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1.
Proc Natl Acad Sci U S A ; 117(52): 33466-33473, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318203

RESUMO

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM +/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM +/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM +/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM +/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm +/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm +/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1ß, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm +/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM +/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.


Assuntos
Asbestose/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Mesotelioma/genética , RecQ Helicases/genética , Adulto , Idoso , Animais , Asbesto Crocidolita , Família , Feminino , Instabilidade Genômica , Heterozigoto , Humanos , Incidência , Inflamação/patologia , Masculino , Camundongos , Pessoa de Meia-Idade
2.
Lancet Oncol ; 21(9): 1213-1223, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888453

RESUMO

BACKGROUND: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. METHODS: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. FINDINGS: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. INTERPRETATION: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/administração & dosagem , Neoplasias Pleurais/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália/epidemiologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Cisplatino/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Pemetrexede/efeitos adversos , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão
4.
Am J Surg Pathol ; 44(9): 1259-1265, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32496433

RESUMO

The differential diagnosis of epithelioid mesothelioma from lung adenocarcinoma using immunohistochemistry is improving. However, immunohistochemical markers with high sensitivity and specificity have yet to be identified. In this study, we investigated the utility of sex-determining region Y box 6 (SOX6) as a novel immunohistochemical marker, identified by analyzing previous gene expression data. Immunohistochemically, SOX6 expression was present in 53 of 54 (98%) cases of epithelioid mesothelioma, compared with its expression in only 5 of 69 (7%) cases of lung adenocarcinoma. The sensitivity and specificity of SOX6 expression for differentiating epithelioid mesothelioma and lung adenocarcinoma were 98% and 93%, respectively. SOX6 expression showed similar sensitivity and far better specificity than those of calretinin or podoplanin (D2-40). In addition, SOX6 expression was more sensitive than Wilms' tumor 1 expression. The combination of SOX6 with other markers showed comparable or better sensitivity and specificity relative to other combinations. In particular, the sensitivity of positivity for both SOX6 and calretinin (96%) and the specificity of positivity for both SOX6 and Wilms' tumor 1 (93%) were higher than those of the other combinations. In conclusion, SOX6 is a novel candidate immunohistochemical marker for differentiating epithelioid mesothelioma from lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/química , Biomarcadores Tumorais/análise , Células Epitelioides/química , Imuno-Histoquímica , Neoplasias Pulmonares/química , Mesotelioma/química , Fatores de Transcrição SOXD/análise , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Células Epitelioides/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Transcrição SOXD/genética
6.
Pol J Pathol ; 71(1): 69-74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32429658

RESUMO

Molecular next gene sequencing was used to evaluate mutations in 409 common mutated cancer-related genes in malignant mesothelioma of tunica vaginalis testis (MMTVT) of 81-year-old man. Multifocal papillary-solid areas contained necrosis among highly cellular fields with multiple mitoses. It was positive for WT1, CKAE1/AE3, calretinin, CK7 with negativity for CK5, PSA, TTF-1. Following mutations were revealed in PARP1 (NM_001618: c.2285TG, p.K135R), MTRR (NM_024010: c.147A>G, p.I49M) and two sorts of mutations in structure of KMT2C gene (NM_170606: c.2447_2448insA (c.2447dupA), p.Y816fs and NM_170606: c.1042G>A, p.D348N) for the first time in MMTVT.


Assuntos
Mesotelioma/genética , Neoplasias Testiculares/genética , Adenosina Trifosfatases/genética , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Ferredoxina-NADP Redutase/genética , Humanos , Masculino , Mutação , Fator de Transcrição PAX8/genética , Poli(ADP-Ribose) Polimerase-1/genética , Ubiquitina-Proteína Ligases/genética
7.
Cancer Invest ; 38(6): 356-364, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32468861

RESUMO

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.


Assuntos
Adenosina Desaminase/genética , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Neoplasias/diagnóstico , Neoplasias Pleurais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/genética , Mesotelioma/patologia , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/patologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/diagnóstico por imagem , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/patologia , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Toracoscopia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/genética , Tuberculose Pleural/microbiologia , Tuberculose Pleural/patologia
8.
Eur J Cancer ; 132: 104-111, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32339978

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumour with poor prognosis. The aim of this study was to identify genetic mutations associated with poor or extended survival in patients who received palliative chemotherapy. METHODS: A total of 720 patients diagnosed with MPM between 2005 and 2015 were identified. Overall survival (OS) was longer than 30 months from diagnosis for 27 patients. Twelve of 27 (44%) of the pleural biopsies from long-term survivors were retrieved and matched with 12 biopsies from patients who survived less than 12 months; one biopsy was then excluded for poor DNA quality. RESULTS: A total of 11 patients had a mean OS of 5.5 months, whereas 12 patients lived more than 30 months (mean OS: 55.8 ± 25). Mutational analysis identified 428 alterations; of which, 148, classified as somatic and functional, were considered further. Among these, 85% were missense variants, 8% were variants causing a stop gain and 6% were splice variants. Loss-of-function mutations in UQCRC1 were significantly associated with reduced survival in patients with MPM (p = 0.027), while a higher frequency of mutations in MXRA5 and RAPGEF6 was registered in long-term survivors. CONCLUSION: This is the first study evaluating the relationship between the mutational profile and outcome in patients with MPM after palliative chemotherapy. UQCRC1 codes for cytochrome b-c1 complex subunit 1 which plays a fundamental role in normal mitochondrial functions and in cell metabolism. Recent studies described UQCRC1 deregulation in other cancers. Our results suggest a possible role for mitochondrial metabolism in the biology of mesothelioma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica/métodos , Neoplasias Pulmonares/genética , Mesotelioma/genética , Mutação , Neoplasias Pleurais/genética , Idoso , Complexo III da Cadeia de Transporte de Elétrons/genética , Feminino , Seguimentos , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Cuidados Paliativos , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologia , Prognóstico , Proteoglicanas/genética , Estudos Retrospectivos , Taxa de Sobrevida
9.
Cancer Sci ; 111(6): 2016-2027, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32248600

RESUMO

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.


Assuntos
Neoplasias Pulmonares/patologia , Mesotelioma/patologia , MicroRNAs/biossíntese , Neoplasias Peritoneais/patologia , Proteína 1 Relacionada a Twist/biossíntese , Animais , Asbestos/toxicidade , Linhagem Celular , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Ferro/toxicidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mesotelioma/genética , Mesotelioma/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Ratos
10.
Anticancer Res ; 40(4): 1867-1874, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234874

RESUMO

BACKGROUND/AIM: Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM. MATERIALS AND METHODS: Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated. RESULTS: NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-time-dependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling. CONCLUSION: The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Indazóis/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Mutação/genética , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos
11.
Arch Environ Occup Health ; 75(8): 471-482, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308151

RESUMO

Malignant mesothelioma is an aggressive tumor resistant to current therapies with a latency period ranging between 20 and 60 years, caused by inhalation of asbestos fibers, that continues to represent a social and healthcare issue. The high percentage of people exposed to asbestos for professional or environmental reasons is associated with the high biopersistence of its fibers and with its widespread use in the last century. Approximately 20-40% of men report an occupational history that might have caused the workplace exposure (criteria Helsinki, 1997). Some authors are evaluating the possible use of bioindicators as a screening and early diagnosis tool. In this regard, the use of microRNAs has been proposed as powerful diagnostic and prognostic biomarkers for many tumors and human diseases. This review focuses on the current state of knowledge on the key role of microRNAs expression as new malignant mesothelioma biomarkers, in early clinical diagnostic applications.


Assuntos
Neoplasias Pulmonares/genética , Mesotelioma/genética , MicroRNAs/análise , Animais , Asbestos/toxicidade , Biomarcadores Tumorais/análise , Humanos , Exposição Ocupacional/efeitos adversos , Valor Preditivo dos Testes , Prognóstico
12.
Biochem Biophys Res Commun ; 526(4): 927-933, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32284171

RESUMO

Malignant mesothelioma (MM) is a fatal tumor, and the absence of a specific diagnostic marker and/or a pathogenic molecule-targeting drug is a major issue for its pathological diagnosis and for targeting therapy. The molecular target of MM has not been elucidated because of unknown survival, death, and cytotoxic signals in MM. HEG homolog 1 (HEG1) is a mucin-like membrane protein that contains epidermal growth factor-like domains, and it plays an important role in cancers through aberrant signaling, including that during cell adhesion, as well as through protection from invasion of tumor cells. HEG1 expression supports the survival and proliferation of MM cells. In this study, functional analysis of HEG1 and microRNAs using MM cell lines (H226, MESO4, H2052) was performed. The MTS assay revealed that cell proliferation was significantly reduced upon transient transfection with microRNA-23b (miR-23b) inhibitor and/or HEG1 siRNA. The Annexin V assay revealed that apoptosis was induced upon suppression of miR-23b and/or HEG1. Western blotting showed that the autophagy-related protein LC3-II was induced upon suppression of miR-23b and/or HEG1. These results revealed that miR-23b contributes to HEG1-dependent cell proliferation through evasion of cytotoxicity induced by apoptosis and autophagy in MM cells. HEG1-dependent/mediated miR-23b signaling may therefore be a potential target for MM diagnosis and therapy.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Mesotelioma/genética , Mesotelioma/patologia , MicroRNAs/metabolismo , Apoptose/genética , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Epitélio/metabolismo , Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Anticancer Res ; 40(3): 1307-1314, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132027

RESUMO

BACKGROUND/AIM: Malignant pleural mesothelioma (MPM) is an intractable cancer, and causes of its malignant transformation are not well known. Adenosine deaminase acting on RNA (ADAR) is an RNA-editing enzyme that converts adenosine into inosine in double-stranded RNAs potentially involved in malignant development. MATERIALS AND METHODS: To examine the role of ADAR1 and ADAR2 in MPM, small interfering RNAs (siRNAs) against ADAR1 or ADAR2 were used. RESULTS: Transfection of siRNA against ADAR2 suppressed proliferation, motility, and invasiveness of MPM cells expressing both ADAR1 and ADAR2; however, siRNA against ADAR1 did not affect these cellular activities. Overexpression of ADAR2, that was incapable of binding to RNA, suppressed growth, motility, and invasion of MPM cells. However, overexpression of ADAR2 that had no enzyme activity did not alter the malignant properties of MPM cells. CONCLUSION: Enhancement of the malignant characteristics of cultured MPM cells via ADAR2 was independent of RNA-editing activity.


Assuntos
Adenosina Desaminase/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mesotelioma/genética , Mesotelioma/metabolismo , Edição de RNA , Proteínas de Ligação a RNA/metabolismo , Adenosina Desaminase/biossíntese , Adenosina Desaminase/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Mesotelioma/enzimologia , Mesotelioma/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Transfecção
14.
Int J Biochem Cell Biol ; 121: 105700, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32006662

RESUMO

MiR-222 and miR-126 are associated with asbestos exposure and the ensuing malignancy, but the mechanism(s) of their regulation remain unclear. We evaluated the mechanism by which asbestos regulates miR-222 and miR-126 expression in the context of cancer etiology. An 'in vitro' model of carcinogen-induced cell transformation was used based on exposing bronchial epithelium BEAS-2B cells to three different carcinogens including asbestos. Involvement of the EGFR pathway and the role of epigenetics have been investigated in carcinogen-transformed cells and in malignant mesothelioma, a neoplastic disease associated with asbestos exposure. Increased expression of miR-222 and miR-126 were found in asbestos-transformed cells, but not in cells exposed to arsenic and chrome. Asbestos-mediated activation of the EGFR pathway and macrophages-induced inflammation resulted in miR-222 upregulation, which was reversed by EGFR inhibition. Conversely, asbestos-induced miR-126 expression was affected neither by EGFR modulation nor inflammation. Rather than methylation of the miR-126 host gene EGFL7, epigenetic mechanism involving DNMT1- and PARP1-mediated chromatin remodeling was found to upregulate of miR-126 in asbestos-exposed cells, while miR-126 was downregulated in malignant cells. Analysis of MM tissue supported the role of PARP1 in miR-126 regulation. Therefore, activation of the EGFR pathway and the PARP1-mediated epigenetic regulation both play a role in asbestos-induced miRNA expression, associated with in asbestos-induced carcinogenesis and tumor progression.


Assuntos
Asbestos/efeitos adversos , Carcinógenos/química , Neoplasias Pulmonares/genética , Mesotelioma/genética , MicroRNAs/metabolismo , Idoso , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia
15.
Cancer Sci ; 111(4): 1180-1192, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32080953

RESUMO

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 undertaken, 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, whereas 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 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 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.


Assuntos
Asbestos/toxicidade , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Animais , Amiantos Anfibólicos/toxicidade , Asbesto Crocidolita/toxicidade , Asbestos Serpentinas/toxicidade , Hibridização Genômica Comparativa , Homozigoto , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Mesotelioma/induzido quimicamente , Mesotelioma/patologia , Ratos , Fatores de Risco , Deleção de Sequência/genética
16.
Cancer Chemother Pharmacol ; 85(2): 425-432, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31974652

RESUMO

Activated cap-dependent translation promotes cancer by stimulating translation of mRNAs encoding malignancy-promoting proteins. The nucleoside monophosphate Protide, 4Ei-10, undergoes intracellular uptake and conversion by Hint1 to form 7-Cl-Ph-Ethyl-GMP. 7-Cl-Ph-Ethyl-GMP is an analog of cap and inhibits protein translation by binding and sequestering eIF4E thus blocking eIF4E from binding to the mRNA cap. The effects of inhibiting translation initiation by disruption of the eIF4F complex with 4Ei-10 were examined in malignant mesothelioma (MM). In a cell-free assay system, formation of the eIF4F complex was disabled in response to exposure to 4Ei-10. Treatment of MM with 4Ei-10 resulted in decreased cell proliferation, increased sensitivity to pemetrexed and altered expression of malignancy-related proteins. In light of these findings, suppression of translation initiation by small molecule inhibitors like 4Ei-10 alone or in combination with pemetrexed represents an encouraging strategy meriting further evaluation in the treatment of MM.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Fator de Iniciação 4F em Eucariotos/genética , Humanos , Pemetrexede/farmacologia , RNA Mensageiro/genética , Bibliotecas de Moléculas Pequenas/farmacologia
17.
Cancer Res ; 80(4): 843-856, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31911549

RESUMO

Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110ß/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110ß/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110ß/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking. SIGNIFICANCE: Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Cromonas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Epitélio/patologia , Feminino , Técnicas de Introdução de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular/métodos , PTEN Fosfo-Hidrolase/genética , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Peritônio/patologia , Pleura/patologia , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Cultura Primária de Células , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Supressora de Tumor p53/genética
18.
Am J Surg Pathol ; 44(2): 288-292, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31567203

RESUMO

Neurofibromatosis type 2 (NF2), an inherited disorder associated with multiple inherited schwannomas, meningiomas and ependymomas is caused by an autosomal dominant, likely loss of function germline mutation of the NF2 gene. Interestingly, biallelic NF2 gene inactivation is one of the most common mutations associated with the development of malignant mesothelioma (MM), a highly fatal malignancy that arises in the pleura and less frequently in the pericardium, peritoneum, and tunica vaginalis. It has been proposed that NF2 patients could potentially be at increased risk of developing MM. However, patients with inherited NF2 rarely develop MM. To date, only 2 cases describing patients diagnosed with both have been reported in the literature. Here, we describe the third case and for the first time, also provide molecular evidence that a "second hit" involving a somatic mutation is likely required to trigger the development of MM in this rare cohort. In our patient diagnosed with NF2 at age 25 who developed an aggressive peritoneal MM 15 years later, we identified a germline NF2 mutation and somatic mutations including BAP1. Of clinical relevance, our case supports a germline NF2 mutation may not necessarily be more susceptible to develop mesothelioma without a "second hit" mutation.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Neurofibromatose 2/patologia , Neurofibromina 2/genética , Neoplasias Peritoneais/patologia , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adulto , Evolução Fatal , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mesotelioma/diagnóstico , Mesotelioma/genética , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/genética
19.
Hum Cell ; 33(1): 272-282, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31583526

RESUMO

Malignant peritoneal mesothelioma (MPeM) is a rare and aggressive form of malignant mesothelioma. Sufficient biological tools for studying the functional characteristics of this cancer have not been developed. Therefore, in this study, a novel human cancer cell line, KOG-1, was established from ascites fluids isolated from a 39-year-old Japanese woman with pemetrexed-resistant MPeM. Cells were dendritic or linear immediately after thawing, showed a jigsaw puzzle-like and spindle arrangement during growth, and formed monolayers without contact inhibition in two-dimensional (2D) culture. The population doubling time was 13.7 h. Karyotypic and molecular genetic analyses showed that chromosome numbers ranged from 62 to 142, with a peak of 73 with complicated copy number alterations. No germline BAP1 pathogenic variant was detected. Cells expressed various tumor markers of mesothelioma, such as calretinin, podoplanin, and Wilms tumor 1 (WT-1). Drug sensitivity and resistance testing with a set of 36 drugs using 2D and three-dimensional (3D) culture models demonstrated that KOG-1 cells showed high and low sensitivity to pemetrexed under 2D and 3D culture conditions, respectively, whereas control ovarian cancer cell lines showed low sensitivity to pemetrexed under both culture conditions. This newly established cell line will be a valuable biological resource to expand the feasibility of functional studies as well as drug testing for potential therapeutic purposes in MPeM.


Assuntos
Mesotelioma/genética , Terapia de Alvo Molecular , Neoplasias Peritoneais/genética , Resistencia a Medicamentos Antineoplásicos , Humanos , Mesotelioma/terapia , Neoplasias Peritoneais/terapia
20.
Acta Cytol ; 64(4): 378-385, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31661685

RESUMO

BACKGROUND: A case of peritoneal mesothelioma with an anaplastic lymphoma kinase (ALK) translocation was identified, and we conducted further studies to obtain diagnostic and therapeutic insights. We believe that this is the first report describing the cytology of this new tumor type. CASE: A teenage woman was referred for severe pleural effusion. Enhanced computed tomography indicated an abdominal mass with ascites. Laparoscopy revealed tumor dissemination from the pelvis to the upper abdomen. Because a high-grade serous carcinoma was suspected, ascitic cytology and biopsy were performed. Cytologically, the tumor displayed characteristics of both adenocarcinoma and reactive or neoplastic mesothelial cells. After extensive pathological evaluation, the tumor was diagnosed as malignant peritoneal mesothelioma. To verify the diagnosis and aid in developing a therapeutic strategy, several companion diagnostics were tried. Surprisingly, the tumor was ALK-positive, and ALK recombination was confirmed by an ALK break-apart test. Retrospectively, cells and tissue specimens were stained with ALK intercalated antibody-enhanced polymer. Tumor cells were clearly distinguished from the nonneoplastic background. Recombination in ALK was reconfirmed by the National Cancer Center Japan, and the patient was enrolled in a clinical trial for alectinib. CONCLUSION: Companion diagnostics-based cytology may provide a useful means of monitoring and evaluating a molecular-targeted therapy.


Assuntos
Quinase do Linfoma Anaplásico/genética , Ascite/diagnóstico , Ascite/genética , Rearranjo Gênico/genética , Mesotelioma/diagnóstico , Mesotelioma/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adolescente , Citodiagnóstico/métodos , Feminino , Humanos , Estudos Retrospectivos
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