Mechanisms of Asbestos-Induced Carcinogenesis

Toyokuni, Shinya; Jiang, Li; Hu, Qian; Nagai, Hirotaka; Okazaki, Yasumasa; Akatsuka, Shinya; Yamashita, Yoshihisa

doi:10.1265/jjh.66.562

Cited by 80 publications

(114 citation statements)

References 30 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…Indeed, iron reduction can lower the risk for hepatic cancer (17) and probably in other cancers (18). Concerning mesothelioma, iron overload as a major pathogenic process has been recently studied (3,19,20). We reported that intraperitoneal injection of iron saccharate into rats induced mesothelioma (21) with loss of the Cdkn2a/2b tumor suppressor gene, the same genetic feature as asbestos-induced mesothelioma, supporting the hypothesis that iron overload is responsible for asbestos-induced mesothelial carcinogenesis (22).…”

Section: Introductionsupporting

confidence: 60%

“…Although malignant mesothelioma is a relatively rare cancer originating from mesothelial cells on the somatic cavity, epidemiologic studies have firmly linked this tumor with asbestos exposure in the 1960s (1)(2)(3)(4). Asbestos is a group of natural fibrous minerals that reveal unique properties such as heat-, acid-, and friction-resistance with versatility and low cost for industrial use.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Deferasirox Induces Mesenchymal–Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

Nagai

Okazaki

Chew

et al. 2013

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction. Cancer Prev Res; 6(11); 1222-30. Ó2013 AACR.

show abstract

Section: Introductionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Deferasirox Induces Mesenchymal–Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

Nagai

Okazaki

Chew

et al. 2013

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Currently, three hypotheses exist regarding the pathogenesis of asbestos-induced mesothelioma. 4 The 'oxidative stress theory' 5 is based on the fact that fibrous mineral foreign substances in asbestos are phagocytosed by macrophages, which are unable to digest them, resulting in the massive generation of ROS. Alternatively, crocidolite and amosite may present catalyzing reactive environments with exposed surface iron.…”

mentioning

confidence: 99%

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Akatsuka

Yamashita

et al. 2010

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by microarray. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2 0 -deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

show abstract

“…However, the roles and alterations of Th17 in silica-exposed patients are unknown and should be clarified through further research in order to obtain a better understanding of the immunological effects of silica on the human immune system. Many issues remain to be resolved, such as delineating the complications of SSc in SILs (Barnadas, 1986;Cowie, 1987Haustein, 1990Haustein & Anderegg, 1998;Sluis-Cremer, 1985), or those complications associated with malignant tumors such as mesothelioma and lung cancer in patients exposed to the mineral silicate asbestos (Greillier, 2008;Toyokuni, 2009;Miura, 2008). Regarding the relationship between tumor immunity and Treg function, it may be that Treg enhances cell numbers or function to reduce tumor immunity (Chattopadhyay, 2005;Danese & Rutella, 2007;Kretschmer, 2006).…”

Section: Silica-induced Dysfunction Of the Treg Fraction In Silsmentioning

confidence: 99%