Asbestos-induced Mesothelioma Research Articles

Targeting inflammatory factors for chemoprevention and cancer interception to tackle malignant mesothelioma.

Mesothelioma is an incurable cancer of the mesothelial lining often caused by exposure to asbestos. Asbestos-induced inflammation is a significant contributing factor in the development of mesothelioma, and genetic factors also play a role in the susceptibility to this rapidly progressive and treatment-resistant malignancy. Consequently, novel approaches are urgently needed to treat mesothelioma and prevent or reduce the overall incidence of this fatal disease. In this research perspective, we review the current state of chemoprevention and cancer interception progress in asbestos-induced mesothelioma. We discuss the different preclinical mouse models used for these investigations and the inflammatory factors that may be potential targets for mesothelioma prevention. Preliminary studies with naturally occurring phytochemicals and synthetic agents are reviewed. Results of previous clinical chemoprevention trials in populations exposed to asbestos and considerations regarding future trials are also presented.

HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma

Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.

Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma.

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+/-;Cdkn2a+/- mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.

Asbestos-induced mesothelial injury and carcinogenesis: Involvement of iron and reactive oxygen species.

Asbestos fibers have been used as an industrial and construction material worldwide due to their high durability and low production cost. Commercial usage of asbestos is currently prohibited in Japan; however, the risk of asbestos-induced malignant mesothelioma (MM) remains. According to epidemiological data, the onset of MM is estimated to occur after a latent period of 30-40 years from initial exposure to asbestos fibers; thus, the continuous increase in MM is a concern. To explore the molecular mechanisms of MM using animal models, iron saccharate with iron chelator-induced sarcomatoid mesothelioma (SM) revealed hallmarks of homozygous deletion of Cdkn2a/2b by aCGH and microRNA-199/214 by expression microarray. Oral treatment of iron chelation by deferasirox decreased the rate of high-grade SM. Moreover, phlebotomy delayed MM development in crocidolite-induced MM in rats. In Divalent metal transporter 1 (Dmt1) transgenic mice, MM development was delayed because of low reactive oxygen species (ROS) production. These results indicate the importance of iron and ROS in mesothelial carcinogenesis. The aims of this review focus on the pathogenesis of elongated mineral particles (EMPs), including asbestos fibers and multiwalled carbon nanotubes (MWCNTs) that share similar rod-like shapes in addition to the molecular mechanisms of MM development.

The pathogenesis of mesothelioma is driven by a dysregulated translatome

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no ‘druggable’ driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.

The usefulness of biomarkers in diagnosis of asbestos-induced malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a malignant tumor that is associated mostly with asbestos exposure. The present study was to evaluates the diagnostic value of neopterin, periostin, YKL-40, Tenascin-C (TNC), and Indolamine 2,3-dioxygenase (IDO) as noninvasive markers of malign pleural mesothelioma. Included in the study were 30 patients diagnosed with malign pleural mesothelioma, and 25 people as a control group. Biomarker levels were determined using an enzyme immunoassay . A Mann-Whitney U test and Spearman correlation methods were used for the statistical analysis. All evaluated biomarkers were found to be significantly higher in the MPM group than in the control group (p < 0.05). There was no effect of such variables as gender, age or MPMsubtype on the parameters (p > 0.05) in the patient group. All biomarkers were positively correlated with each other (p < 0.001). The current non-invasive biomarkers that can be used in the diagnosis of MPM yielded significant results and can make important contributions to the early diagnosis of MPM.

Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development.

Early events in an experimental model of mesothelioma development include increased levels of editing in double-stranded RNA (dsRNA). We hypothesised that expression of endogenous retroviruses (ERV) contributes to dsRNA formation and type-I interferon signaling. ERV and interferon stimulated genes (ISGs) expression were significantly higher in tumor compared to non-tumor samples. 12 tumor specific ERV ("MesoERV1-12") were identified and verified by qPCR in mouse tissues. "MesoERV1-12" expression was lower in mouse embryonic fibroblasts (MEF) compared to mesothelioma cells. "MesoERV1-12" levels were significantly increased by demethylating agent 5-Aza-2'-deoxycytidine treatment and were accompanied by increased levels of dsRNA and ISGs. Basal ISGs expression was higher in mesothelioma cells compared to MEF and was significantly decreased by JAK inhibitor Ruxolitinib, by blocking Ifnar1 and by silencing Mavs. "MesoERV7" promoter was demethylated in asbestos-exposed compared to sham mice tissue as well as in mesothelioma cells and MEF upon 5-Aza-CdR treatment. These observations uncover novel aspects of asbestos-induced mesothelioma whereby ERV expression increases due to promoter demethylation and is paralleled by increased levels of dsRNA and activation of type-I IFN signaling. These features are important for early diagnosis and therapy.

Clinical analysis of 30 cases with asbestos-related occupational tumors

Asbestos is classified as a Class 1 carcinogen by the International Cancer Organization (IARC) , and almost all types of asbestos are carcinogenic. The clinical data of 30 asbestos-induced occupational tumor patients in Qingdao city from January 2002 to May 2019 were analyzed, including 24 cases of asbestos-induced lung cancer and 6 cases of asbestos-induced malignant mesothelioma. Mesothelioma was significantly worse than lung cancer in terms of malignancy, the survival time of patients is shorter, and the mortality rate was higher. Both its diagnostic methods and treatment methods should be improved. The high incidence of asbestos-caused tumors is coming. It is recommended that workers exposed to asbestos dust should undergo regular chest CT examinations for early detection, early diagnosis and early treatment.

Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats.

Malignant mesothelioma (MM) is one of the most lethal tumors in humans. The onset of MM is linked to exposure to asbestos, which generates reactive oxygen species (ROS). ROS are believed to be derived from the frustrated phagocytosis and the iron in asbestos. To explore the pathogenesis of MM, peritoneal MM was induced in rats by the repeated intraperitoneal injection of iron saccharate and nitrilotriacetate. In the present study, we used microarray techniques to screen the microRNA (miR) expression profiles of these MM. We observed that the histological subtype impacted the hierarchical clustering of miR expression profiles and determined that miR‐199/214 is a distinctive feature of iron saccharate‐induced sarcomatoid mesothelioma (SM). Twist1, a transcriptional regulator of the epithelial‐mesenchymal transition, has been shown to activate miR‐199/214 transcription; thus, the expression level of Twist1 was examined in iron‐induced and asbestos‐induced mesotheliomas in rats. Twist1 was exclusively expressed in iron saccharate‐induced SM but not in the epithelioid subtype. The Twist1‐miR‐199/214 axis is activated in iron saccharate‐induced and asbestos‐induced SM. The expression levels of miR‐214 and Twist1 were correlated in an asbestos‐induced MM cell line, suggesting that the Twist1‐miR‐199/214 axis is preserved. MeT5A, an immortalized human mesothelial cell line, was used for the functional analysis of miR. The overexpression of miR‐199/214 promoted cellular proliferation, mobility and phosphorylation of Akt and ERK in MeT5A cells. These results indicate that miR‐199/214 may affect the aggressive biological behavior of SM.

MicroRNA-98 is a prognostic factor for asbestos-induced mesothelioma

ABSTRACTMalignant pleural mesothelioma (MPM) is a type of cancer characterized by a short survival time and poor prognosis. Malignant pleural mesothelioma is most frequently associated with exposure to asbestos and other elongated mineral fibers. The aim of this study was to examine molecular differences between asbestos-exposed and non-exposed MPM patients and assess prognostic significances of molecular factors. Clinical and genetic data were downloaded from Cancer Genome Atlas. To identify the molecular differences, Significant Analysis of Microarray method was used. Prognostic significances of differentially expressed genes were confirmed by using Kaplan–Meier curve with the Log-Rank test. Although mRNAs did not exhibit any significant differences between the two patient groups, nine miRNAs were found to be down-regulated in the asbestos-exposed group. The top five pathways most relevant to the selected miRNAs were extracted through pathway enrichment analysis. Survival analysis revealed that high expression of only hsa-miR-98 was significantly associated with poor prognosis in patients with asbestos-exposed MPM. Evidence suggests that management of the aggressiveness and progression of asbestos-induced MPM may require high levels of hsa-miR-98 due to its tumor-suppressive role. This study might be helpful in enhancing our understanding of the biological mechanisms underlying asbestos-induced MPM and for acquiring greater insights into targeted therapy.Abbreviations: FDR: false discovery rate; MM: malignant mesothelioma; MPM: malignant pleural mesothelioma; mRNA: messenger RNA; miRNA: microRNA; SAM: significance analysis of microarrays; TCGA: the cancer genome atlas

Evaluation of manganese superoxide dismutase and thioredoxin2 levels in asbestos-induced pleural mesothelioma

Asbestos is a mineral known as human carcinogenic material. Exposure to asbestos both in an occupational and environmental way causes asbestosis and mesothelioma. ROS contributes to the development of pulmonary-toxicity induced asbestos.We aimed to determine the levels of important mitochondrial substances such as manganese superoxide dismutase (MnSOD) and Thioredoxin (Trx2) in asbestosis and mesothelioma patients. The study was performed with the patients admitted to outpatient clinics of Chest Diseases and Thoracic Surgery, at Medicine Faculty, Bozok University. Group 1 (healthy control group, n=27): Consisting of healthy individuals (54.18±9.89 years old), Group 2 (patients group, n=34): Evaluation of clinical, pathological and radiological analysis, patients who defined as mesothelioma and/or pleural plaques and asbestosis (60.24±15.24 years old). Patients, who were not biopsied or not available for biopsy due to comorbid diseases, were not included in the study.Biochemical analysis was done in Selcuk University Medicine Faculty Research Laboratories.Serum Trx2 and MnSOD levels were determined by the Elisa method. The results of Trx2 were calculated as pg/µg protein. MnSOD samples were determined as ng/µg protein. MnSOD and Trx2 levels in the patients’ group were statistically lower than the levels of the healthy group (p=0.000, p=0.048), respectively.Trx2 levels were 1.74±0.33 pg/µg protein in a healthy group whereas were 0.89±0.10 pg/µg protein in asbestosis and mesothelioma group. Serum MnSOD levels were 1.38±0.24 and 0.29±0.11 ng/µg protein in healthy and patients’ groups, respectively.These significant changes in malignant mesothelioma patients reflect the impairment of the oxidant-antioxidant balance system. The study presents basic findings for the clinical meaning of mentioned biochemical parameters in mesothelioma patients.

Ferroptosis in carcinogenesis and tumor biology

Excess iron is associated with carcinogenesis. Ferric nitrilotriacetate-induced renal cancers in wild-type rats reveal similar genetic alterations to those in humans. Ferroptosis may be defined as a form of regulated necrosis, characterized by lipid peroxidation through high iron/sulfur(antioxidants) ratio. Considering that cancer cells in general retain more catalytic Fe(II) than non-tumorous cells, many iron-induced carcinogenesis models, including asbestos-induced mesothelioma, suggest that cancer is a state of iron addiction with ferroptosis-resistance. Non-thermal plasma (NTP) is a novel physical technique that emits abundant electrons, leading to a variety of ROS products by reaction with atmospheric oxygen. Exposure of NTP to biomolecules, cells or tissues causes oxidative stress in situ, resulting in DNA breaks and lipid peroxidation products, such as HNE. We found that NTP exposure is highly dependent on Fe(II) in situ, causing cancer cell-specific ferroptosis, which was associated with autophagy activation and lysosome genesis. Thus, we discuss the role of phlebotomy for cancer prevention and the use of NTP as a new cancer therapy.

Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf)

SummaryMesothelioma is a fatal tumor of the pleura and is strongly associated with asbestos exposure. The molecular mechanisms underlying the long latency period of mesothelioma and driving carcinogenesis are unknown. Moreover, late diagnosis means that mesothelioma research is commonly focused on end-stage disease. Although disruption of the CDKN2A (INK4A/ARF) locus has been reported in end-stage disease, information is lacking on the status of this key tumor suppressor gene in pleural lesions preceding mesothelioma. Manufactured carbon nanotubes (CNTs) are similar to asbestos in terms of their fibrous shape and biopersistent properties and thus may pose an asbestos-like inhalation hazard. Here we show that instillation of either long CNTs or long asbestos fibers into the pleural cavity of mice induces mesothelioma that exhibits common key pro-oncogenic molecular events throughout the latency period of disease progression. Sustained activation of pro-oncogenic signaling pathways, increased proliferation, and oxidative DNA damage form a common molecular signature of long-CNT- and long-asbestos-fiber-induced pathology. We show that hypermethylation of p16/Ink4a and p19/Arf in CNT- and asbestos-induced inflammatory lesions precedes mesothelioma; this results in silencing of Cdkn2a (Ink4a/Arf) and loss of p16 and p19 protein, consistent with epigenetic alterations playing a gatekeeper role in cancer. In end-stage mesothelioma, silencing of p16/Ink4a is sustained and deletion of p19/Arf is detected, recapitulating human disease. This study addresses the long-standing question of which early molecular changes drive carcinogenesis during the long latency period of mesothelioma development and shows that CNT and asbestos pose a similar health hazard.

Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma

BackgroundMalignant mesothelioma (MM) is an aggressive cancer of the pleural and peritoneal cavities caused by exposure to asbestos. Asbestos-induced mesotheliomas in wild-type mice have been used extensively as a preclinical model because they are phenotypically identical to their human counterpart. However, it is not known if the genetic lesions in these mice tumours are similar to in the human disease, a prerequisite for any new preclinical studies that target genetic abnormalities.MethodsWe performed whole exome sequencing of fifteen asbestos-induced murine MM tumour cell lines from BALB/c, CBA and C57BL/6 mouse strains and compared the somatic mutations and copy number variations with those recurrently reported in human MM. We then catalogued and characterised the mutational landscape of the wild-type murine MM tumours. Quantitative RT-PCR was used to interrogate the expression of key MM genes of interest in the mRNA.ResultsConsistent with human MM tumours, we identified homozygous loss of the tumour suppressor Cdkn2a in 14/15 tumours. One tumour retained the first exon of both of the p16INK4a and p19ARF isoforms though this tumour also contained genetic amplification of Myc resulting in increased expression of the c-Myc proto-oncogene in the mRNA. There were no chromosomal losses in either the Bap1 or Nf2 regions. One tumour harbored homozygous loss of Trp53 in the DNA. Mutation rates were similar in tumours generated in the CBA and C57BL/6 strains when compared to human MM. Interestingly, all BALB/c tumour lines displayed high mutational loads, consistent with the known mutator phenotype of the host strain. The Wnt, MAPK and Jak-STAT signaling pathways were found to be the most commonly affected biological pathways. Mutations and copy number deletions also occurred in the Hedgehog and Hippo pathways.ConclusionsThese data suggest that in the wild-type murine model asbestos causes mesotheliomas in a similar way to in human MM. This further supports the notion that the murine model of MM represents a genuine homologue of the human disease, something uncommon in cancer, and is thus a valuable tool to provide insight into MM tumour development and to aide the search for novel therapeutic strategies.

Molecular mechanisms of HMGB1 extracellular secretion in asbestos-induced malignant mesothelioma

Molecular mechanisms of HMGB1 extracellular secretion in asbestos-induced malignant mesothelioma

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

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.

Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma

Exposure to asbestos is causally associated with the development of malignant mesothelioma, a cancer of cells lining the internal body cavities. Malignant mesothelioma is an aggressive cancer resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including malignant mesothelioma. The NALP3/NLRP3 inflammasome, including the component ASC, is thought to be an important mediator of inflammation in cells that sense extracellular insults, such as asbestos, and activate a signaling cascade resulting in release of mature IL1β and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to asbestos and evaluated differences in tumor incidence and latency. The Asc-deficient mice showed significantly delayed tumor onset and reduced malignant mesothelioma incidence compared with wild-type animals. We also tested whether inflammation-related release of IL1β contributes to tumor development in an accelerated mouse model of asbestos-induced malignant mesothelioma. Nf2(+/-);Cdkn2a(+/-) mice exposed to asbestos in the presence of anakinra, an IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL1β/IL1R signaling and the development of asbestos-induced malignant mesothelioma. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL1β/IL1R signaling in high-risk, asbestos-exposed populations. Cancer Prev Res; 9(5); 406-14. ©2016 AACR.

Asbestos and SV40 in malignant pleural mesothelioma from a hyperendemic area of north-eastern Italy.

Malignant mesothelioma is a fatal cancer of increasing incidence in north-eastern Italy. Together with asbestos, the polyomavirus SV40 was hypothesized to contribute to the onset of malignant mesothelioma. To investigate the putative role of SV40 in the individual susceptibility to asbestos-induced malignant mesothelioma, we conducted a molecular epidemiological study on a series of malignant mesothelioma patients from an area in north-eastern Italy hyperendemic for malignant pleural mesothelioma. We collected 63 mesothelioma samples from incidence cases of patients diagnosed with malignant pleural mesothelioma in the period 2009-2010. DNA was extracted from patients' tissue biopsies using the BioRobot EZ1 Qiagen workstation. SV40 sequence detection and quantification was performed by specific real time PCR. The 74.6% of the 63 enrolled patients had a history of asbestos exposure. The epithelioid histotype was more prevalent in males (64.0%) and the mixed in females (61.5%) who showed significantly higher cancer co-morbidity (46.1% vs 12%, P = 0.005). SV40 was detected in 22% of MM tumors, with a low viral load. In SV40-positive patients, a threefold increased risk of asbestos exposure was observed, more evident in females (OR 4.32) than in males (OR 1.20). Our findings indicate that a high prevalence of SV40 was present in malignant mesothelioma incident cases from an area hyperendemic for malignant mesothelioma in north-eastern Italy. Although asbestos is considered the main risk factor in malignant mesothelioma onset, a role for SV40 could be hypothesized.

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.

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.

Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605)

The interaction of asbestos fibers with macrophages generates harmful reactive oxygen species (ROS) and subsequent oxidative cell damage that are key processes linked to malignancy. Secoisolariciresinol diglucoside (SDG) is a non-toxic, flaxseed-derived pluripotent compound that has antioxidant properties and may thus function as a chemopreventive agent for asbestos-induced mesothelioma. We thus evaluated synthetic SDG (LGM2605) in asbestos-exposed, elicited murine peritoneal macrophages as an in vitro model of tissue phagocytic response to the presence of asbestos in the pleural space. Murine peritoneal macrophages (MFs) were exposed to crocidolite asbestos fibers (20 µg/cm2) and evaluated at various times post exposure for cytotoxicity, ROS generation, malondialdehyde (MDA), and levels of 8-iso Prostaglandin F2α (8-isoP). We then evaluated the ability of LGM2605 to mitigate asbestos-induced oxidative stress by administering LGM2605 (50 µM) 4-h prior to asbestos exposure. We observed a significant (p < 0.0001), time-dependent increase in asbestos-induced cytotoxicity, ROS generation, and the release of MDA and 8-iso Prostaglandin F2α, markers of lipid peroxidation, which increased linearly over time. LGM2605 treatment significantly (p < 0.0001) reduced asbestos-induced cytotoxicity and ROS generation, while decreasing levels of MDA and 8-isoP by 71%–88% and 41%–73%, respectively. Importantly, exposure to asbestos fibers induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1 that were further enhanced by LGM2605 treatment. LGM2605 boosted antioxidant defenses, as well as reduced asbestos-induced ROS generation and markers of oxidative stress in murine peritoneal macrophages, supporting its possible use as a chemoprevention agent in the development of asbestos-induced malignant mesothelioma.