surface or frustrated phagocytosis of macrophages, and specific adsorption of hemoglobin and histones by asbestos fibers in the presence of phagocytic activity of mesothelial cells. Multiwall carbon nanotubes of ~50 nm-diameter, additionally adsorbing transferrin, are similarly carcinogenic to mesothelial cells in rodents and were thus classified as Group 2B carcinogens. Genetic alterations found in human and rat mesothelioma notably contain changes found in other excess iron-induced carcinogenesis models. Phlebotomy and iron chelation therapies have been successful in the prevention of mesothelioma in rats. Alternatively, loading of oxidative stress by non-thermal plasma to mesothelioma cells causes ferroptosis. Therefore, carcinogenesis by foreign fibrous inorganic materials may overlap the uncovered molecular mechanisms of birth of life and its evolution.

2 Review Malignant mesothelioma as an oxidative stress-induced cancer: An update. 2015

Chew, Shan Hwu / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. · Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Free Radic Biol Med · Pubmed #25975982.

ABSTRACT: Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. On fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasomes in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and TGF-β pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP1 as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still ~8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by β-catenin, has been recognized as a hopeful target for therapy, especially in sarcomatoid subtype. Recent research outcomes related to microRNAs and cancer stem cells also offer additional novel targets for the treatment of MM. Iron reduction as chemoprevention of mesothelioma is helpful at least in an animal preclinical study. Integrated approaches to fiber-induced oxidative stress would be necessary to overcome this currently fatal disease.

3 Review Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis. 2014

Toyokuni, Shinya. · ·Redox Rep · Pubmed #24257681.

ABSTRACT: Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated because of the long incubation period for MM.

4 Review Genotoxicity and carcinogenicity risk of carbon nanotubes. 2013

Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Adv Drug Deliv Rev · Pubmed #23751780.

ABSTRACT: Novel materials are often commercialized without a complete assessment of the risks they pose to human health because such assessments are costly and time-consuming; additionally, sometimes the methodology needed for such an assessment does not exist. Carbon nanotubes have the potential for widespread application in engineering, materials science and medicine. However, due to the needle-like shape and high durability of multiwalled carbon nanotubes (MWCNTs), concerns have been raised that they may induce asbestos-like pathogenicity when inhaled. Indeed, experiments in rodents supported this hypothesis. Notably, the genetic alterations in MWCNT-induced rat malignant mesothelioma were similar to those induced by asbestos. Single-walled CNTs (SWCNTs) cause mitotic disturbances in cultured cells, but thus far, there has been no report that SWCNTs are carcinogenic. This review summarizes the recent noteworthy publications on the genotoxicity and carcinogenicity of CNTs and explains the possible molecular mechanisms responsible for this carcinogenicity. The nanoscale size and needle-like rigid structure of CNTs appear to be associated with their pathogenicity in mammalian cells, where carbon atoms are major components in the backbone of many biomolecules. Publishing adverse events associated with novel materials is critically important for alerting people exposed to such materials. CNTs still have a bright future with superb economic and medical merits. However, appropriate regulation of the production, distribution and secondary manufacturing processes is required, at least to protect the workers.

5 Review [Mechanisms of asbestos-induced carcinogenesis]. 2011

Toyokuni, Shinya / Jiang, Li / Hu, Qian / Nagai, Hirotaka / Okazaki, Yasumasa / Akatsuka, Shinya / Yamashita, Yoriko. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. toyokuni@med.nagoya-u.ac.jp ·Nihon Eiseigaku Zasshi · Pubmed #21701088.

ABSTRACT: Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.

6 Review [Archives of "comprehensive approach on asbestos-related diseases" supported by the "special coordination funds for promoting science and technology (H18-1-3-3-1)"-- overview of group research project, care and specimen registration, cellular characteristics of mesothelioma and immunological effects of asbestos]. 2011

Otsuki, Takemi / Nakano, Takashi / Hasegawa, Seiki / Okada, Morihito / Tsujimura, Tohru / Sekido, Yoshitaka / Toyokuni, Shinya / Nishimoto, Hiroshi / Fukuoka, Kazuya / Tanaka, Fumihiro / Kumagai, Naoko / Maeda, Megumi / Nishimura, Yasumitsu. ·Department of Hygiene, Kawasaki Medical School, Matsushima, Japan. takemi@med.kawasaki-m.ac.jp ·Nihon Eiseigaku Zasshi · Pubmed #21701085.

ABSTRACT: The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.

7 Review Biopersistent fiber-induced inflammation and carcinogenesis: lessons learned from asbestos toward safety of fibrous nanomaterials. 2010

Nagai, Hirotaka / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan. ·Arch Biochem Biophys · Pubmed #20599674.

ABSTRACT: Nano-sized durable fibrous materials such as carbon nanotubes have raised safety concerns similar to those raised by asbestos. However, the mechanism by which particulates with ultrafine structure cause inflammation and ultimately cancer (e.g. malignant mesothelioma and lung cancer) is largely unknown. This is partially because the particulates are not uniform and they vary in a plethora of factors. Such variances include length, diameter, surface area, density, shape, contaminant metals (including iron) and crystallinity. Each of these factors is involved in particulate toxicity both in vitro and in vivo. Thus, the elicited biological responses are incredibly complicated. Various kinds of fibers were evaluated with different cells, animals and methods. The aim of this review is to concisely summarize previous reports from the standpoint that activation of macrophages and mesothelial injury are the two major mechanisms of inflammation and possibly cancer. Importantly, these two mechanisms appear to be interacting with each other. However, there is a lack of data on the interplay of macrophage and mesothelium especially in vivo. Since fibrous nanomaterials present potential applications in various fields, it is necessary to develop standard evaluation methods to minimize risks for human health.

8 Article None 2020

Funahashi, Satomi / Okazaki, Yasumasa / Akatsuka, Shinya / Takahashi, Takashi / Sakumi, Kunihiko / Nakabeppu, Yusaku / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Department of Food and Nutritional Environment, Kinjo Gakuin University of Human Life and Environment, Nagoya, Japan. · Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Aichi Cancer Center Research Institute , Nagoya, Japan. · Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyusyu University, Higashi-ku, Japan. · Sydney Medical School, the University of Sydney, Sydney, Australia. ·Free Radic Res · Pubmed #32183600.

ABSTRACT: Exposure to asbestos fiber is central to mesothelial carcinogenesis. Recent sequencing studies on human and rodent malignant mesothelioma (MM) revealed frequently mutated genes, including

9 Article Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats. 2020

Okazaki, Yasumasa / Misawa, Nobuaki / Akatsuka, Shinya / Kohyama, Norihiko / Sekido, Yoshitaka / Takahashi, Takashi / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan. · Faculty of Economics, Toyo University Graduate School of Economics, Bunkyo-ku, Tokyo, Tokyo, 112-8606, Japan. · National Institute of Occupational Safety and Health, Kawasaki, Kanagawa, 214-8585, Japan. · Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan. · Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan. · Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Aichi, 464-8181, Japan. ·Cancer Sci · Pubmed #32080953.

ABSTRACT: The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite and actinolite types. Although few studies have been conducted, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7) and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, while the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a two-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, while anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, while anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Further, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in eight cases of rat MM [homozygous deletion (5/8) and loss of heterozygosity (3/8)] by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.

10 Article Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia. 2019

Li, Zan / Jiang, Li / Chew, Shan Hwu / Hirayama, Tasuku / Sekido, Yoshitaka / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. · Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu, 501-1113, Japan. · Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan. · Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan; Sydney Medical School, The University of Sydney, NSW, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Redox Biol · Pubmed #31442913.

ABSTRACT: Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO

11 Article Polymer coating on carbon nanotubes into Durobeads is a novel strategy for human environmental safety. 2018

Ito, Fumiya / Hisashi, Hideyuki / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 46, Japan. · Mitsubishi Corporation, 3-1 Marunouchi 2-chome, Chiyoda-ku, Tokyo, Japan. ·Nagoya J Med Sci · Pubmed #30587874.

ABSTRACT: Carbon nanotubes (CNTs) have attracted much business interest in industrial applications due to their high electrical and heat conductivities while being both durable and versatile. However, multiwall CNTs (MWCNTs) of ~50 nm diameter (NT50) have been shown to cause mesothelioma in rodents after direct exposure to mesothelial cells, and thus were classified as a Group 2B carcinogen to humans, which requires considerable regulations for use. In contrast, tangled MWCNTs of ~15 nm diameter (NTtngl) are not carcinogenic to rats, indicating that the physical dimension linked with mesothelial cellular uptake is an important factor for human environmental risk. In the present study, hypothesizing that dustability is another distinct risk factor, for the first time, we evaluated the toxicity of CNT granules (Durobeads) that were generated with a polymer coating to mesothelial cells. Polymer coating induced prominent agglomeration and significantly suppressed the dustability of CNTs in a dose-dependent manner, with a 10% polymer coating resulting in 730 times less dustability. These CNT granules revealed significantly lower mesothelial uptake and cytotoxicity in comparison to NT50 in

12 Article Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice. 2018

Funahashi, Satomi / Okazaki, Yasumasa / Nishiyama, Takahiro / Ohyoshi, Hidekazu / Yasui, Hiroyuki / Nishida, Kazuki / Matsui, Shigeyuki / Toyokuni, Shinya. ·a Department of Pathology and Biological Responses , Nagoya University Graduate School of Medicine , Nagoya , Japan. · b Department of Food and Nutritional Environment , Kinjo Gakuin University of Human Life and Environment , Nagoya , Japan. · c Department of Hematology and Oncology , Nagoya University Graduate School of Medicine , Nagoya , Japan. · d Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry , Kyoto Pharmaceutical University , Kyoto , Japan. · e Department of Biostatistics , Nagoya University Graduate School of Medicine , Nagoya , Japan. · f Sydney Medical School , the University of Sydney , Sydney , Australia. ·Free Radic Res · Pubmed #30309285.

ABSTRACT: Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.

13 Article Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model. 2018

Ohara, Yuuki / Chew, Shan Hwu / Misawa, Nobuaki / Wang, Shenqi / Somiya, Daiki / Nakamura, Kae / Kajiyama, Hiroaki / Kikkawa, Fumitaka / Tsuyuki, Yuta / Jiang, Li / Yamashita, Kyoko / Sekido, Yoshitaka / Lipson, Kenneth E / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. · Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. · Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. · Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. · FibroGen, Inc., San Francisco, CA 94158, USA. · Sydney Medical School, The University of Sydney, Sydney 2006, Australia. ·Oncotarget · Pubmed #29719620.

ABSTRACT: Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma

14 Article Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. 2018

Ohara, Yuuki / Chew, Shan-Hwu / Shibata, Takahiro / Okazaki, Yasumasa / Yamashita, Kyoko / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. ·Cancer Sci · Pubmed #29193587.

ABSTRACT: Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial-mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

15 Article Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy. 2017

Shi, Lei / Ito, Fumiya / Wang, Yue / Okazaki, Yasumasa / Tanaka, Hiromasa / Mizuno, Masaaki / Hori, Masaru / Hirayama, Tasuku / Nagasawa, Hideko / Richardson, Des R / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. · Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan. · Plasma Nanotechnology Research Center, Nagoya University, Nagoya 464-8603, Japan. · The Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu, Japan. · Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au. · Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Free Radic Biol Med · Pubmed #28465262.

ABSTRACT: Non-thermal plasma (NTP) is a potential new therapeutic modality for cancer. However, its mechanism of action remains unclear. Herein, we studied the effect of NTP on mesothelioma cells and fibroblasts to understand its anti-proliferative efficacy. Interestingly, NTP demonstrated greater selective anti-proliferative activity against mesothelioma cells relative to fibroblasts than cisplatin, which is used for mesothelioma treatment. The anti-proliferative effect of NTP was enhanced by pre-incubation with the cellular iron donor, ferric ammonium citrate (FAC), and inhibited by iron chelation using desferrioxamine (DFO). Three oxidative stress probes (CM-H2DCFDA, MitoSOX and C11-BODIPY) demonstrated reactive oxygen species (ROS) generation by NTP, which was inhibited by DFO. Moreover, NTP decreased transferrin receptor-1 and increased ferritin-H and -L chain expression that was correlated with decreased iron-regulatory protein expression and RNA-binding activity. This regulation was potentially due to increased intracellular iron in lysosomes, which was demonstrated via the Fe(II)-selective probe, HMRhoNox-M, and was consistent with autophagic-induction. Immunofluorescence using LysoTracker and Pepstatin A probes demonstrated increased cellular lysosome content, which was confirmed by elevated LAMP1 expression. The enhanced lysosomal biogenesis after NTP could be due to the observed increase in fluid-phase endocytosis and early endosome formation. These results suggest NTP acts as a stressor, which results in increased endocytosis, lysosome content and autophagy. In fact, NTP rapidly increased autophagosome formation, as judged by increased LC3B-II expression, which co-localized with LAMP1, indicating autophagolysosome formation. Autophagic-induction by NTP was confirmed using electron microscopy. In summary, NTP acts as a cellular stressor to rapidly induce fluid-phase endocytosis, lysosome biogenesis and autophagy.

16 Article Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. 2017

Chew, Shan Hwu / Okazaki, Yasumasa / Akatsuka, Shinya / Wang, Shenqi / Jiang, Li / Ohara, Yuuki / Ito, Fumiya / Saya, Hideyuki / Sekido, Yoshitaka / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. · Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan. · Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. · Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Free Radic Biol Med · Pubmed #28185919.

ABSTRACT: CD44 exists as a standard (CD44s) isoform and different variant isoforms (CD44v) due to alternative splicing. While the complex nature of these different isoforms has not been fully elucidated, CD44v expression has been shown to exert oncogenic effects by promoting tumor progression, metastasis and resistance of tumor cells to chemotherapy. One of the CD44v isoforms, CD44v8-10, was recently shown to protect cancer cells from oxidative stress by increasing the synthesis of glutathione (GSH). However, data regarding CD44 isoform expression in malignant mesothelioma (MM) are still lacking. Here, we show that most of the MM cell lines express both the CD44s and CD44v isoforms, in contrast to non-tumorigenic mesothelial cells, which express only CD44s. Moreover, we show here that these MM cell lines are positive for CD44 variable exon 9, with CD44v8-10 among the variant isoforms expressed. The expression of CD44 variable exon 9 was found to be statistically associated with NF2 inactivation, a common occurrence in MM. Knockdown of CD44 reduced the protein level of xCT, a cystine transporter, and increased oxidative stress. However, an increase in GSH was also observed and was associated with enhanced chemoresistance in CD44-knockdown cells. Increased GSH was mediated by the Nrf2/AP-1-induced upregulation of GCLC, a subunit of the enzyme catalyzing GSH synthesis. Our results thus suggest that the response to CD44 depletion is cell type-dependent and, in cases such as MM cells, compensatory pathway(s) might be activated rheostatically to account for the loss of CD44 and counteract enhanced oxidative stress.

17 Article Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma. 2016

Wang, Shenqi / Jiang, Li / Han, Yipeng / Chew, Shan Hwu / Ohara, Yuuki / Akatsuka, Shinya / Weng, Liang / Kawaguchi, Koji / Fukui, Takayuki / Sekido, Yoshitaka / Yokoi, Kohei / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. · Department of Tumor Pathology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. · Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. · Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. · Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan. ·Oncotarget · Pubmed #27602956.

ABSTRACT: Malignant mesothelioma (MM) is a rare neoplasm associated with asbestos exposure. The prognosis of MM is poor because it is aggressive and highly resistant to chemotherapy. Using a rat model of asbestos-induced MM, we found elevated urokinase-type plasminogen activator receptor (uPAR; Plaur) expression in rat tissues, which was associated with poor prognosis. The proliferation, migration and invasion of MM cells were suppressed by uPAR knockdown and increased by overexpression experiments, irrespective of urokinase-type plasminogen activator (uPA; Plau) levels. More importantly, we found that uPAR expression is associated with sensitivity to cisplatin in MM through the PI3K/AKT pathway, which was demonstrated with specific inhibitors, LY294002 and Akti-1/2. uPAR knockdown significantly increased sensitivity to cisplatin whereas its overexpression significantly decreased cisplatin sensitivity. Furthermore, sera and tissues from MM patients showed significantly high uPAR levels, which suggested the pathogenic role of uPAR in the tumor biology of human MM. In conclusion, our findings indicate that uPAR levels are associated with malignant characteristics and cisplatin sensitivity of MM. In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM.

18 Article Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells. 2016

Shi, Lei / Wang, Yue / Ito, Fumiya / Okazaki, Yasumasa / Tanaka, Hiromasa / Mizuno, Masaaki / Hori, Masaru / Richardson, Des R / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. · Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan. · Plasma Nanotechnology Research Center, Nagoya University, Nagoya 464-8603, Japan. · Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia. · Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Arch Biochem Biophys · Pubmed #27235332.

ABSTRACT: Non-thermal plasma (NTP) is a recently developed technology that elicits a variety of biological effects. This includes cancer cell-specific cytotoxicity, which is mainly attributed to the regional generation of reactive oxygen species (ROS). We studied the effects of NTP on malignant mesothelioma (MM) and its modulation by l-ascorbate. l-ascorbate is a major water-soluble anti-oxidant in vivo, but its pro-oxidant activity in vitro has been well recognized. Thus, the effects of ascorbate on the efficacy of NTP is important to examine. NTP exposure dose-dependently killed MM cells, whereas MM cells tolerated 1 mM l-ascorbate. However, brief pre-treatment with a pharmacological dose (250-750 μM) of l-ascorbate immediately prior to NTP exposure significantly increased its cytotoxicity in a dose-dependent manner, which was inhibited by the iron chelator, deferoxamine. However, paradoxically, this potentiating effect of l-ascorbate was completely abolished by a prolonged 4 h pre-incubation with l-ascorbate (500 μM). MM cytotoxicity induced by NTP was associated with immediate oxidative stress evaluated by 2',7'-dichlorodihydrofluorecein diacetate, which was followed by an increase in the expression of the autophagosome marker, LC3B-II. In conclusion, MM can be a target for NTP treatment and l-ascorbate can increase or decrease its efficacy depending on the length of the pre-incubation period.

19 Article Oxidative stress as an iceberg in carcinogenesis and cancer biology. 2016

Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan. Electronic address: toyokuni@med.nagoya-u.ac.jp. ·Arch Biochem Biophys · Pubmed #27095214.

ABSTRACT: After the conquest of numerous infectious diseases, the average life span for humans has been enormously prolonged, reaching more than 80 years in many developed countries. However, cancer is one of the top causes of death, and its incidence continues to increase in many countries, including Japan. I was deeply influenced during my career as a cancer researcher by the concept of oxidative stress, which was established by Helmut Sies in 1985. I have no doubt that oxidative stress is a major cause of carcinogenesis in humans but that other factors and chemicals modify it. Notably, established cancer cells are more oxidatively stressed than their non-tumorous counterparts are, and this stress may be associated with selection under oxidative stress and, thus, faster proliferation compared with non-tumorous cells. For cancer prevention, both avoidance of specific risks that are associated with genetic susceptibility and decreasing oxidative stress in general should delay carcinogenesis. For cancer therapy, individualization and precision medicine require further research in the future. In addition to the currently burgeoning array of humanized antibodies and protein kinase inhibitors, novel methods to increase oxidative stress only in cancer cells would be helpful.

20 Article Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis. 2016

Jiang, Li / Chew, Shan-Hwu / Nakamura, Kosuke / Ohara, Yuuki / Akatsuka, Shinya / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan. ·Cancer Sci · Pubmed #27088640.

ABSTRACT: Asbestos-induced mesothelial carcinogenesis is currently a profound social issue due to its extremely long incubation period and high mortality rate. Therefore, procedures to prevent malignant mesothelioma in people already exposed to asbestos are important. In previous experiments, we established an asbestos-induced rat peritoneal mesothelioma model, which revealed that local iron overload is a major cause of pathogenesis and that the induced genetic alterations are similar to human counterparts. Furthermore, we showed that oral administration of deferasirox modified the histology from sarcomatoid to the more favorable epithelioid subtype. Here, we used i.p. administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate was used to promote an iron-catalyzed Fenton reaction as a positive control. Desferal significantly decreased peritoneal fibrosis, iron deposition, and nuclear 8-hydroxy-2'-deoxyguanosine levels in mesothelial cells, whereas nitrilotriacetate significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells to counteract asbestos-induced cytotoxicity than in murine macrophages (RAW264.7). Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than rat peritoneal mesothelial cells. Because inflammogenicity of a fiber is proportionally associated with subsequent mesothelial carcinogenesis, iron elimination from the mesothelial environment can confer dual merits for preventing asbestos-induced mesothelial carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously.

21 Article Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. 2016

Wang, Yue / Okazaki, Yasumasa / Shi, Lei / Kohda, Hiro / Tanaka, Minoru / Taki, Kentaro / Nishioka, Tomoki / Hirayama, Tasuku / Nagasawa, Hideko / Yamashita, Yoriko / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Department of Cellular Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu, Japan. ·Cancer Sci · Pubmed #26679080.

ABSTRACT: Multi-wall carbon nanotubes (MWCNT) are a form of flexible fibrous nanomaterial with high electrical and thermal conductivity. However, 50-nm MWCNT in diameter causes malignant mesothelioma (MM) in rodents and, thus, the International Agency of Research on Cancer has designated them as a possible human carcinogen. Little is known about the molecular mechanism through which MWCNT causes MM. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100; 150 nm, NT150; and 15 nm/tangled, NTtngl) using mass spectrometry. We identified >400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNT to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMC). Cytotoxicity to RPMC was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMC, with an increase in cellular catalytic ferrous iron and DNA damage also observed. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor 1. Modifications of NT50 surface may decrease this human risk.

22 Article Receptor role of the annexin A2 in the mesothelial endocytosis of crocidolite fibers. 2015

Yamashita, Kyoko / Nagai, Hirotaka / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan. ·Lab Invest · Pubmed #25915724.

ABSTRACT: Asbestos-induced mesothelioma is a worldwide problem. Parietal mesothelial cells internalize asbestos fibers that traverse the entire lung parenchyma, an action that is linked to mesothelial carcinogenesis. Thus far, vitronectin purified from serum reportedly enhances the internalization of crocidolite by mesothelial cells via integrin αvβ5. To reveal another mechanism by which mesothelial cells endocytose (phagocytose) asbestos, we first evaluated the effects of serum on asbestos uptake, which proved to be nonessential. Thereafter, we undertook a study to identify proteins on the surface of mesothelial cells (MeT5A) that act as receptors for asbestos uptake based on the assumption that receptors bind to asbestos with physical affinity. To this end, we incubated the membrane fraction of MeT5A cells with crocidolite or chrysotile and evaluated the adsorbed proteins using sodium dodecyl sulfate polyacrylamide gel analysis. Next, we extensively identified the proteins using an in-solution or in-gel digestion coupled with mass spectrometry. Among the identified proteins, annexin A2 (ANXA2) and transferrin receptor protein 1 (TFRC) were distinguished because of their high score and presence at the cell surface. Crocidolite uptake by MeT5A cells was significantly decreased by shRNA (short hairpin RNA)-induced knockdown of ANXA2 and direct blockade of cell surface ANXA2 using anti-ANXA2 antibody. In addition, abundant ANXA2 protein was present on the cell membrane of mesothelial cells, particularly facing the somatic cavity. These findings demonstrate that ANXA2 has a role in the mesothelial phagocytosis of crocidolite and may serve as its receptor.

23 Article Minimal inflammogenicity of pristine single-wall carbon nanotubes. 2015

Toyokuni, Shinya / Jiang, L I / Kitaura, Ryo / Shinohara, Hisanori. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Department of Chemistry and Institute for Advanced Research, Nagoya University, Nagoya, Japan. ·Nagoya J Med Sci · Pubmed #25797984.

ABSTRACT: Carbon nanotubes (CNTs) are a novel synthetic material comprising only carbon atoms. Based on its rigidity, its electrical and heat conductivity and its applicability to surface manufacturing, this material is expected to have numerous applications in industry. However, due to the material's dimensional similarity to asbestos fibers, its carcinogenicity was hypothesized during the last decade, and indeed, we have shown that multi-wall CNTs (MWCNTs) of 50 nm in diameter are potently carcinogenic to mesothelial cells after intraperitoneal injection. Additionally, we suggested that inflammogenicity after intraperitoneal injection can predict mesothelial carcinogenesis. However, few data have been published on the intraperitoneal inflammogenicity of single-wall CNTs (SWCNTs). Here, we conducted a series of studies on SWCNTs using both intraperitoneal injection into rats and MeT5A mesothelial cells. Intraperitoneal injection of 10 mg SWCNTs caused no remarkable inflammation in the abdominal cavity, and the exposure of MeT5A cells to up to 25 μg/cm(2) SWCNTs did not alter proliferation. MWCNTs of 50 nm in diameter were used as a positive control, and tangled MWCNTs of 15 nm in diameter were used as a negative control. The results suggest that SWCNTs are a low-risk material with respect to mesothelial carcinogenesis.

24 Article Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis. 2014

Aierken, Dilinuer / Okazaki, Yasumasa / Chew, Shan Hwu / Sakai, Akihiro / Wang, Yue / Nagai, Hirotaka / Misawa, Nobuaki / Kohyama, Norihiko / Toyokuni, Shinya. · ·Nagoya J Med Sci · Pubmed #25130001.

ABSTRACT: Asbestos was abundantly used in industry during the last century. Currently, asbestos confers a heavy social burden due to an increasing number of patients with malignant mesothelioma (MM), which develops after a long incubation period. Many studies have been conducted on the effects of the asbestos types that were most commonly used for commercial applications. However, there are few studies describing the effects of the less common types, or minor asbestos. We performed a rat carcinogenesis study using Japanese tremolite and Afghan anthophyllite. Whereas more than 50% of tremolite fibers had a diameter of < 500 nm, only a small fraction of anthophyllite fibers had a diameter of < 500 nm. We intraperitoneally injected 1 or 10 mg of asbestos into F1 Fischer-344/Brown-Norway rats. In half of the animals, repeated intraperitoneal injections of nitrilotriacetate (NTA), an iron chelator to promote Fenton reaction, were performed to evaluate the potential involvement of iron overload. Tremolite induced MM with a high incidence (96% with 10 mg; 52% with 1 mg), and males were more susceptible than females. Histology was confirmed using immunohistochemistry, and most MMs were characterized as the sarcomatoid or biphasic subtype. Unexpectedly NTA showed an inhibitory effect in females. In contrast, anthophyllite induced no MM after an observation period of 550 days. The results suggest that the carcinogenicity of anthophyllite is weaker than formerly reported, whereas that of tremolite is as potent as major asbestos as compared with our previous data.

25 Article Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. 2014

Jiang, Li / Yamashita, Yoriko / Chew, Shan-Hwu / Akatsuka, Shinya / Ukai, Shun / Wang, Shenqi / Nagai, Hirotaka / Okazaki, Yasumasa / Takahashi, Takashi / Toyokuni, Shinya. ·Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Japan. ·J Pathol · Pubmed #24839947.

ABSTRACT: Due to the formerly widespread use of asbestos, malignant mesothelioma (MM) is increasingly frequent worldwide. MM is classified into epithelioid (EM), sarcomatoid (SM), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM, and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM, we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor (Ctgf), whose expression was significantly increased in SM compared with EM; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM, Ctgf was a major regulator of MM proliferation and invasion through activation of the β-catenin-TCF-LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial-mesenchymal transition in MM. Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6-GSK3β-β-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target.

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