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
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
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
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
Squamous cell carcinoma (SCC) and premalignant endobronchial lesions have been difficult to study in murine models. In this study, we evaluate the topical N-nitroso-tris-chloroethylurea (NTCU) murine SCC model, determine the extent to which resulting premalignant airway dysplasia develops, discuss clinicopathologic grading criteria in lesion progression, and confirm that immunohistochemical (IHC) staining patterns are consistent with those observed in human endobronchial dysplasia and SCC. Male and female FVB mice were treated biweekly with topical NTCU (4, 8, or 40 mmol/L) or vehicle for 32 weeks. Following sacrifice, squamous cell lesions were enumerated and categorized into the following groups: flat atypia, low-grade dysplasia, high-grade dysplasia, and invasive SCC. The 40 mmol/L NTCU concentration produced the entire spectrum of premalignant dysplasias and squamous cell carcinomas, but was associated with poor survival. Concentrations of 4 and 8 mmol/L NTCU were better tolerated and produced only significant levels of flat atypia. Squamous origin of the range of observed lesions was confirmed with IHC staining for cytokeratin 5/6, p63, thyroid transcription factor-1 (TTF-1), and Napsin-A. This study shows that topical application of high-dose NTCU produces endobronchial premalignant lesions with classic squamous characteristics and should allow for improved preclinical evaluation of potential chemopreventive agents.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/induzido quimicamente , Carmustina/análogos & derivados , Modelos Animais de Doenças , Lesões Pré-Cancerosas/induzido quimicamente , Administração Tópica , Animais , Neoplasias Brônquicas/mortalidade , Neoplasias Brônquicas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carmustina/toxicidade , Feminino , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Lesões Pré-Cancerosas/mortalidade , Lesões Pré-Cancerosas/patologia , Taxa de SobrevidaRESUMO
Silica was listed as a human carcinogen by International Agency for Research on Cancer (IARC) in 1996. However, the molecular mechanisms to induce cancer are not understood yet. Our recent published study showed that silica inhibited the expression of poly(ADP-ribose) polymerases-1 (PARP-1) mRNA. However, the mechanisms responsible for low PARP-1 expression have not yet been elucidated. In this study, the human bronchial epithelial cells (16HBE) were treated with 300 microg/ml silicon dioxide for 35 passages, the mode of silica-associated malignant transformation of human bronchial epithelial cells (M-16HBE) was established and identified by soft agar assay and nude mouse tumorigenesis. The mRNA expression and methylation status of PARP-1 in M-16HBE with or without treatment of the cytosine methylation inhibitor 5-aza-2'-deoxycytidine (5-aza) were detected by real-time PCR and methylation-specific PCR (MSP), respectively. The data showed that silica decreased PARP-1 expression at the transcriptional levels in M-16HBE and the above epigenetic inhibitors reversed the transcriptional inhibition of PARP-1 through the demethylation of PARP-1, suggesting that the epigenetic mediated transcriptional activation of PARP-1.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Transformação Celular Neoplásica , Epigênese Genética , Poli(ADP-Ribose) Polimerases/metabolismo , Dióxido de Silício/toxicidade , Ativação Transcricional , Animais , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Células Cultivadas , Decitabina , Ativação Enzimática , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genéticaRESUMO
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
Nose-only exposure of male and female Wistar rats to a surrogate for environmental tobacco smoke, termed room-aged sidestream smoke (RASS), to diesel engine exhaust (DEE), or to filtered, fresh air (sham) was performed 6 hours/day, 7 days/week for 2 years, followed by a 6-month post-exposure period. The particulate concentrations were 3 and 10 mg/m3. Markers of inflammation in bronchoalveolar lavage showed that DEE (but not RASS) produced a dose-related and persistent inflammatory response. Lung weights were increased markedly in the DEE (but not RASS) groups and did not decrease during the 6-month post-exposure period. Bulky lung DNA adducts increased in the RASS groups, but not in the DEE groups. Cell proliferation in the lungs was unaffected by either experimental treatment. Histopathological responses in the RASS groups were minimal and almost completely reversible; lung tumors were similar in number to those seen in the sham-exposed groups. Rats exposed to DEE showed a panoply of dose-related histopathological responses: largely irreversible and in some cases progressive. Malignant and multiple tumors were seen only in the DEE groups; after 30 months, the tumor incidence (predominantly bronchiolo-alveolar adenomas) was 2% in the sham-exposed groups, 5%in the high RASS groups, and 46% in the high DEE groups (sexes combined). Our results suggest that in rats exposed to DEE, but not to RASS, the following series of events occurs: particle deposition in lungs --> lung "overload" --> pulmonary inflammation --> tumorigenesis, without a significant modifying role of cell proliferation or DNA adduct formation.
Assuntos
Poluentes Atmosféricos/toxicidade , Poluição por Fumaça de Tabaco/análise , Emissões de Veículos/toxicidade , Adenoma/induzido quimicamente , Adenoma/patologia , Aerossóis/química , Poluentes Atmosféricos/análise , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/patologia , Carbono/análise , Carboxihemoglobina/metabolismo , Testes de Carcinogenicidade/instrumentação , Testes de Carcinogenicidade/métodos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Exposição por Inalação/análise , Exposição por Inalação/estatística & dados numéricos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Nicotina/metabolismo , Nicotina/urina , Tamanho da Partícula , Ratos , Ratos Wistar , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Neoplasias do Sistema Respiratório/induzido quimicamente , Neoplasias do Sistema Respiratório/patologia , Fatores de Tempo , Emissões de Veículos/análiseRESUMO
BACKGROUND: Clear cell adenocarcinoma (CCA) of the vagina and cervix in young women is associated with prenatal exposure to diethylstilbestrol (DES). Parenchymal pulmonary metastases are known to occur following treatment of the primary tumor. Most recurrences present within 2 to 3 years of the initial diagnosis. CASE: This is a case report of a solitary endobronchial clear cell adenocarcinoma occurring 15.3 years after the initial diagnosis of DES-induced CCA. CONCLUSIONS: This case suggests that management of clear cell cancer survivors should involve long-term follow-up because of the potential for the appearance of a new focus of clear cell adenocarcinoma.
Assuntos
Adenocarcinoma de Células Claras/induzido quimicamente , Neoplasias Brônquicas/induzido quimicamente , Dietilestilbestrol/efeitos adversos , Estrogênios não Esteroides/efeitos adversos , Neoplasias Vaginais/induzido quimicamente , Adenocarcinoma de Células Claras/patologia , Adulto , Neoplasias Brônquicas/patologia , Feminino , Humanos , Neoplasias Vaginais/patologiaRESUMO
Squamous cell carcinoma (SCC) of the bronchus is considered to develop from preneoplastic 'dysplasia', but reports of sequential observation of this dysplasia-carcinoma sequence in humans are very few. We followed four dysplastic lesions found in the bronchi of three ex-chromate workers by bronchoscopy and biopsy and found that all of them progressed to SCC. Of the four lesions, three were severe dysplasias at the first biopsy which progressed to SCCs in 7-13 months. The last one was a slight dysplasia at the first biopsy and showed progression of the atypia to carcinoma in 6 years and 10 months. An immunohistochemical analysis of the chronological change in p53 protein expression in these lesions and in normal ciliated epithelium taken from the surroundings was conducted in each case. Overexpression of p53 protein was observed in two of the severe dysplasias and the one slight dysplasia, as well as their eventual SCCs. However, no such change was apparent in one case of severe dysplasia or its eventual SCC. Normal epithelium was consistently negative. Our results provide direct proof of the dysplasia-carcinoma sequence and suggest that alteration in the expression of p53 protein might be an important early event which persists. Therefore, the immunohistochemical detection of p53 overexpression in biopsy specimens of bronchial epithelium might be useful for evaluation of preneoplastic lesions in high-risk group individuals and for early diagnosis of bronchial cancer.
Assuntos
Neoplasias Brônquicas/patologia , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Cromatos/efeitos adversos , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/patologia , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Proteína Supressora de Tumor p53/análise , Idoso , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/química , Carcinoma de Células Escamosas/química , Progressão da Doença , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/metabolismo , Lesões Pré-Cancerosas/metabolismo , Fatores de TempoRESUMO
250,000 new cases of endobronchial carcinoma are diagnosed each year in France. Risk factors are well known: 80-90% are related to smoking. With an overall 5-year survival rate of only 10%, preventive measures must be our number one priority, especially for young patients, but are their parents a lost generation? Curative therapy has made some progress, particularly with surgery, although only 20% of the patients are potential candidates at diagnosis, and chemotherapy, sometimes in combination with radiotherapy for nonoperable patients. Interesting results have also been achieved with gene therapy where direct intratumoral injection of cytokine genes on recombinant adenoviruses has provided response in certain cases. Interventional bronchoendoscopy provides another promising option as demonstrated by Jeanfaivre and Tuchais who report their results with electrotherapy in this issue of La Presse Médicale.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Fumar/efeitos adversos , Neoplasias da Traqueia/induzido quimicamente , Neoplasias Brônquicas/mortalidade , Neoplasias Brônquicas/terapia , Terapia Combinada , Quimioterapia Combinada , Humanos , Cuidados Paliativos , Neoplasias da Traqueia/mortalidade , Neoplasias da Traqueia/terapiaRESUMO
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
Alveolar type II cells are not present in normal epithelium of canine segmental bronchi but after carcinogen exposure they do occur in intra-epithelial lesions with all degrees of atypia and in invasive lesions with different glandular growth patterns. Immunohistochemistry for proliferation markers (PCNA; Ki-67) strongly suggest that such novel type II cells are pluripotential stem cells in canine bronchial carcinogenesis. Very likely, bronchial carcinogenesis is subject to an oncofetal mechanism of differentiation: bronchial epithelial retrodifferentiation followed by novel differentiation of alveolar tumor stem cells.
Assuntos
Neoplasias Brônquicas/patologia , Células-Tronco Neoplásicas/patologia , Alvéolos Pulmonares/patologia , Animais , Antígenos de Neoplasias/análise , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/química , Cães , Epitélio/química , Epitélio/efeitos dos fármacos , Epitélio/patologia , Antígeno Ki-67 , Metilcolantreno , Camundongos , Camundongos Nus , Proteínas de Neoplasias/análise , Células-Tronco Neoplásicas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Nucleares/análise , Antígeno Nuclear de Célula em Proliferação/análise , Proteolipídeos/análise , Alvéolos Pulmonares/química , Alvéolos Pulmonares/efeitos dos fármacos , Proteínas Associadas a Surfactantes Pulmonares , Surfactantes Pulmonares/análiseRESUMO
There is a certain controversy over whether there is a relationship between passive smoking and bronchogenic cancer. The first epidemiology studies has found a small increase in the relative risk. Experimental work in animals have demonstrated that the smoke produced by a burning cigarette contains more cancerogenic agents than the smoke inhaled by a smoker. In man where only epidemiology studies are possible, the problem lies in quantifying exposure to passive smoking. Questionnaires or assay of markers such as CO and HbCO, thiocyanates, nicotine and its metabolite cotinine and certain adduits have been used. There are many possibilities for bias in such studies including classification of smokers among non-smokers, confounding factors (age, profession, eating habits), subjects' memory, and data collection errors. Meta-analyses have attempted to overcome the lack of power in many studies. Some of these meta-analyses have used correction factors to take into account publication bias. Meta-analyses have led to the conclusion that the risk for women exposed to their husband's tobacco smoke is somewhat increased compared with a non-smoking non-exposed population. The relative risk is about 2-fold higher and has been observed in Greece. The existence of a dose-intensity relationship has not been confirmed. Likewise, it is impossible to conclude concerning the role of passive smoking in children due to the small amount of data available.
Assuntos
Neoplasias Brônquicas/induzido quimicamente , Poluição por Fumaça de Tabaco , Métodos Epidemiológicos , Feminino , Humanos , MasculinoRESUMO
The commonly used spice and flavouring agent, rosemary, derived from the leaves of the plant Rosmarinus officinalis L., displays antioxidant properties in foods and in biological systems. Moreover, in animal models rosemary components were found to inhibit the initiation and tumour promotion phases of carcinogenesis. In this work, we studied the mechanisms by which rosemary components block initiation of carcinogenesis by the procarcinogen benzo[a]pyrene (B[a]P) in human bronchial epithelial cells (BEAS-2B). Whole rosemary extract (6 micrograms/ml) or an equivalent concentration of its most potent antioxidant constituents, carnosol or carnosic acid, inhibited DNA adduct formation by 80% after 6 h co-incubation with 1.5 muM B[a]P. Under similar conditions, cytochrome P450 (CYP) 1A1 mRNA expression was 50% lower in the presence of rosemary components, and CYP1A1 activity was inhibited 70-90%. The observed reduction of DNA adduct formation by rosemary components may mostly result from the inhibition of the activation of benzo[a]pyrene to its ultimate metabolites. Carnosol also affected expression of the phase II enzyme glutathione-S-transferase which is known to detoxify the proximate carcinogenic metabolite of B[a]P. Treatment of BEAS-2B cells with carnosol (1 microgram/ml) for 24 h resulted in a 3- to 4-fold induction of GST pi mRNA. Moreover, expression of a second important phase II enzyme, NAD(P)H: quinone reductase, was induced by carnosol in parallel with GST pi. Therefore, rosemary components have the potential to decrease activation and increase detoxification of an important human carcinogen, identifying them as promising candidates for chemopreventive programs.