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1.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445271

RESUMO

This study aimed to identify the proteomic changes produced by curcumin treatment following stimulation of the host immune system in a rat model of malignant mesothelioma. We analyzed the proteomes of secondary lymphoid organs from four normal rats, four untreated tumor-bearing rats, and four tumor-bearing rats receiving repeated intraperitoneal administrations of curcumin. Cross-comparing proteome analyses of histological sections of the spleen from the three groups first identified a list of eighty-three biomarkers of interest, thirteen of which corresponded to proteins already reported in the literature and involved in the anticancer therapeutic effects of curcumin. In a second step, comparing these data with proteomic analyses of histological sections of mesenteric lymph nodes revealed eight common biomarkers showing a similar pattern of changes in both lymphoid organs. Additional findings included a partial reduction of the increase in spleen-circulating biomarkers, a decrease in C-reactive protein and complement C3 in the spleen and lymph nodes, and an increase in lymph node purine nucleoside phosphorylase previously associated with liver immunodeficiency. Our results suggest some protein abundance changes could be related to the systemic, distant non-target antitumor effects produced by this phytochemical.


Assuntos
Biomarcadores Tumorais/metabolismo , Curcumina/farmacologia , Linfonodos/metabolismo , Mesotelioma , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais , Neoplasias Peritoneais , Proteoma/metabolismo , Animais , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/metabolismo , Mesotelioma/patologia , Invasividade Neoplásica , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Ratos , Ratos Endogâmicos F344
2.
Cell Death Dis ; 12(7): 663, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34230456

RESUMO

A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.


Assuntos
Adenoviridae/genética , Proteínas E1 de Adenovirus/genética , Antineoplásicos/farmacologia , Imidazóis/farmacologia , Imidazolinas/farmacologia , Mesotelioma/terapia , Neurofibromina 1/metabolismo , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Adenoviridae/crescimento & desenvolvimento , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Regulação Neoplásica da Expressão Gênica , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/virologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Neurofibromina 1/genética , Vírus Oncolíticos/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299035

RESUMO

SET domain bifurcated 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase that exerts important effects on epigenetic gene regulation. SETDB1 complexes (SETDB1-KRAB-KAP1, SETDB1-DNMT3A, SETDB1-PML, SETDB1-ATF7IP-MBD1) play crucial roles in the processes of histone methylation, transcriptional suppression and chromatin remodelling. Therefore, aberrant trimethylation at H3K9 due to amplification, mutation or deletion of SETDB1 may lead to transcriptional repression of various tumour-suppressing genes and other related genes in cancer cells. Lung cancer is the most common type of cancer worldwide in which SETDB1 amplification and H3K9 hypermethylation have been indicated as potential tumourigenesis markers. In contrast, frequent inactivation mutations of SETDB1 have been revealed in mesothelioma, an asbestos-associated, locally aggressive, highly lethal, and notoriously chemotherapy-resistant cancer. Above all, the different statuses of SETDB1 indicate that it may have different biological functions and be a potential diagnostic biomarker and therapeutic target in lung cancer and mesothelioma.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Animais , Humanos , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo
4.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922336

RESUMO

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes' recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.


Assuntos
Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Mesotelioma/patologia , Monócitos/patologia , Morfolinas/farmacologia , Piridonas/farmacologia , Esferoides Celulares/patologia , Macrófagos Associados a Tumor/patologia , Proliferação de Células , Humanos , Mesotelioma/tratamento farmacológico , Mesotelioma/metabolismo , Monócitos/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Células Tumorais Cultivadas , Microambiente Tumoral , Macrófagos Associados a Tumor/efeitos dos fármacos
5.
Mol Carcinog ; 60(7): 429-439, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33872411

RESUMO

Mesothelioma is a highly aggressive cancer of the mesothelial lining that is caused by exposure to asbestos. Surgical resection followed by chemotherapy is the current treatment strategy, but this is marginally successful and leads to drug-resistant disease. We are interested in factors that maintain the aggressive mesothelioma cancer phenotype as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions in concert with the methylosome protein 50 (MEP50) cofactor to catalyze symmetric dimethylation of key arginine resides in histones 3 and 4 which modifies the chromatin environment to alter tumor suppressor and oncogene expression and enhance cancer cell survival. Our studies show that PRMT5 or MEP50 loss reduces H4R3me2s formation and that this is associated with reduced cancer cell spheroid formation, invasion, and migration. Treatment with sulforaphane (SFN), a diet-derived anticancer agent, reduces PRMT5/MEP50 level and H4R3me2s formation and suppresses the cancer phenotype. We further show that SFN treatment reduces PRMT5 and MEP50 levels and that this reduction is required for SFN suppression of the cancer phenotype. SFN treatment also reduces tumor formation which is associated with reduced PRMT5/MEP50 expression and activity. These findings suggest that SFN may be a useful mesothelioma treatment agent that operates, at least in part, via suppression of PRMT5/MEP50 function.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Isotiocianatos/farmacologia , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Proteína-Arginina N-Metiltransferases/metabolismo , Sulfóxidos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Anticarcinógenos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Mesotelioma/metabolismo , Camundongos Endogâmicos NOD , Fenótipo , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Sci ; 112(6): 2185-2198, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33665882

RESUMO

A rat model of mesothelioma development by peritoneal injection of multiwalled carbon nanotube (MWCNT) has been established and found to be useful to understand the mechanisms underlying fibrous particles-associated carcinogenesis. Its detailed histological sequence, however, remains largely obscure. We therefore aimed to assess the time-course of mesothelioma development by MWCNT and evaluate a set of lipoprotein-related molecules as potential mechanism-based biomarkers for the phenomenon. Male Fischer 344 rats were injected intraperitoneally (ip) with MWCNT (MWNT-7) at 1 mg/kg body weight, and necropsied at 8, 16, 24, 32, or 42 wk after injection. For biochemical analyses of the lipoprotein-related molecules, more samples, including severe mesothelioma cases, were obtained from 2 other carcinogenicity tests. Histologically, in association with chronic inflammation, mesothelial proliferative lesions appeared at c. Wk-24. Before and at the beginning of the tumor development, a prominent infiltration of CD163-positive cells was seen near mesothelial cells. The histological pattern of early mesothelioma was not a papillary structure, but was a characteristic structure with a spherical appearance, composed of the mesothelioma cells in the surface area that were underlain by connective tissue-like cells. Along with the progression, mesotheliomas started to show versatile histological subtypes. Serum levels of apolipoprotein A-I and A-IV, and a ratio of HDL cholesterol to total cholesterol were inversely correlated with mesothelioma severity. Overall, the detailed histological sequence of mesotheliomagenesis by MWCNT is demonstrated, and indicated that the altered profile of apolipoproteins may be involved in its underlying mechanisms.


Assuntos
Apolipoproteínas/metabolismo , Carcinógenos/toxicidade , Mesotelioma/patologia , Nanotubos de Carbono/toxicidade , Animais , Líquido Ascítico/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinogênese , Colesterol/metabolismo , Masculino , Mesotelioma/induzido quimicamente , Mesotelioma/metabolismo , Ratos , Ratos Endogâmicos F344
7.
Cancer Cytopathol ; 129(6): 468-478, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33493383

RESUMO

BACKGROUND: Malignant mesothelioma (MM) is a therapy-resistant tumor, often causing an effusion. Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have shown promising results, but assessment of PD-L1 expression to select patients for therapy has mainly been performed on histologic tissue samples. In a previous study, we showed that MM effusions are suitable for PD-L1 assessment with results comparable to those reported in histologic studies, but no studies have compared PD-L1 expression in histologic and cytologic samples. METHODS: PD-L1 expression was determined immunohistochemically (clone 28-8) in 61 paired samples of effusions and biopsies from patients with pleural MM, obtained at the time of diagnosis. Only cases with >100 tumor cells were included. Membranous staining in tumor cells was considered positive at ≥1%, >5%, >10%, and >50% cutoff levels. RESULTS: Of 61 histologic samples, PD-L1 expression was found in 28 and 7 samples at ≥1% and >50% cutoffs, respectively; the corresponding figures for cytology were 21 and 5, respectively. The overall percentage agreement between histology and cytology was 69% and 84%, with a kappa (κ) of 0.36 and 0.08 at ≥1% and >50% cutoffs, respectively. The concordance between cytology and histology tended to be higher for epithelioid MM versus nonepithelioid MM at a ≥1% cutoff. PD-L1 positivity in biopsies, but not in effusions, correlated with the histologic subtype at a ≥1% cutoff. CONCLUSIONS: A moderate concordance of PD-L1 expression between biopsies and effusions from pleural MM, especially for the epithelioid subtype, indicates biological differences between the 2 types of specimens. Cytology and histology may be complementary.


Assuntos
Antígeno B7-H1/metabolismo , Células Epitelioides/patologia , Mesotelioma/patologia , Derrame Pleural Maligno/patologia , Neoplasias Pleurais/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Citodiagnóstico/métodos , Células Epitelioides/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Mesotelioma/metabolismo , Mesotelioma/cirurgia , Pessoa de Meia-Idade , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/cirurgia , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/cirurgia , Prognóstico
8.
Proc Natl Acad Sci U S A ; 117(41): 25543-25552, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32999071

RESUMO

Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.


Assuntos
Asbestos/efeitos adversos , Autofagia/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Proteína HMGB1/metabolismo , Mesotelioma/metabolismo , Adulto , Idoso , Animais , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Exposição Ocupacional
9.
Respir Res ; 21(1): 187, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32677949

RESUMO

BACKGROUND: Mesothelioma is histologically divided into three subgroups: epithelioid, sarcomatoid, and biphasic types. The epithelioid or sarcomatoid type is morphologically defined by polygonal or spindle-like forms of cells, respectively. The biphasic type consists of both components. It is not yet understood how histological differentiation of mesothelioma is regulated. ERC/mesothelin is expressed in most cases of the epithelioid type, but not in the sarcomatoid type of mesothelioma. Consequently, its expression is well correlated to the histological subtype. We hypothesized that ERC/mesothelin expression influences the histological differentiation of mesothelioma, and tested this hypothesis. METHODS: We performed studies using the overexpression or knockdown of ERC/mesothelin in mesothelioma cells to examine its effect on cellular morphology, growth kinetics, or migration/invasion activity, in vitro. We then transplanted ERC/mesothelin-overexpressing and control cells into the intraperitoneal space of mice. We examined the effect of ERC/mesothelin overexpression on mouse survival and tumor phenotype. RESULTS: In vitro cell culture manipulations of ERC/mesothelin expression did not affect cellular morphology or proliferation, although its overexpression enhanced cellular adhesion and the migration/invasion activity of mesothelioma cells. The survival rate of mice following intraperitoneal transplantation of ERC/mesothelin-overexpressing mesothelioma cells was significantly lower than that of mice with control cells. The histological evaluation of the tumors, however, did not show any morphological difference between two groups, and our hypothesis was not validated. Unexpectedly, both groups (ERC/mesothelin-overexpressing and control) of mesothelioma cells that were morphologically monophasic and spindle-like in vitro differentiated into a biphasic type consisting of polygonal and spindle-like components in the transplanted tumor, irrespective of ERC/mesothelin expression. CONCLUSIONS: These results suggested that the histological transition of mesothelioma between epithelioid and sarcomatoid types may be reversible and regulated not by ERC/mesothelin, but by other unknown mechanisms.


Assuntos
Diferenciação Celular , Células Epitelioides/metabolismo , Proteínas Ligadas por GPI/metabolismo , Mesotelioma/metabolismo , Proteínas Oncogênicas/metabolismo , Sarcoma/metabolismo , Animais , Linhagem Celular Tumoral , Células Epitelioides/patologia , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Mesotelioma/genética , Mesotelioma/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Oncogênicas/genética , Fenótipo , Sarcoma/genética , Sarcoma/patologia , Transdução de Sinais
10.
Life Sci ; 257: 118123, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32710945

RESUMO

Malignant mesothelioma (MM) is a cancer of the mesothelial lining of the pleura, peritoneum, pericardium and testes. The most common form is asbestos-linked MM that is etiologically linked to repeated asbestos exposure with a long latency period, although non-asbestos MM has also been reported. Late diagnosis, poor survival rates, lack of diagnostic and prognostic markers act as major impediments in the clinical management of MM. Despite advances in immune checkpoint inhibition and CAR T-cell-based therapies, MM which is of different histologic subtypes remains challenging to treat. We review microRNAs (miRNAs) and the miRNA interactome implicated in MM which can be useful as circulating miRNA biomarkers for early diagnosis of MM and as biomarkers for prognostication in MM. Further, we underscore the relevance of the NRF2/MAPK signal transduction pathway that has been implicated in MM which may be useful as druggable targets or as biomarkers of predictive response. In addition, since MM is driven partly by inflammation, we elucidate chemopreventive phytochemicals that are beneficial in MM, either via crosstalk with the NRF2/MAPK pathway or via concerted anticancer mechanisms, and may be of benefit as adjuvants in chemotherapy. Taken together, a multifactorial approach comprising identification of miRNA target hubs and NRF2/MAPK biomarkers along with appropriately designed clinical trials may enable early detection and faster intervention in MM translating into better patient outcomes for this aggressive cancer.


Assuntos
Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , Mesotelioma/metabolismo , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Biomarcadores Tumorais , Humanos , Mesotelioma Maligno
11.
Biomolecules ; 10(7)2020 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-32664515

RESUMO

Syndecan-1 (SDC1) is a cell surface heparan sulfate proteoglycan (HSPG), which regulates various signaling pathways controlling the proliferation and migration of malignant mesothelioma and other types of cancer. We have previously shown that SDC1 can translocate to the nucleus in mesothelioma cells through a tubulin-dependent transport mechanism. However, the role of nuclear SDC1 is largely unknown. Here, we performed co-immunoprecipitation (Co-IP) of SDC1 in a mesothelioma cell line to identify SDC1 interacting proteins. The precipitates contained a large number of proteins, indicating the recovery of protein networks. Proteomic analysis with a focus on nuclear proteins revealed an association with pathways related to cell proliferation and RNA synthesis, splicing and transport. In support of this, the top RNA splicing candidates were verified to interact with SDC1 by Co-IP and subsequent Western blot analysis. Further loss- and gain-of-function experiments showed that SDC1 influences RNA levels in mesothelioma cells. The results identify a proteomic map of SDC1 nuclear interactors in a mesothelioma cell line and suggest a previously unknown role for SDC1 in RNA biogenesis. The results should serve as a fundament for further studies to discover the role of nuclear SDC1 in normal and cancer cells of different origin.


Assuntos
Núcleo Celular/metabolismo , Mesotelioma/metabolismo , Proteômica/métodos , Sindecana-1/metabolismo , Linhagem Celular , Núcleo Celular/genética , Proliferação de Células , Mutação com Ganho de Função , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação com Perda de Função , Mesotelioma/genética , Mapas de Interação de Proteínas , Splicing de RNA , Sindecana-1/genética
12.
Biomolecules ; 10(7)2020 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-32605175

RESUMO

Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox's has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox's. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.


Assuntos
Proteínas Ligadas por GPI/metabolismo , Imunotoxinas/uso terapêutico , Mesotelioma/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/metabolismo , Ensaios Clínicos como Assunto , Proteínas Ligadas por GPI/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunotoxinas/química , Imunotoxinas/farmacologia , Mesotelioma/metabolismo , Terapia de Alvo Molecular , Neoplasias Pancreáticas/metabolismo
13.
Nanotoxicology ; 14(7): 947-967, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32574520

RESUMO

Multi-walled carbon nanotubes (MWCNTs) are one of the most widely used types of novel nano-fiber materials. The aim of this study was to establish an experimental system based on actual exposure dosage and environments and explore the roles and mechanisms of inflammation in the malignant transformation of pleural mesothelial cells induced by MWCNTs after low doses and long-term exposure. Here, we established an in vitro system by co-culturing macrophages and mesothelial cells and exposing these cells to high aspect ratio MWCNTs (0.1 µg/mL) for three months. Results indicated that IL-1ß, secreted by macrophages stimulated by MWCNTs, may significantly enhance the release of inflammatory cytokines, such as IL-8, TNF-α, and IL-6, from mesothelial cells. Results obtained from proliferation, migration, invasion, colony formation, and chromosomal aberration studies indicated that MWCNTs may promote malignant transformation of mesothelial cells after long-term and low-dose exposure via inflammation. Furthermore, the obtained results demonstrated that the NF-κB/IL-6/STAT3 pathway was active in the malignant transformation of Met 5A cells, induced by MWCNTs, and played an important role in the process. In conclusion, our results showed that the NF-κB (p65)/IL-6/STAT3 molecular pathway, which was mediated by inflammation, played an important role in the malignant transformation of pleural mesothelial cells induced by MWCNTs. These findings also provide novel ideas and references for the treatment of mesothelioma and offers options for the occupational safety of nanomaterial practitioners.


Assuntos
Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Neoplasias Pulmonares/imunologia , Macrófagos/efeitos dos fármacos , Mesotelioma/imunologia , Nanotubos de Carbono/toxicidade , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Células Epiteliais/imunologia , Células Epiteliais/patologia , Técnicas de Silenciamento de Genes , Humanos , Inflamação , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mesotelioma/metabolismo , Mesotelioma/patologia , Mesotelioma Maligno , Células THP-1 , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
JCI Insight ; 5(12)2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32554927

RESUMO

Oxidative stress and inadequate redox homeostasis is crucial for tumor initiation and progression. MTH1 (NUDT1) enzyme prevents incorporation of oxidized dNTPs by sanitizing the deoxynucleoside triphosphate (dNTP) pool and is therefore vital for the survival of tumor cells. MTH1 inhibition has been found to inhibit the growth of several experimental tumors, but its role in mesothelioma progression remained elusive. Moreover, although MTH1 is nonessential to normal cells, its role in survival of host cells in tumor milieu, especially tumor endothelium, is unclear. We validated a clinically relevant MTH1 inhibitor (Karonudib) in mesothelioma treatment using human xenografts and syngeneic murine models. We show that MTH1 inhibition impedes mesothelioma progression and that inherent tumoral MTH1 levels are associated with a tumor's response. We also identified tumor endothelial cells as selective targets of Karonudib and propose a model of intercellular signaling among tumor cells and bystander tumor endothelium. We finally determined the major biological processes associated with elevated MTH1 gene expression in human mesotheliomas.


Assuntos
Células Endoteliais/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Mesotelioma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/metabolismo , Pirimidinas/farmacologia , Animais , Linhagem Celular Tumoral , Enzimas Reparadoras do DNA/efeitos dos fármacos , Enzimas Reparadoras do DNA/metabolismo , Células Endoteliais/metabolismo , Endotélio/metabolismo , Mesotelioma/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nucleotídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
15.
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 , Mesotelioma Maligno , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Ratos
16.
Mol Oncol ; 14(5): 933-950, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32147909

RESUMO

The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell type-specific methylation differed across tumor and cell types. However, in melanomas immune cell type-specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan-cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.


Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Linfócitos/citologia , Melanoma/imunologia , Melanoma/metabolismo , Células Mieloides/citologia , Neoplasias Cutâneas/metabolismo , Microambiente Tumoral/imunologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Carcinoma/genética , Carcinoma/imunologia , Carcinoma/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Bases de Dados Genéticas , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Epigênese Genética , Glioma/genética , Glioma/imunologia , Glioma/metabolismo , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Linfócitos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Melanoma/genética , Melanoma/secundário , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/metabolismo , Fator de Transcrição Associado à Microftalmia/metabolismo , Células Mieloides/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Regiões Promotoras Genéticas , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Linfócitos T/citologia , Linfócitos T/metabolismo
17.
Nat Rev Clin Oncol ; 17(6): 349-359, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152484

RESUMO

Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody-drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices.


Assuntos
Antineoplásicos/uso terapêutico , Receptor 1 de Folato/metabolismo , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imagem Molecular , Neoplasias/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/terapia , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/terapia , Feminino , Corantes Fluorescentes , Ácido Fólico , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Imunoterapia Adotiva , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Mesotelioma/diagnóstico por imagem , Mesotelioma/metabolismo , Mesotelioma/terapia , Terapia de Alvo Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Imagem Óptica , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Cintilografia , Nanomedicina Teranóstica , Moduladores de Tubulina/uso terapêutico
18.
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 , Mesotelioma Maligno , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Transfecção
19.
Int J Cancer ; 146(1): 192-207, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31107974

RESUMO

Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM-initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness-related pathways determine chemoresistance. Moreover, there are no predictive markers of IC-associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness-related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo-sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5-knocked-out (KO) IC clones were resensitized to the drugs in vitro and in patient-derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3ß/ß-catenin/c-myc axis that also increased IL-8 and IL-1ß production. IL-8 and IL-1ß-KO IC clones reduced the c-myc-driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5-KO clones had lower IL-8 and IL-1ß secretion, and c-myc transcriptional activity, suggesting that either Wnt/GSK3ß/ß-catenin and IL-8/IL-1ß signaling drive c-myc-mediated transcription of ABCB5. ABCB5 correlated with lower time-to-progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first-line chemotherapy in MPM patients.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Resistencia a Medicamentos Antineoplásicos/genética , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Via de Sinalização Wnt , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Mesotelioma/metabolismo , Mesotelioma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia
20.
Biotech Histochem ; 95(3): 171-175, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31570005

RESUMO

Malignant mesothelioma (MM) is a rare tumor of serous surfaces that has a poor prognosis. Cancer is a multistage process by which cells undergo metabolic and behavioral changes that cause excessive and untimely proliferation. Asprosin (ASP) and meteorin-like (METRNL) are two peptides associated with glucose and energy metabolism. We used immunohistochemistry to investigate whether these peptides could be biomarkers for diagnosis and treatment of MM. We reviewed 30 cases of MM and 30 cases of reactive mesothelial hyperplasia (RMH); we used the cases with RMH as control group. The specimens were examined using immunohistochemical staining for ASP and METRNL. ASP and METRNL immunoreactivity was more prominent in the MM specimens than the RMH specimens. Therefore, ASP and METRNL potentially could be used as markers for differentiating MM from benign diseases.


Assuntos
Adipocinas/metabolismo , Biomarcadores Tumorais/análise , Fibrilina-1/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesotelioma/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/diagnóstico , Mesotelioma/patologia , Mesotelioma Maligno/metabolismo , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade
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