RESUMO
Rodent alveolar/bronchiolar carcinomas (ABC) that arise either spontaneously or due to chemical exposure are similar to a subtype of lung adenocarcinomas in humans. B6C3F1/N mice and F344/NTac rats exposed to cobalt metal dust (CMD) by inhalation developed ABCs in a dose dependent manner. In CMD-exposed mice, the incidence of Kras mutations in ABCs was 67% with 80% of those being G to T transversions on codon 12 suggesting a role of oxidative stress in the pathogenesis. In vitro studies, such as DMPO (5,5-dimethyl-1-pyrroline N-oxide) immune-spin trapping assay, and dihydroethidium (DHE) fluorescence assay on A549 and BEAS-2B cells demonstrated increased oxidative stress due to cobalt exposure. In addition, significantly increased 8-oxo-dG adducts were demonstrated by immunohistochemistry in lungs from mice exposed to CMD for 90 days. Furthermore, transcriptomic analysis on ABCs arising spontaneously or due to chronic CMD-exposure demonstrated significant alterations in canonical pathways related to MAPK signaling (IL-8, ErbB, Integrin, and PAK pathway) and oxidative stress (PI3K/AKT and Melatonin pathway) in ABCs from CMD-exposed mice. Oxidative stress can stimulate PI3K/AKT and MAPK signaling pathways. Nox4 was significantly upregulated only in CMD-exposed ABCs and NOX4 activation of PI3K/AKT can lead to increased ROS levels in human cancer cells. The gene encoding Ereg was markedly up-regulated in CMD-exposed mice. Oncogenic KRAS mutations have been shown to induce EREG overexpression. Collectively, all these data suggest that oxidative stress plays a significant role in CMD-induced pulmonary carcinogenesis in rodents and these findings may also be relevant in the context of human lung cancers.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Cobalto/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Células A549 , Adenocarcinoma Bronquioloalveolar/induzido quimicamente , Adenocarcinoma Bronquioloalveolar/patologia , Animais , Neoplasias Brônquicas/patologia , Carcinogênese/induzido quimicamente , Linhagem Celular , Relação Dose-Resposta a Droga , Poeira , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Alvéolos Pulmonares/patologia , Ratos , Ratos Endogâmicos F344RESUMO
Quantum dots (QDs) are semiconducting nanocrystals with unique optical properties. When coated with shell/capping, QDs are not deleterious to cells and organisms. However, when QDs are retained in the cellular environment for a certain period of time, their coatings may be degraded, yielding "naked" QDs. Although some studies have documented the acute effects of cadmium telluride (CdTe) QDs in various cell lines, however, to our knowledge, there are no published studies on the chronic effects of CdTe QDs in normal lung cells. In this study, we therefore sought to study the effects of CdTe QDs of various particle sizes on their cytotoxicity and carcinogenicity in normal human bronchial epithelial cells (BEAS-2B). A total of three particle sizes of CdTe QD with emission maximum at 520, 580, and 730 nm were employed (abbreviated as 520Q, 580Q, and 730Q, respectively). Our results indicated that acute exposure to 520Q (â¼2.04 nm in diameter) and 580Q (â¼3.24 nm in diameter) elicited dose-dependent cytotoxicity; while acute exposure to 730Q (â¼5.40 nm in diameter) elicited negligible cytotoxicity in BEAS-2B cells. Notably, chronic exposure to CdTe QD of all three tested particle sizes induced BEAS-2B cell transformation as evidenced by enhanced cell migration and anchorage-independent growth on soft agar. Taken together, our findings suggest that CdTe QDs are potent human lung carcinogens.
Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Neoplasias Brônquicas/induzido quimicamente , Compostos de Cádmio/toxicidade , Transformação Celular Neoplásica/efeitos dos fármacos , Pontos Quânticos/toxicidade , Pontos Quânticos/ultraestrutura , Telúrio/toxicidade , Doença Aguda , Células Epiteliais Alveolares/patologia , Neoplasias Brônquicas/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Doença Crônica , Relação Dose-Resposta a Droga , Humanos , Tamanho da Partícula , Testes de ToxicidadeRESUMO
Nickel (Ni) compounds are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC) and are known to be carcinogenic to the lungs. In our previous study, special ATrich sequencebinding protein 2 (SATB2) was required for Niinduced BEAS2B cell transformation. In the present study, a pathway that regulates the expression of SATB2 protein was investigated in Nitransformed BEAS2B cells using western blotting and RTqPCR for expression, and soft agar, migration and invasion assays for cell transformation. Runtrelated transcription factor 2 (RUNX2), a master regulator of osteogenesis and an oncogene, was identified as an upstream regulator for SATB2. Ni induced RUNX2 expression and initiated BEAS2B transformation and metastatic potential. Previously, miRNA31 was identified as a negative regulator of SATB2 during arsenicinduced cell transformation, and in the present study it was identified as a downstream target of RUNX2 during carcinogenesis. miR31 expression was reduced in Nitransformed BEAS2B cells, which was required to maintain cancer hallmarks. The expression level of miR31 was suppressed by RUNX2 in BEAS2B cells, and this increased the expression level of SATB2, initiating cell transformation. Ni caused the repression of miR31 by placing repressive marks at its promoter, which in turn increased the expression level of SATB2, leading to cell transformation.
Assuntos
Neoplasias Brônquicas/genética , Transformação Celular Neoplásica/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , MicroRNAs/genética , Níquel/efeitos adversos , Fatores de Transcrição/genética , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/metabolismo , Adesão Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Chronic exposure to arsenic increases the risk of developing a variety of human cancers including lung carcinomas. However, the exact molecular mechanism underlying arsenic carcinogenicity remains largely unknown. Autophagy is a conserved catabolic process for maintaining cellular protein homeostasis whose defects might result in accumulation of dysfunctional organelles and damaged proteins thus promoting tumorigenesis. In the present study, we found that chronic exposure of human bronchial epithelial BEAS-2B cells to sub-lethal dose of sodium arsenite led to autophagy activation and induced an epithelial-to-mesenchymal transition (EMT) to enhance cell migratory and invasive capability. The malignant transformation was mediated via activation of MEK/ERK1/2 signaling. Importantly, inhibition of autophagy in these arsenic-exposed cells by pharmacological intervention or genetic deletion further promoted the EMT and increased the generation of inflammasomes. Both autophagy inhibitor and genetic deletion of autophagy core gene Beclin-1 produced similar effects. These results may suggest the important role of autophagy in sodium arsenite-induced lung tumorigenesis which may serve as a potential target in prevention and treatment of arsenic-imposed lung cancer.
Assuntos
Arsênio/toxicidade , Autofagia/fisiologia , Brônquios/patologia , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/patologia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Beclina-1/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
Poly (ADP-ribosylation) is a key post-translational modification (PTM), and poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme that hydrolyzes poly (ADP-ribose) in eukaryotic organisms. Our previous findings suggested that knockdown of PARG attenuates benzo(a)pyrene (BaP) carcinogenesis. However, the mechanisms underlying PARG-mediated protective effects remain limited. In this study, the expression levels of histones were analyzed by Western blotting and immunofluorescence. Histone H2A levels were abnormally decreased by BaP-induced carcinogenesis, but were maintained by knockdown of PARG in the 16HBE human bronchial epithelial cell line. The interaction between poly (ADP-ribose) and H2A was confirmed by co-immunoprecipitation. PARG-related modifications in H2A were profiled by immune antibody enrichment coupled with mass spectrometry. H2AK5ac, H2AK9ac, H2AK13ac, H2A.ZK4K7K11ac, and H2AK9me were expressed in BaP-transformed 16HBE (BTC-16HBE) cells, but were not detectable in normal 16HBE or BaP-transformed 16HBE cells with knockdown of PARG (BTC-shPARG). Further verification by Western blotting indicated that H2AK9me was elevated in BTC-16HBE cells but decreased in BTC-shPARG cells. These findings suggest that knockdown of PARG protects against BaP-induced carcinogenesis in 16HBE cells by downregulating H2AK9me. Our in vivo studies confirmed that PARG silencing decreased H2AK9me levels, thereby countering the carcinogenic teratogenic effects induced by BaP.
Assuntos
Benzo(a)pireno/toxicidade , Brônquios/efeitos dos fármacos , Neoplasias Brônquicas/prevenção & controle , Carcinógenos/toxicidade , Transformação Celular Neoplásica/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Glicosídeo Hidrolases/metabolismo , Histonas/metabolismo , Interferência de RNA , ADP-Ribosilação , Brônquios/enzimologia , Brônquios/patologia , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/enzimologia , Neoplasias Brônquicas/genética , Linhagem Celular , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Glicosídeo Hidrolases/genética , HumanosRESUMO
We present a rare case of recurrent multiple lesions of bronchial epithelial-myoepithelial carcinoma in a 74-year-old man treated with local resection. Two cellular types were found: epithelial cells and myoepithelial cells. The patient remains asymptomatic at 4-years of follow-up, supporting the fact that epithelial-myoepithelial carcinoma is a tumor of low-grade malignancy.
Assuntos
Neoplasias Brônquicas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Mioepitelioma/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias das Glândulas Salivares/diagnóstico , Idoso , Neoplasias Brônquicas/induzido quimicamente , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/induzido quimicamente , Masculino , Mioepitelioma/induzido quimicamente , Recidiva Local de Neoplasia/induzido quimicamente , Neoplasias Epiteliais e Glandulares/induzido quimicamente , Neoplasias das Glândulas Salivares/induzido quimicamenteRESUMO
The neoplastic progression induced by intratracheal instillation of benzo[a]pyrene (BP) and magnesium oxide (MgO) was compared with that induced by intratracheal instillation of BP and ferric oxide (Fe2O3). BP and MgO produced squamous cell carcinomas and papillomas in the larynx with a latent period as shor as 9 weeks. They also induced many papillomas as well as squamous cell carcinomas and adenocarcinomas in the trachea and a papilloma, squamous cell carcinomas, adenocarcinomas, adenosquamous lesions, and peripheral adenomatoid lesions in the bronchi. They rarely caused tumors in other organs; only a few forestomach papillomas, one melanoma on the dorsal skin, and one ovarian carconoma were seen BP, with Fe2O3 as the carrier, induced a comparable number of histologically similar tumors; however, tumors developed more frequently in the main bronchi. Thus MgO strongly facilitated the tumor-inducing effects of BP, causing tumors in different areas of the respiratory tract, and was as effective as Fe2O3 as a carrier agent in the experimental induction of respiratory tumors.
Assuntos
Benzopirenos , Carcinoma de Células Escamosas/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Óxido de Magnésio , Papiloma/induzido quimicamente , Veículos Farmacêuticos , Animais , Neoplasias Brônquicas/induzido quimicamente , Cricetinae , Feminino , Compostos Férricos , Intubação Intratraqueal , Neoplasias Laríngeas/induzido quimicamente , Masculino , Melanoma/induzido quimicamente , Neoplasias Experimentais/induzido quimicamente , Neoplasias Ovarianas/induzido quimicamente , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Gástricas/induzido quimicamente , Fatores de Tempo , Neoplasias da Traqueia/induzido quimicamente , Zigoto/ultraestruturaRESUMO
Oxidation at the beta carbon occurred in metabolism of di-n-propylnitrosamine (DPN), previously shown to be carcinogenic for animals. When 2,2'-dimethyldipropylnitrosamine (DMDPN) was injected sc once a week for life into male and female Syrian hamsters at levels of 500, 250, 125, and 62.5 mg/kg body weight, it induced neoplasms in the nasal cavities, larynx, trachea, and stem bronchi. Since the presence of a methyl group on the beta carbon suggested that DMDPN could not undergo beta oxidation, the carcinogenicity of DPN for these portions of the respiratory tract was probably unrelated to beta oxidation, though earlier experiments had indicated the possibility of this mechanism. Because DMDPN failed to induce neoplasms in other organs, the carcinogenicity of DPN or its beta metabolites for the lungs, liver, pancreas, and kidneys was not explained by this experiment.
Assuntos
Dimetilnitrosamina/toxicidade , Nitrosaminas/toxicidade , Neoplasias do Sistema Respiratório/induzido quimicamente , Adenocarcinoma/induzido quimicamente , Animais , Neoplasias Brônquicas/induzido quimicamente , Carcinoma de Células Escamosas/induzido quimicamente , Cricetinae , Feminino , Neoplasias Laríngeas/induzido quimicamente , Dose Letal Mediana , Masculino , Neoplasias Experimentais/induzido quimicamente , Neoplasias Nasais/induzido quimicamenteRESUMO
The effects of two types of research cigarettes, which differed in their total smoke delivery and condensate, on the bronchial epithelium of Syrian hamsters were examined electronmicroscopically. The animals were exposed once a day for 5 days each week for 1 year to the total smoke of the cigarettes. Two groups and a control group were killed 1 day after the last exposure, and one group 12 months after the last exposure. The bronchial epithelia of all smoke-exposed animals were hyperplastic, and their ultrastructure showed invaginations, tilt of nuclear axes, an increase in the number and size of lysosomes and multivesiculated bodies, and increased numbers of enlarged intramitochondrial granules. Squamous metaplasia, rarely found, was present at the stage of filamentous bundle formation. The induced alterations were independent of the type of cigarette used. One year after smoking was terminated, the alterations had neither reversed nor advanced, as compared to those occurring 1 day after the last smoke exposure.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Lesões Pré-Cancerosas/induzido quimicamente , Fumar/complicações , Animais , Brônquios/patologia , Neoplasias Brônquicas/patologia , Cricetinae , Células Epiteliais , Epitélio/patologia , Epitélio/ultraestrutura , Hiperplasia/induzido quimicamente , Lisossomos/ultraestrutura , Metaplasia/induzido quimicamente , Mitocôndrias/ultraestrutura , Plantas Tóxicas , Lesões Pré-Cancerosas/patologia , Fatores de Tempo , NicotianaRESUMO
2, 2-Dihydroxy-di-n-propylnitrosamine (DHPN), an assumed metabolite of di-n-propylnitrosamine (DPN), injected subcutaneously once weekly for life, was carcinogenic in Syrian hamsters. The main target organs were the respiratory tract, pancreas, liver, and kidneys. In the respiratory system the most affected segments were the nasal cavities and the lungs. Adenomas and adenocarcinomas, mostly of ductal origin, were induced in the pancreas. Liver neoplasms were hemangloendotheliomas, angiosarcomas, hepatocellular adenomas, cholangiomas, and cholangiocarcinomas. Kidney neoplasms were adenomas and adenocarcinomas. The morphology of the induced neoplasms was described, as well as the effects of DHPN, compared to those another possible metabolite of DPN, 2-hydroxypropyl-n-propylnitrosamine (2-HPPN), which is formed in vivo with only 1 aliphatic chain degraded via theta-oxidation.
Assuntos
Carcinógenos , Neoplasias Experimentais/induzido quimicamente , Nitrosaminas/toxicidade , Adenocarcinoma/induzido quimicamente , Adenoma/induzido quimicamente , Adenoma de Ducto Biliar/induzido quimicamente , Animais , Neoplasias Brônquicas/induzido quimicamente , Carcinoma Hepatocelular/induzido quimicamente , Cricetinae , Feminino , Neoplasias da Vesícula Biliar/induzido quimicamente , Hemangioendotelioma/induzido quimicamente , Hemangiossarcoma/induzido quimicamente , Neoplasias Renais/induzido quimicamente , Neoplasias Laríngeas/induzido quimicamente , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Masculino , Nitrosaminas/metabolismo , Neoplasias Nasais/induzido quimicamente , Oxirredução , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias da Traqueia/induzido quimicamenteRESUMO
The acidic Fractions (including phenols) were separated from two somewhat different coal tars. Various blends and an original tar produced aerosols to which 5 groups of male C3H/HeJ mice were exposed 2 hours, 3 times weekly, for 55 weeks. Animals were killed at intervals. The lungs and tracheas of all mice were examined grossly and microscopically for neoplasms or relevant morphologic changes. After 46 weeks, 32 survivors in groups 2 and 4, which received similar aerosols containing phenols, had 4 incidences of adenocarcinoma, 19 of intrabronchial adenoma, and 10 of squamous metaplasia. In 20 survivors of group 3, which received the same far without phenols, there was no incidence of adenocarcinoma, 11 had intrabronchial adenoma and 2 had squamous metaplasia.
Assuntos
Carcinógenos/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Pulmão/patologia , Neoplasias Experimentais/induzido quimicamente , Fenóis/toxicidade , Traqueia/patologia , Adenocarcinoma/induzido quimicamente , Adenoma/induzido quimicamente , Aerossóis , Animais , Benzo(a)pireno/metabolismo , Neoplasias Brônquicas/induzido quimicamente , Exposição Ambiental , Pulmão/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Metaplasia/induzido quimicamente , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , RNA Catalítico/metabolismo , Solubilidade , Gravidade Específica , Fatores de Tempo , Tolueno/metabolismo , Traqueia/efeitos dos fármacos , Neoplasias da Traqueia/induzido quimicamenteRESUMO
Previous studies of chemical carcinogenesis in the lung of Syrian golden hamsters have utilized outbred (nonsyngeneic) animals. Using the endobronchial sustained release implant technique, which causes focally originating cancers in outbred hamsters, we studied the course of bronchial carcinogenesis in two varieties of syngeneic Syrian golden hamsters, the LSH and the F1D strains (BIO 15.16 male X BIO 87.20 female). With either 10% benzo(a)pyrene or 10% methylcholanthrene sustained release implants the time course of epithelial transition from normal to neoplastic was the same for F1D hamsters as previously described for outbred hamsters. Using 10% benzo(a)pyrene sustained release implants the incidence of cancers as a function of time was significantly lower (P less than 0.001) in LSH hamsters as compared to outbred and F1D animals. Of 19 tumors transplanted into syngeneic F1D hamsters, 16 have been successfully propagated by serial transplantation. We conclude that (a) F1D hamsters are comparable to outbred animals in the response of their bronchial epithelium to endobronchial benzo(a)pyrene and methylcholanthrene, (b) there are significant differences in susceptibility to bronchial chemical carcinogenesis among hamster strains, thereby giving opportunity to study potential genetic control mechanisms during bronchial carcinogenesis, and (c) F1D hamsters are suitable for studies of lung cancer biology using tumor transplantation methods.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Animais , Neoplasias Brônquicas/patologia , Carcinógenos/administração & dosagem , Cricetinae , Implantes de Medicamento , Feminino , Masculino , Mesocricetus , Transplante de Neoplasias , Especificidade da Espécie , Fatores de TempoRESUMO
Models of the sequential process of lung carcinomas have been developed in dogs and hamsters. The bronchial mucosa, or the pulmonary parenchyma, was exposed at selected focal sites to polycyclic aromatic hydrocarbons [most often benzo(a)pyrene or methylcholanthrene]. In hamsters, sustained release implants that contained carcinogen were implanted into the right lower lobe bronchus. In dogs, for orthotopic carcinogenesis the carcinogens were repeatedly injected into the bronchial submucosa or topically applied to the bronchus; sustained release implants were implanted into the pulmonary parenchyma. Heterotopic focal canine bronchial carcinogenesis was accomplished by exposing s.c. bronchial autografts (8-12/dog) to methylcholanthrene. In both species a predictable, reproducible, preneoplastic continuum that leads to bronchial squamous cell carcinoma that metastasizes has been characterized; serial measurements of total cellular DNA showed that ploidy increased in proportion to the stage of preneoplasia. In both species there were adenocarcinomas, including bronchiolar (bronchioloalveolar) carcinomas and other varieties of non-small cell cancers. Different susceptibility to carcinogenesis has been demonstrated among different inbred strains of hamsters; 58% of cancers were adenocarcinomas in one strain. From these models, specimens that are not readily available from humans can be obtained for the study of cellular events during lung carcinogenesis. In parallel with studies in humans, these animal models can be used to evaluate methods of possible chemoprevention and early detection.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Carcinógenos/administração & dosagem , Modelos Animais de Doenças , Neoplasias Pulmonares/induzido quimicamente , Animais , Benzo(a)pireno/administração & dosagem , Broncoscopia , Cricetinae , Cães , Implantes de Medicamento , Injeções , Metilcolantreno/administração & dosagem , Metilnitrosoureia/administração & dosagem , MucosaRESUMO
Sputum samples were collected from a group of private patients who had no respiratory symptoms but who frequently used aerosols generated by pressurized cans, and from two groups of controls. Atypical metaplastic changes in exfoliated cells were compared between the groups. An excess of moderate and marked atypical metaplastic cells was found among the frequent aerosol users. This association, which suggests that some aerosol preparations either alter the flora of the bronchial tree or contain carcinogenic agents, strongly suggests that additional studies be done on aerosol can ingredients, and that these sprays be used in a manner to minimize inhalation of the resultant aerosol, except for medical preparations where proper control is exercised.
Assuntos
Aerossóis , Neoplasias Brônquicas/induzido quimicamente , Lesões Pré-Cancerosas/diagnóstico , Escarro/citologia , Adulto , Idoso , Neoplasias Brônquicas/diagnóstico , Citodiagnóstico , Feminino , Humanos , Masculino , Metaplasia/diagnóstico , Pessoa de Meia-Idade , FumarRESUMO
Because epidermal growth factor (EGF) is rapidly bound and internalized into rat pancreas, stimulates uptake of tritiated thymidine, and increases pancreatic weight, a cocarcinogenic effect on pancreatic cancer seemed likely. Pancreatic adenocarcinomas were induced in 70 female Syrian hamsters by 19 weekly s.c. injections of N-nitrosobis(2-oxopropyl)amine (BOP) (10 mg/kg). From Wk 5 through Wk 8 of BOP injections, additional s.c. injections of EGF (5 micrograms every 3 days for 10 injections) were given to 45 animals, while 25 received saline solution. An additional group of 10 received EGF alone, and another 10 animals received saline solution alone (controls). Eleven wk later, the mean body weight of EGF-treated animals increased by 29% as compared with that of controls, and their mean pancreatic weight relative to body weight increased by 44% as compared with controls. The mean body weight of EGF + BOP-treated animals increased by 10%, and their pancreatic weight relative to body weight increased by 22% as compared with that of animals treated with BOP alone. The incidence of pancreatic cancer in the EGF + BOP-treated animals was 75% versus 44% in those treated with BOP alone (P = 0.016). No tumors developed in either animals treated with EGF alone or control animals. EGF augments pancreatic carcinogenesis induced by BOP. The incidence of bronchial carcinomas doubles.
Assuntos
Carcinógenos , Cocarcinogênese , Fator de Crescimento Epidérmico/toxicidade , Nitrosaminas/toxicidade , Neoplasias Pancreáticas/induzido quimicamente , Adenocarcinoma/induzido quimicamente , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias Brônquicas/induzido quimicamente , Cricetinae , Receptores ErbB , Feminino , Mesocricetus , Oncogenes , Receptores de Superfície Celular/genética , Receptores do Fator de Crescimento Derivado de PlaquetasRESUMO
When given intratracheal injections of a suspension of benzo(alpha)pyrene-ferric oxide, rats and hamsters showed striking species differences in the response of their respiratory tracts to the carcinogen. Hamsters produced squamous metaplasia of the trachea and large bronchi; in contrast, squamous cell nodules of bronchioloalveolar origin developed in rats within a few weeks after carcinogen application. The different sites of the early proliferative and metaplastic responses correlated in their location with the sites of later tumor development. There were no obvious differences between the two species in retention of benzo(alpha)pyrene in the lungs or tracheas. A species difference was observed, however, in the localization of the benzo(alpha)pyrene in the tracheal tissues using ultraviolet fluorescence microscopy. Carcinogen was found to be present in the epithelium of hamsters but not in the epithelium of rats, suggesting a species difference in penetration of carcinogen from the lumen into the tracheal tissues.
Assuntos
Benzopirenos , Compostos Férricos , Ferro , Neoplasias do Sistema Respiratório/induzido quimicamente , Especificidade da Espécie , Animais , Benzopirenos/administração & dosagem , Benzopirenos/metabolismo , Neoplasias Brônquicas/induzido quimicamente , Embrião de Galinha , Cricetinae , Cães , Pulmão/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Microscopia de Fluorescência , Neoplasias Experimentais/induzido quimicamente , Ratos , Ratos Endogâmicos , Neoplasias do Sistema Respiratório/patologia , Fatores de Tempo , Traqueia/metabolismo , Neoplasias da Traqueia/induzido quimicamente , Raios UltravioletaRESUMO
Arsenic is a well-documented human carcinogen. The present study explored the role of the onco-miR, miR-21 and its target protein, programmed cell death 4 (PDCD4) in arsenic induced malignant cell transformation and tumorigenesis. Our results showed that treatment of human bronchial epithelial (BEAS-2B) cells with arsenic induces ROS through p47phox, one of the NOX subunits that is the key source of arsenic-induced ROS. Arsenic exposure induced an upregulation of miR-21 expression associated with inhibition of PDCD4, and caused malignant cell transformation and tumorigenesis of BEAS-2B cells. Indispensably, STAT3 transcriptional activation by IL-6 is crucial for the arsenic induced miR-21 increase. Upregulated miR-21 levels and suppressed PDCD4 expression was also observed in xenograft tumors generated with chronic arsenic exposed BEAS-2B cells. Stable shut down of miR-21, p47phox or STAT3 and overexpression of PDCD4 or catalase in BEAS-2B cells markedly inhibited the arsenic induced malignant transformation and tumorigenesis. Similarly, silencing of miR-21 or STAT3 and forced expression of PDCD4 in arsenic transformed cells (AsT) also inhibited cell proliferation and tumorigenesis. Furthermore, arsenic suppressed the downstream protein E-cadherin expression and induced ß-catenin/TCF-dependent transcription of uPAR and c-Myc. These results indicate that the ROS-STAT3-miR-21-PDCD4 signaling axis plays an important role in arsenic -induced carcinogenesis.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Arsênio/toxicidade , Brônquios/metabolismo , Neoplasias Brônquicas , Transformação Celular Neoplásica , Células Epiteliais/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Proteínas de Ligação a RNA/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/metabolismo , Fator de Transcrição STAT3/metabolismo , Brônquios/patologia , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/metabolismo , Neoplasias Brônquicas/patologia , Linhagem Celular Transformada , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Epiteliais/patologia , Humanos , Mucosa Respiratória/patologiaRESUMO
BACKGROUND: In 1978, asbestos-related occupational cancers were added to the Spanish list of occupational diseases. However, there are no full accounts of compensated cases since their inclusion. OBJECTIVE: To analyze the cases of asbestos-related cancer recognized as occupational in Spain between 1978 and 2011. METHODS: Cases were obtained from the Spanish Employment Ministry. Specific incidence rates by year, economic activity, and occupation were obtained. We compared mortality rates of mesothelioma and bronchus and lung cancer mortality in Spain and the European Union. RESULTS: Between 1978 and 2011, 164 asbestos-related occupational cancers were recognized in Spain, with a mean annual rate of 0·08 per 10(5) employees (0·13 in males, 0·002 in females). Under-recognition rates were an estimated 93·6% (males) and 99·7% (females) for pleural mesothelioma and 98·8% (males) and 100% (females) for bronchus and lung cancer. In Europe for the year 2000, asbestos-related occupational cancer rates ranged from 0·04 per 10(5) employees in Spain to 7·32 per 10(5) employees in Norway. CONCLUSIONS: These findings provide evidence of gross under-recognition of asbestos-related occupational cancers in Spain. Future work should investigate cases treated in the National Healthcare System to better establish the impact of asbestos on health in Spain.
Assuntos
Amianto/toxicidade , Neoplasias Brônquicas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Mesotelioma/epidemiologia , Doenças Profissionais/epidemiologia , Exposição Ocupacional , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/mortalidade , Europa (Continente)/epidemiologia , União Europeia/estatística & dados numéricos , Feminino , Humanos , Incidência , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/mortalidade , Masculino , Mesotelioma/induzido quimicamente , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/estatística & dados numéricos , Espanha/epidemiologiaRESUMO
Endobronchial sustained release implants of carcinogen were placed in males (m) and females (f) of four varieties of syngeneic hamsters: BIOF1D; BIO87.20; BIO1.5; BIO15.16. The sequential progression of carcinogenesis that occurred was faster for 1.5m than for 1.5f (P = 0.01) and less rapid for 15.16m than for 87.20m and F1Dm (P < 0.05). Fewer invasive cancers occurred in 15.16m than in the other male varieties (P < 0.01), in 1.5m than in 87.20m (P < 0.05), and in 87.20f than in 87.20m (P < 0.05). Adenocarcinoma occurred with greater frequency in the 1.5 variety than in the F1D variety (P < 0.05). Significant variability in susceptibility, incidence, and types of invasive cancers formed exists, providing new opportunities for further study of bronchial carcinogenesis.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Animais , Neoplasias Brônquicas/patologia , Carcinógenos , Cricetinae , Preparações de Ação Retardada , Feminino , Masculino , Mesocricetus , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Fatores Sexuais , Especificidade da EspécieRESUMO
Two groups of male and female Syrian golden hamsters, of which the trachea was severely injured by electrocoagulation, received 6 weekly intratracheal instillations of benzo[a]pyrene (BaP) + ferric oxide in saline or saline alone. Two comparable groups of hamsters were similarly treated but had an undamaged trachea. The experiment was terminated in week 82. Treatment with BaP resulted in hyper- and metaplastic lesions and tumours of the laryngeal, tracheal, bronchial and pulmonary epithelium. There was no evidence of an increased incidence of BaP-induced tumours in the injured trachea.