RESUMO
Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.
Assuntos
Neoplasias Associadas a Colite/etiologia , Granulócitos/patologia , Interleucina-17/fisiologia , Fator de Transcrição STAT1/fisiologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/fisiopatologia , Progressão da Doença , Feminino , Granulócitos/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/fisiopatologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: to develop an experimental model of exposure to tobacco burning (cigarette) products to assess the effects of its chronic use in relation to cancers of the bladder. METHODS: the animals were chronically exposed to the burning tobacco products in a semi-open chamber to simulate smoking. Thirty young Wistar rats were divided into two groups: one with 20 animals simulating smoking for six months, and ten not exposed control animals for the same period. After exposure by inhalation of cigarette smoke, animals were euthanized and subjected to histopathological study of the bladder wall. RESULTS: no tumor was found but mild and non significant alterations. The studies of hemo-oximetry (carboxyhemoglobin and methemoglobin) and the concentration of carbon dioxide (CO2) confirm that the animals were exposed to high concentrations of tobacco smoke and its derivatives. CONCLUSION: no bladder mucosal neoplasia was found in the pathological study of animals. The developed experimental models were highly efficient, practical and easy to use and can be used in other similar studies to determine the harmful effects caused by smoking.
Assuntos
Modelos Animais de Doenças , Produtos do Tabaco , Neoplasias da Bexiga Urinária/etiologia , Animais , Masculino , Neoplasias Experimentais/etiologia , Ratos , Ratos WistarRESUMO
OBJECTIVE: to develop an experimental model of exposure to tobacco burning (cigarette) products to assess the effects of its chronic use in relation to cancers of the bladder. METHODS: the animals were chronically exposed to the burning tobacco products in a semi-open chamber to simulate smoking. Thirty young Wistar rats were divided into two groups: one with 20 animals simulating smoking for six months, and ten not exposed control animals for the same period. After exposure by inhalation of cigarette smoke, animals were euthanized and subjected to histopathological study of the bladder wall. RESULTS: no tumor was found but mild and non significant alterations. The studies of hemo-oximetry (carboxyhemoglobin and methemoglobin) and the concentration of carbon dioxide (CO2) confirm that the animals were exposed to high concentrations of tobacco smoke and its derivatives. CONCLUSION: no bladder mucosal neoplasia was found in the pathological study of animals. The developed experimental models were highly efficient, practical and easy to use and can be used in other similar studies to determine the harmful effects caused by smoking. .
OBJETIVO: desenvolver modelo experimental de exposição aos produtos da queima do tabaco (cigarro) para avaliar os efeitos do seu uso crônico em relação às neoplasias de bexiga. MÉTODOS: Os animais foram expostos cronicamente aos produtos da queima do tabaco em câmara semi-aberta para simular o tabagismo. Trinta ratos jovens da raça Wistar foram distribuídos em dois grupos: um com 20 animais simulando o tabagismo por período de seis meses, e um com dez animais controle sem exposição por igual período. Após exposição por inalação da fumaça do cigarro, os animais foram eutanasiados e submetidos a estudo histopatológico da parede da bexiga. RESULTADOS: Não foi encontrada neoplasia e sim alterações leves e não significativas. Os estudos da hemo-oximetria (carboxiemoglobina e metemoglobina) e da concentração de dióxido de carbono (CO2) confirmam que os animais foram expostos a altas concentrações da fumaça do tabaco e de seus derivados. CONCLUSÃO: No estudo anatomopatológico dos animais não foi encontrada neoplasia na mucosa da bexiga. Os modelos experimentais desenvolvidos foram altamente eficientes, práticos e fáceis de usar podendo ser empregados em outros estudos semelhantes para determinar os efeitos nocivos causados pelo tabagismo. .
Assuntos
Animais , Masculino , Ratos , Modelos Animais de Doenças , Produtos do Tabaco , Neoplasias da Bexiga Urinária/etiologia , Neoplasias Experimentais/etiologia , Ratos WistarRESUMO
OBJECTIVES: To evaluate the effects of nicotine and cigarette smoke exposure on mice submitted to 7,12-dimethylbenzanthracene (DMBA) model of pancreatic carcinogenesis. METHODS: One hundred fourteen male mice were divided into the DMBA-n and DMBA-s groups: the DMBA-n group was given 2 mg/kg per dose of nicotine ([3-(1-methyl-2-pyrrolidinyl)pyridine]) subcutaneously for 45 days, and the DMBA-s group was exposed to 100 mg/m of cigarette smoke. At day 16, 1 mg of DMBA crystals was implanted in the pancreatic head of both groups. Euthanasia was performed in all mice 30 days after the surgery. The specimens were evaluated according to the following criteria: normal ducts, reactive hyperplasia, pancreatic intraepithelial neoplasm 3 (PanIN-3), and carcinoma. For statistical analysis, DMBA-exclusive ([DMBA-e] historical control group) was included. RESULTS: The frequency of PanIN in the 3 groups was almost the same when considering the higher-grade lesions: DMBA-e (16 [66.7%]), DMBA-s (20 [66.7%]), and DMBA-n (12 [44.4%]). Pancreatic adenocarcinoma has a higher frequency in the DMBA-n group (14 [51.9%]) than in the DMBA-e (4 [16.7%]) and DMBA-s (4, 13.3%) groups. The DMBA-s group has the highest score of PanIN-3 (40%). The differences among the groups were statistically significant (P = 0.05, Fisher exact test). CONCLUSIONS: Nicotine but not cigarette smoke promotes pancreatic DMBA carcinogenesis in mice. Pancreatic adenocarcinomas and PanINs have the same phenotypic appearance as those that occur in humans.
Assuntos
Adenocarcinoma/etiologia , Carcinógenos/toxicidade , Carcinoma in Situ/etiologia , Nicotina/toxicidade , Neoplasias Pancreáticas/etiologia , Fumar/efeitos adversos , 9,10-Dimetil-1,2-benzantraceno , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/patologia , Animais , Carcinógenos/administração & dosagem , Carcinoma in Situ/induzido quimicamente , Carcinoma in Situ/patologia , Cocarcinogênese , Injeções Subcutâneas , Masculino , Camundongos , Neoplasias Experimentais/etiologia , Nicotina/administração & dosagem , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/patologiaRESUMO
Several genetic alterations occur during the transformation process from normal to tumor cells, that involve the loss of fidelity of processes as replication, reparation, and segregation of the genomic material. Although normal cells have defense mechanisms against cancer progression, in tumor cells different escape pathways are activated leading to tumor progression. Recent advances have permitted cancer research to focus on the identification of some of its etiological factors. The knowledge of cell cycle reveals a precise mechanism achieved by the coordinated interactions and functions of cyclin-dependent kinases, control checkpoint, and repair pathways. Furthermore, it has been demonstrated that this coordinated function can be abrogated by specific genetic changes. These findings suggest that the molecular mechanisms responsible for cellular transformation may help to identify potential targets to improve cancer therapies.
Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Genes do Retinoblastoma/fisiologia , Humanos , Neoplasias/etiologia , Neoplasias/prevenção & controle , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/prevenção & controle , Transcrição Gênica/fisiologia , Proteína Supressora de Tumor p53/fisiologiaRESUMO
Polyomavirus is able to induce tumors in its natural host as well as to transform cells in cultures. On the other hand, human papillomavirus has been involved in several types of neoplasias such as anogenital lesions. Little is known about the mechanisms through which these viruses induce both transformation and tumorigenesis. The present, work shows some characteristics of the mechanisms that papillomavirus and polyomavirus use to participate in tumorigenesis. It has also been noticed that the infection caused by polyomavirus resembles that performed by papillomaviruses (which belong to the same Papovaviridae family). Some similarities and differences between these viruses are considered.
Assuntos
Transformação Celular Neoplásica , Transformação Celular Viral , Papillomaviridae , Infecções por Polyomavirus , Polyomavirus , Infecções Tumorais por Vírus , Animais , Capsídeo/genética , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Neoplasias Experimentais/etiologia , Proteínas Oncogênicas/genética , Oncogenes/genética , Papillomaviridae/genética , Polyomavirus/genética , Infecções por Polyomavirus/genética , Infecções Tumorais por Vírus/genéticaRESUMO
BK virus (BKV) is a human papovavirus that readily transforms rodent cells, but not human cells, to a neoplastic phenotype, suggesting that tumor-suppressor functions expressed in human cells control BKV oncogenicity. Transfer of a normal human chromosome 11 to BKV-transformed mouse cells suppresses the malignant phenotype. In this report we map the regions of chromosome 11 involved in tumor suppression. Transfer of chromosome 11 to the BKV-transformed hamster cell line HKBK produces monochromosomic hybrids retaining only portions of the transferred human chromosome. We have compared the tumorigenicity of the hybrids with the molecular mapping of chromosome 11 retained regions. This analysis indicated that 3 regions of human chromosome 11, 11p15.5, 11p13 and 11q13, cooperate in tumor suppression. However, 11q13 seems the most important, since all the HKBK/H11-induced tumors analysed had lost this region, whereas 11p15.5 and 11p13 were sometimes retained. The chromosomal regions identified in this study are deleted in several types of human tumors, suggesting that the BKV transformation system specifically detects tumor-suppressor genes on chromosome 11 that are involved in human oncogenesis. This model may be of use in isolating and cloning such genes. The results of this report raise the possibility that BKV may have a synergistic tumorigenic effect in human cells where tumor-suppressor genes controlling its oncogenic potential are inactivated.
Assuntos
Vírus BK/patogenicidade , Transformação Celular Neoplásica , Cromossomos Humanos Par 11 , Genes Supressores de Tumor , Neoplasias Experimentais/etiologia , Animais , Linhagem Celular , Aberrações Cromossômicas , Cricetinae , Humanos , Células Híbridas , Camundongos , FenótipoRESUMO
The effect of EJ-ras oncogene dosage on the phenotype of Balb/3T3 transfectants was analyzed with respect to: a) peptide growth factors' requirement; b) relaxation of cell cycle control; c) tumorigenic potential. Mouse embryo-derived Balb/3T3 cells were transfected with the mutated form of the human c-Ha-ras-1 (EJ-ras) along with a genetic marker (neo gene). Transfectants displaying high EJ-ras expression presented a relaxed cell cycle control, required only insulin to initiate DNA synthesis and were highly tumorigenic. On the other hand, low expression EJ-ras transfectants required both competence (FGF) and progression factors (EGF and insulin) exactly like the parental cells. But, upon serial cultivation, these transfectants became fully transformed and highly tumorigenic without EJ-ras amplification and/or overexpression. Therefore, low EJ-ras expression primes the cells to become tumorigenic but neither overrides the cells' requirement for competence growth factor nor deregulates the cell cycle.