Mesothelium environment changes following repeated asbestos exposure
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PROVIDER: PRJEB15230 | ENA |
REPOSITORIES: ENA
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Project description:We hypothesize that the observed differences in incidences of pleural and peritoneal malignant mesothelioma (MM) are the result of differences in the direct response of these cell types to asbestos rather than to differences mediated by the in vivo microenvironment. To test this hypothesis, we characterized cellular responses to asbestos in a controlled environment using high-throughput RNA sequence and other assays. Examination of asbestos-treated versus untreated mesothelial cells from four cell lines representing two tissue types in culture.
2015-03-02 | E-GEOD-63966 | biostudies-arrayexpress
Project description:Asbestos-associated diseases remain a social burden worldwide. Our previous studies identified asbestos-induced iron-rich milieu for mesothelial cells with ceaseless macrophage ferroptosis. However, molecular mechanisms how this mutagenic milieu influences mesothelial cells have not been elucidated yet. Here, we propose a novel mechanism that extracellular vesicles (EVs) mediate asbestos-associated mutagenic factors to mesothelial cells. In a mice model of intraperitoneal crocidolite injection, mutagenic milieu highly expressed CD63, an exosomal marker. We then used a CD63-GFP labeled THP-1 macrophage model exposed to crocidolite/iron, which generated EVs under ferroptotic process. We observed that MeT-5A mesothelial cells can receive and internalize these EVs. Furthermore, we comprehensively analyzed the ferroptosis-dependent EVs (FedEVs) for transported proteins and identified ferritin heavy/light chains as major proteins. Therefore, we inferred that FedEVs transport iron from ferroptotic macrophages to mesothelial cells. RNA sequencing revealed that the mesothelial cells receiving higher amounts of the FedEVs were mitotic, especially at the S and G2/M phases, by the use of Fucci mesothelial cells. Nuclear 8-hydroxy-2`-deoxyguanosine and γ-H2AX were significantly increased in the recipient mesothelial cells after exposure to FedEVs. Collectively, we here demonstrate a novel mechanism that FedEVs act as a key mutagenic mediator by transporting iron, which contribute to asbestos-induced mesothelial carcinogenesis.
2021-10-22 | GSE184368 | GEO
Project description:Human mesothelial cells (LP9/TERT-1) were exposed to low and high (15 and 75 μm2/cm2 dish) equal surface area concentrations of crocidolite asbestos, nonfibrous talc, fine titanium dioxide (TiO2), or glass beads for 8 or 24 h. RNA was then isolated for Affymetrix microarrays, GeneSifter analysis and QRT-PCR. Gene changes by asbestos were concentration- and time-dependent. At low nontoxic concentrations, asbestos caused significant changes in mRNA expression of 29 genes at 8 h and 205 genes at 24 h, whereas changes in mRNA levels of 236 genes occurred in cells exposed to high concentrations of asbestos for 8 h. Human primary pleural mesothelial cells also showed the same patterns of increased gene expression by asbestos. Nonfibrous talc at low concentrations in LP9/TERT-1 mesothelial cells caused increased expression of 1 gene Activating Transcription Factor 3 (ATF3) at 8 h and no changes at 24 h, whereas expression levels of 30 genes were elevated at 8 h at high talc concentrations. Fine TiO2 or glass beads caused no changes in gene expression. In human ovarian epithelial (IOSE) cells, asbestos at high concentrations elevated expression of 2 genes (NR4A2, MIP2) at 8 h and 16 genes at 24 h that were distinct from those elevated in mesothelial cells. Since ATF3 was the most highly expressed gene by asbestos, its functional importance in cytokine production by LP9/TERT-1 cells was assessed using siRNA approaches. Results reveal that ATF3 modulates production of inflammatory cytokines (IL-1β, IL-13, G-CSF) and growth factors (VEGF and PDGF-BB) in human mesothelial cells.
2011-09-19 | GSE14034 | GEO
Project description:Human mesothelial cells (LP9/TERT-1) were exposed to low and high (15 and 75 μm2/cm2 dish) equal surface area concentrations of crocidolite asbestos, nonfibrous talc, fine titanium dioxide (TiO2), or glass beads for 8 or 24 h. RNA was then isolated for Affymetrix microarrays, GeneSifter analysis and QRT-PCR. Gene changes by asbestos were concentration- and time-dependent. At low nontoxic concentrations, asbestos caused significant changes in mRNA expression of 29 genes at 8 h and 205 genes at 24 h, whereas changes in mRNA levels of 236 genes occurred in cells exposed to high concentrations of asbestos for 8 h. Human primary pleural mesothelial cells also showed the same patterns of increased gene expression by asbestos. Nonfibrous talc at low concentrations in LP9/TERT-1 mesothelial cells caused increased expression of 1 gene Activating Transcription Factor 3 (ATF3) at 8 h and no changes at 24 h, whereas expression levels of 30 genes were elevated at 8 h at high talc concentrations. Fine TiO2 or glass beads caused no changes in gene expression. In human ovarian epithelial (IOSE) cells, asbestos at high concentrations elevated expression of 2 genes (NR4A2, MIP2) at 8 h and 16 genes at 24 h that were distinct from those elevated in mesothelial cells. Since ATF3 was the most highly expressed gene by asbestos, its functional importance in cytokine production by LP9/TERT-1 cells was assessed using siRNA approaches. Results reveal that ATF3 modulates production of inflammatory cytokines (IL-1β, IL-13, G-CSF) and growth factors (VEGF and PDGF-BB) in human mesothelial cells. Microarrays were performed on samples from 3 independent experiments. All cell types, time points, and mineral types and concentrations were included in all 3 experiments. For each experiment, n=3 dishes were pooled into one sample per treatment group. Each of the pooled samples was analyzed on a separate array, i.e., n=3 arrays per condition (3 independent biological replicates). We tested the hypothesis that alteration in gene expression in human cells correlate with mineral pathogenicity. We used GeneSifter program to analyze our data and pairwise analysis showed that number of gene changes correlate with toxicity of pathogenic minerals. While non-pathogenic minerals glass beads and fine TiO2 treatment to cell resulted in no gene change, crocidolite asbestos caused maximum number of gene changes followed by talc.
2011-09-18 | E-GEOD-14034 | biostudies-arrayexpress
Project description:Malignant mesothelioma is an aggressive tumour arising from the mesothelial cells lining the pleura, peritoneum or pericardium. The principal carcinogen associated with malignant mesothelioma is asbestos . A transgenic mouse model, denoted MexTAg, which encodes the Simian Virus 40 (SV40) large T antigen (TAg) downstream of the mesothelin promoter was developed. Inactivation of the tumour suppressors p53 and RB following binding to TAg results. In this model mesothelioma develops in the mesothelial cell compartment after the mice have been exposed to asbestos. The MexTAg transgenic mouse model of mesothelioma model enables analysis of the molecular events associated with asbestos induced mesothelioma and is utilised here to investigate the molecular dynamics of tumours induced in these mice, using gene expression patterns as a read out.
2016-01-30 | E-MTAB-3988 | biostudies-arrayexpress
Project description:We hypothesize that the observed differences in incidences of pleural and peritoneal malignant mesothelioma (MM) are the result of differences in the direct response of these cell types to asbestos rather than to differences mediated by the in vivo microenvironment. To test this hypothesis, we characterized cellular responses to asbestos in a controlled environment using high-throughput RNA sequence and other assays.
2015-03-02 | GSE63966 | GEO
Project description:Malignant mesothelioma (MM) is an aggressive tumor strongly associated with asbestos exposure. The granuloma capturing crocidolite contribute to mutagenesis, cell death and regenerative activity. To clarify the biological responses of mesothelial cells after crocidolite exposure, we compared the microarray gene expression profiles of no treatment and crocidolite exposure (1 wks) mesothelial cells induced by intraperitoneal injections.
2020-06-26 | GSE149285 | GEO
Project description:Human malignant mesothelioma (MM) is an aggressive tumor strongly associated with asbestos exposure. SM patients generally have poorer prognosis compared to EM patients. To identify potential genes accounting for the differential prognosis between these two subtypes, we compared the microarray gene expression profiles of rat SM and EM tissues induced by intraperitoneal injections of 3 types of asbestos (chrysotile,crocidolite and amosite). Carcinogenesis protocol was performed using specific pathogen-free male and female F1 hybrid rats between Fischer344 and Brown-Norway strains. A total of 28 microarrays (Whole Rat Genome Microarray) were used for screening purpose: The 2 arrays were used for knife-scraped peritoneal mesothelial cells, 2 arrays for cultured peritoneal mesothelial cells and 24 arrays for MM samples.
2014-06-04 | E-GEOD-48298 | biostudies-arrayexpress
Project description:Asbestos is the general term for a family of naturally occurring fibrous silicate minerals having commercial importance. They have been used widely for construction and for a number of industrial applications until early 70’s. It is now well known that workers exposed to asbestos are at high risk of developing many lung diseases including asbestosis, malignant mesothelioma, bronchial adenocarcinoma; squamous cell carcinoma of the respiratory epithelium and large/ small cell lung carcinoma. However, the disease causing potential and related processes associated with various asbestos/asbestiform fiber exposures are still largely unknown. In this study, we exposed C57BL6 female mice to asbestos (crocidolite, tremolite), asbestiform fibers (erionite) and a low pathogenicity mineral fiber (wollastonite) to assess pulmonary toxicity responses along with gene expression profiles in the lungs following 7 days post pharyngeal aspiration.
2018-03-01 | GSE100900 | GEO
Project description:Malignant mesothelioma is one of the most aggressive forms of cancer known. Recent studies have shown that carbon nanotubes (CNTs) are biopersistent and induce mesothelioma in animals, but the underlying mechanisms are not known. Here, we investigate the effect of long-term exposure to CNTs on the aggressive behaviors of human pleural mesothelial cells, the primary cellular target of human lung mesothelioma. We show that sub-chronic exposure (4 month) to single- and multi-walled CNTs induced proliferation, migration and invasion of the cells similar to that observed in asbestos-exposed cells. An up-regulation of several key genes known to be important in cell invasion, notably matrix metalloproteinase-2 (MMP-2), was observed in the exposed mesothelial cells as determined by real-time PCR. Western blot and enzyme activity assays confirmed the increased expression and activity of MMP-2. Whole genome expression microarray analysis further indicated the importance of MMP-2 in the invasion gene signaling network of the exposed cells. Knockdown of MMP-2 in CNT and asbestos-exposed cells by shRNA-mediated gene silencing effectively inhibited the aggressive phenotypes. This study provides new evidence for CNT-induced cell invasion and indicates the role of MMP-2 in the process. Whole genome expression profiling was conducted on human immortalized pleural mesothelial cells (MeT5A) following 4 month in vitro sub-chronic exposure to six separate treatments to assess differences in carbon nanotube (CNT) vs. asbestos potential tumorigenesis signaling. Dispersed single wall CNT (D-SWCNT), multi-wall CNT (D-MWCNT), crocidolite asbestos (ASB) and saline (SAL) exposed cells were compared to Survanta® dispersant (DISP) passage control cells. DISP and SAL cells served as control treatments for CNT- and ASB-exposed cells, respectively. Each treatment possessed 3 biological cDNA replicates. One technical replicate was performed per biological sample.
2015-11-23 | E-GEOD-48855 | biostudies-arrayexpress