RESUMO
BACKGROUND: Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model. METHODS: To find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis. RESULTS: The multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival. CONCLUSIONS: These results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior.
Assuntos
Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/complicações , Helicobacter pylori , Isoantígenos/genética , Receptores de Superfície Celular/genética , Sódio na Dieta/efeitos adversos , Neoplasias Gástricas/genética , Animais , Proteínas Ligadas por GPI/análise , Proteínas Ligadas por GPI/genética , Mucosa Gástrica/química , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Isoantígenos/análise , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Associadas a Pancreatite , Prognóstico , Proteínas/genética , Receptores de Superfície Celular/análise , Neoplasias Gástricas/etiologiaRESUMO
Nuclear factor-kappaB (NF-kappaB) plays a major role in host inflammatory responses and carcinogenesis and as such is an important drug target for adjuvant therapy. In this study, we examined the effect of caffeic acid phenethyl ester (CAPE), an NF-kappaB inhibitor, on Helicobacter pylori (H. pylori)-induced NF-kappaB activation in cell culture and chronic gastritis in Mongolian gerbils. In AGS gastric cancer cells, CAPE significantly inhibited H. pylori-stimulated NF-kappaB activation and mRNA expression of several inflammatory factors in a dose-dependent manner, and prevented degradation of IkappaB-alpha and phosphorylation of p65 subunit. To evaluate the effects of CAPE on H. pylori-induced gastritis, specific pathogen-free male, 6-week-old Mongolian gerbils were intragastrically inoculated with H. pylori, fed diets containing CAPE (0-0.1%) and sacrificed after 12 weeks. Infiltration of neutrophils and mononuclear cells and expression of NF-kappaB p50 subunit and phospho-IkappaB-alpha were significantly suppressed by 0.1% CAPE treatment in the antrum of H. pylori-infected gerbils. Labeling indices for 5'-bromo-2'-deoxyuridine both in the antrum and corpus and lengths of isolated pyloric glands were also markedly reduced at the highest dose, suggesting a preventive effect of CAPE on epithelial proliferation. Furthermore, in the pyloric mucosa, mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-6, KC (IL-8 homologue), and inducible nitric oxide synthase was significantly reduced. These results suggest that CAPE has inhibitory effects on H. pylori-induced gastritis in Mongolian gerbils through the suppression of NF-kappaB activation, and may thus have potential for prevention and therapy of H. pylori-associated gastric disorders.
Assuntos
Ácidos Cafeicos/farmacologia , Citotoxinas/farmacologia , Gastrite/tratamento farmacológico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/patogenicidade , NF-kappa B/antagonistas & inibidores , Álcool Feniletílico/análogos & derivados , Animais , Western Blotting , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite/metabolismo , Gastrite/microbiologia , Gerbillinae , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Técnicas Imunoenzimáticas , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Álcool Feniletílico/farmacologia , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We have investigated the expression of osteopontin (OPN) and CDX2 in advanced gastric cancers, and analyzed correlations with clinicopathological features to assess their prognostic potential. One-hundred and nine patients suffering from gastric cancer were recruited. Expression of OPN and CDX2 and other molecular markers was determined by immunohistochemistry. The total positive rate for OPN expression was 46.8%, with a relation to depth of cancer invasion and down regulation of intestinal markers (P<0.001), but not age, gender, or histological type. OPN was more frequently expressed in CDX2-negative (39/109=35.7%) as compared with positive lesions (12/109=11.0%) and a significant reverse correlation was noted between the two factors (P<0.001). Patients with positive OPN tumors had worse 5-year survival than those with OPN-negative cancer (P<0.001). Further analysis revealed the OPN-/CDX2+ group to have better 5-year survival than all the other three groups: OPN+/CDX2-, OPN-/CDX2- and OPN+/CDX2+. With multivariate analysis for 5-year survival, OPN was the most significant predictor of a poor prognosis of advanced gastric cancer (P=0.0043), with tumor depth of invasion as another independent indicator (P=0.0315). Osteopontin is a useful prognostic marker in gastric cancer, and combined with CDX2, may have particular advantage for predicting survival of advanced gastric cancer patients. Furthermore the present results provide a clue that in gastric cancer, CDX2 may be a transcription factor modulating the expression of osteopontin.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/análise , Proteínas de Homeodomínio/biossíntese , Osteopontina/biossíntese , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Fator de Transcrição CDX2 , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Prognóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologiaRESUMO
Oxidative stress is linked to gastric carcinogenesis because of its ability to damage DNA. Here we examined antioxidative and anti-inflammatory effects of 4-vinyl-2,6-dimethoxyphenol (canolol), a recently identified potent antioxidative compound obtained from crude canola oil, on Helicobacter (H.) pylori-induced gastritis and gastric carcinogenesis using a Mongolian gerbil model. The animals were allocated to H. pylori-infection alone (12 weeks) or H.pylori + N-methyl-N-nitrosourea (MNU) administration (52 weeks). After oral inoculation of H. pylori, they were fed for 10 and 44 weeks with or without 0.1% canolol. H. pylori-induced gastritis, 5'-bromo-2'-deoxyuridine (BrdU) labeling and scores for cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) immunohistochemistry were attenuated in the canolol-treated groups. Expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), COX-2 and iNOS mRNA in the gastric mucosa, and serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), anti-H. pylori IgG and gastrin levels were also significantly lower in canolol-treated groups. Furthermore, the incidence of gastric adenocarcinomas was markedly reduced in the H. pylori + MNU + canolol-treated group [15.0% (6/40)] compared to the control group [39.4% (13/33)] (p < 0.05). These data indicate canolol to be effective for suppressing inflammation, gastric epithelial cell proliferation and gastric carcinogenesis in H. pylori-infected Mongolian gerbils. Interestingly, the viable H. pylori count was not changed by the canolol containing diet. Thus, the data point to the level of inflammation because of H. pylori rather than the existence of the bacteria as the determining factor. Importantly, canolol appears to suppress induction of mRNAs for inflammatory cytokines.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Gastrite/complicações , Infecções por Helicobacter/complicações , Helicobacter pylori , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Neoplasias Gástricas/prevenção & controle , Compostos de Vinila/farmacologia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Anticorpos Antibacterianos/sangue , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Modelos Animais de Doenças , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrinas/sangue , Gastrite/metabolismo , Gastrite/microbiologia , Gerbillinae , Infecções por Helicobacter/metabolismo , Imunoglobulina G/sangue , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
K19-C2mE transgenic (Tg) mice, simultaneously expressing cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) in the gastric mucosa under the cytokeratin 19 gene promoter, were here treated with N-methyl-N-nitrosourea (MNU) and inoculated with Helicobacter pylori (H. pylori) to investigate gastric carcinogenesis. Wild-type (WT) and Tg mice undergoing MNU treatment frequently developed tumors in the pyloric region (100% and 94.7%, respectively); multiplicity in Tg was higher than that in WT (P < 0.05) with H. pylori infection. Larger pyloric tumors were more frequently observed in Tg than in WT (P < 0.05). In addition, Tg developed fundic tumors, where WT did not. No gastric tumors were observed without MNU treatment. Transcripts of TNF-alpha, iNOS, IL-1beta, and CXCL14 were up-regulated with H. pylori infection in both genotypes and were also increased more in Tg than in WT within H. pylori-inoculated animals. Immunohistochemical analysis demonstrated significantly greater beta-catenin accumulation in pyloric tumors, compared with those in the fundus (P < 0.01) with mutations of exon 3; 18.2% and 31.6% in MNU-alone and MNU + H. pylori-treated WT, whereas 21.4% and 62.5% was observed in the Tg, respectively; the latter significantly higher (P < 0.05), suggesting the role of H. pylori in Wnt activation. In conclusion, K19-C2mE mice promoted gastric cancer in both fundic and pyloric regions. Furthermore beta-catenin activation may play the important role of pyloric carcinogenesis especially in H. pylori-infected Tg. Induction of various inflammatory cytokines in addition to overexpression of COX-2/mPGES-1 could be risk factors of gastric carcinogenesis and may serve as a better gastric carcinogenesis model.
Assuntos
Carcinógenos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Oxirredutases Intramoleculares/metabolismo , Metilnitrosoureia/farmacologia , Neoplasias Gástricas/etiologia , beta Catenina/metabolismo , Animais , Transformação Celular Neoplásica/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ativação Enzimática , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Imuno-Histoquímica , Oxirredutases Intramoleculares/genética , Camundongos , Camundongos Transgênicos , Microssomos , Prostaglandina-E Sintases , Distribuição Aleatória , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
Carcinogenic potential of heterocyclic amines (HCAs) was investigated using an in vivo 5-week initiation assay with quantitative evaluation of glutathione S-transferase placental form (GST-P) positive foci in rat liver. Numbers of GST-P positive foci were significantly increased with individual administration of six different HCAs, indicating utility of the assay. It was therefore applied to investigate risk with multiple HCAs in combination. Unexpectedly, concomitant treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) did not result in any additive carcinogenicity. In the rats taking MeIQx prior to PhIP the value was almost equal to the sum total of individual data, indicating additive initiation activities. In contrast, simultaneous or prior administration of PhIP rather exerted inhibitory effects on the carcinogenic potential of MeIQx. Moreover, microarray and quantitative RT-PCR assessment revealed that PhIP induced cytochrome P450 1A1, responsible for both activation and detoxification of HCAs, more strongly than MeIQx. It is noteworthy that complex exposure to multiple HCAs is not necessarily associated with increased risk of carcinogenesis because they are simultaneously and continuously ingested under normal circumstances.
Assuntos
Carcinógenos/toxicidade , Compostos Heterocíclicos/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Aminas/toxicidade , Animais , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/biossíntese , Citocromo P-450 CYP1A2/genética , DNA Complementar/biossíntese , DNA Complementar/genética , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/ultraestrutura , Imidazóis/toxicidade , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Quinoxalinas/toxicidade , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , RiscoRESUMO
Recent epidemiological studies have demonstrated that consumption of certain natural products can lower cancer risk in humans. For example, plant-derived lignans have been shown to exert chemopreventive effects against cancer in vitro and in vivo. In the present study, the effects of three such lignans, termed arctiin, arctigenin, and nordihydroguaiaretic acid (NDGA), on the proliferation of Helicobacter pylori and the prevention of H. pylori-associated gastric cancer were investigated in Mongolian gerbils. To examine the effects of arctigenin and NDGA on stomach carcinogenesis, specific pathogen-free male, 5-week-old gerbils were infected with H. pylori, administered 10 p.p.m. N-methyl-N-nitrosourea in their drinking water and fed diets containing various concentrations of lignans until they were killed after 52 weeks. At a dietary level of 0.25%, NDGA significantly decreased the incidence of gastric adenocarcinomas. Arctigenin, in contrast, failed to attenuate neoplasia at a level of 0.1%. Both NDGA and arctigenin significantly reduced serum 8-hydroxy-2'-deoxyguanosine levels at doses of 0.25 and 0.05% (NDGA), and 0.1% (arctigenin). Administration of 0.25% NDGA significantly suppressed the formation of intestinal metaplasia both in the antrum and the corpus. Although all three lignans dose-dependently inhibited the in vitro proliferation of H. pylori, there were no differences in the titers of anti-H. pylori antibodies or the amount of the H. pylori-specific urease A gene among all H. pylori-infected groups. These results suggest that NDGA might be effective for prevention of gastric carcinogenesis. The possible mechanisms appear to be related to inhibitory effects on progression of gastritis and antioxidative activity rather than direct antimicrobial influence.
Assuntos
Adenocarcinoma/prevenção & controle , Furanos/uso terapêutico , Infecções por Helicobacter/prevenção & controle , Helicobacter pylori/citologia , Lignanas/uso terapêutico , Masoprocol/uso terapêutico , Neoplasias Gástricas/prevenção & controle , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Animais , Divisão Celular/efeitos dos fármacos , Modelos Animais de Doenças , Gerbillinae , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , Lignanas/farmacologia , Masculino , Plantas , Reação em Cadeia da Polimerase , Organismos Livres de Patógenos Específicos , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Urease/genéticaRESUMO
p53 knockout mice have been utilized for the functional analysis of p53 in carcinogenic processes and for the evaluation of the carcinogenic potential of chemicals. In this study, we established that p53 knockout mice have an elevated susceptibility to the induction of histiocytic sarcoma (HS) by N-bis(2-hydroxy-propyl)nitrosamine (BHP). p53 heterozygous (+/-) and wild-type (+/+) mice were treated with 20 or 200 ppm BHP in their drinking water for 15 weeks or with 20 ppm BHP for 40 weeks. An additional group of p53 nullizygous (-/-) mice were treated with 20 ppm BHP for 15 weeks. In a 15-week experiment, hepatic HSs were unexpectedly observed in BHP-treated p53 (-/-) mice (30.8%) but not in p53 (+/-) and (+/+) mice and untreated (-/-) mice, indicating that a complete loss of p53 dramatically accelerates the genesis of HS. In a 40-week experiment, HSs were significantly increased in female p53 (+/-) mice (37.5%) as compared with female (+/+) mice (5.0%). Additionally, PCR-SSCP and sequencing analysis revealed a high frequency of p53 gene mutations in HSs, demonstrating the involvement of p53 gene mutations in HS development. Our data add to the understanding of the carcinogenic susceptibility of p53 knockout mice, and may help to elucidate the pathogenesis of HS development.
Assuntos
Carcinógenos/toxicidade , Genes p53/fisiologia , Transtornos Histiocíticos Malignos/induzido quimicamente , Nitrosaminas/toxicidade , Sarcoma Experimental/induzido quimicamente , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Homozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Sarcoma Experimental/genética , Sarcoma Experimental/patologiaRESUMO
AIMS: We have previously demonstrated the importance of gastric and intestinal phenotypic expression for the histogenesis of stomach cancer. However, the phenotypes of stomach cancers arising after Helicobacter pylori (Hp) eradication have hitherto remained unclear. We therefore examined a series of lesions occurring after Hp eradication in the Mongolian gerbil (MG) model. METHODS: Totals of 6 and 20 advanced glandular stomach cancers were evaluated in Hp-eradicated and Hp-infected MGs treated with N-methyl-N-nitrosourea (MNU-MGs), using several gastrointestinal epithelial phenotypic markers. The lesions were divided phenotypically into gastric (G type), gastric-and-intestinal mixed (GI type), intestinal (I type), and null (N type) phenotypes. RESULTS: All 4 differentiated type lesions in Hp-eradicated MNU-MGs were classified as G type, while both of the undifferentiated lesions exhibit the GI type. In Hp-infected MNU-MGs, the lesions were classified as 10 G, 8 GI, and 2 I types, with undifferentiated type lesions having more intestinal phenotypic expression than their differentiated counterparts (P< 0.01). CONCLUSIONS: Our data suggest that the differentiated stomach cancers exhibit the G type in Hp-eradicated MNU-MGs, suggesting that a kind of non-neoplastic G type gland may be precancerous. Intestinalization may still occur, especially in undifferentiated stomach cancers, even if Hp eradication is successful.
Assuntos
Adenocarcinoma/genética , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Animais , Carcinógenos , Modelos Animais de Doenças , Gerbillinae , Infecções por Helicobacter/complicações , Metilnitrosoureia/uso terapêutico , Fenótipo , Neoplasias Gástricas/patologiaRESUMO
Peroxidation products formed from polyunsaturated lipids have DNA damaging potential. 4-oxo-2-hexenal (4-OHE), generated by the oxidation of omega-3 fatty acids, has been demonstrated to be mutagenic in vitro as assessed in the Ames test. To examine the carcinogenic risk of 4-OHE in vivo, initiation activity was investigated in a five-week liver assay, established to be effective for screening of carcinogenic potential of mutagens. Seven-week-old male F344 rats underwent two-thirds partial hepatectomy (PH) and were administered 4-OHE intragastrically at doses of 128, 80, 64, 40, 32, 20, or 0 mg/kg body weight (b.w.) at 18 hours thereafter, then being fed on diet containing 0.015% 2-acetylaminofluorene from weeks 2 to 4. All rats were given with 0.8 ml/kg b.w. CCl4 at week 3. At week 5, all survivors were sacrificed and initiation activity was assessed with reference to induction of glutathione S-transferase placental form (GST-P) positive foci in the liver. Mortality was significantly increased to 72.7% in the 128 mg/kg b.w. dose group compared with 0.9% in the control group. However, the average number of GST-P positive foci in the "128" dose group was 3.26-/+1.66 foci/cm2, not significantly different from the control value (2.78?1.33). Areas of GST-P positive foci were also similar (1.11-/+0.5 and 1.53-/+1.33 mm2/cm2 in "128" and the control groups, respectively). These results showed 4-OHE to have no significant initiation activity in.
Assuntos
Aldeídos/toxicidade , Ácidos Graxos Ômega-3 , Peroxidação de Lipídeos , Fígado/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
Changes in cell cycle regulation are involved in many human cancers, including gastric cancer. In the present study, cyclin D1 expression and localization were immunohistochemically analyzed in 23 N-methyl-N'-nitro-N-nitrosoguanidine-induced rat gastric adenocarcinomas and compared with findings for beta-catenin. Cyclin D1 nuclear overexpression was more frequently observed in tumors displaying nuclear (4/4=100%) and cytoplasmic (3/4=75%) beta-catenin accumulation than those with membranous (3/15=20%) localization (nuclear vs. membranous, P<0.02). In the former cases it was considered that cyclin D1 was induced with beta-catenin activation; in the latter, a direct or indirect pathway for cyclin D1 accumulation bypassing Wnt pathway might be involved. Cyclin D1 was also found to be accumulated in gastric glands within normal-looking mucosa, these perhaps representing preneoplastic lesions for cancers with membranous beta-catenin accumulation.
Assuntos
Adenocarcinoma/metabolismo , Carcinógenos/toxicidade , Ciclinas/metabolismo , Metilnitronitrosoguanidina/toxicidade , Neoplasias Gástricas/metabolismo , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/patologia , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/patologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Ciclina D , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Citoplasma/patologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Imuno-Histoquímica , Masculino , Ratos , Ratos Endogâmicos ACI , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/patologia , beta Catenina/metabolismoRESUMO
Statins are commonly used lipid-lowering drugs that reduce the risk of cardiovascular morbidity and mortality. Although recent studies have pointed to chemopreventive effects of statins against various cancers, their efficacy for gastric cancer is unclear. Here, we examined the effects of pitavastatin, a lipophilic statin, on Helicobacter pylori (H. pylori)-associated stomach carcinogenesis and gastritis using Mongolian gerbil and mouse models. The animals were allocated to H. pylori + N-methyl-N-nitrosourea administration (gerbils, 52 weeks) or H. pylori infection alone groups (gerbils and mice, 12 weeks). After H. pylori infection, they were fed basal diets containing 0 to 10 ppm of pitavastatin. The incidences of H. pylori-associated gastric adenocarcinomas and degrees of chronic gastritis were not decreased by pitavastatin compared with those of control values. Expression of interleukin-1beta and tumor necrosis factor-alpha mRNAs in the pyloric mucosa was markedly up-regulated in pitavastatin-treated animals. Furthermore, in the H. pylori-infected groups, serum total cholesterol, triglyceride, and low-density lipoprotein levels were significantly increased by pitavastatin treatment, contrary to expectation. In the short-term study, H. pylori-infected gerbils and mice also showed significant up-regulation of serum triglyceride levels by pitavastatin, whereas total cholesterol was markedly reduced and low-density lipoprotein exhibited a tendency for decrease in noninfected animals. These findings indicate pitavastatin to be ineffective for suppressing gastritis and chemoprevention of gastric carcinogenesis in H. pylori-infected gerbils. Our serologic results also suggest that the H. pylori infection and consequent severe chronic gastritis interfere with the cholesterol-lowering effects of pitavastatin.
Assuntos
Carcinoma/prevenção & controle , Infecções por Helicobacter/tratamento farmacológico , Lipídeos/sangue , Quinolinas/uso terapêutico , Neoplasias Gástricas/prevenção & controle , Animais , Carcinoma/sangue , Carcinoma/etiologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Gerbillinae , Infecções por Helicobacter/sangue , Infecções por Helicobacter/complicações , Helicobacter pylori , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Quinolinas/farmacologia , Roedores , Neoplasias Gástricas/sangue , Neoplasias Gástricas/etiologia , Falha de TratamentoRESUMO
The relation between Helicobacter pylori (Hp) eradication and prevention of stomach carcinoid development has hitherto remained unclear. We therefore examined this problem using an Hp-infected and Hp-eradicated Mongolian gerbil (MG) model. Enterochromaffin-like (ECL) lesions (hyperplasia/dysplasia and carcinoid) were histopathologically evaluated in the glandular stomachs of Hp-infected and Hp-eradicated MGs. In addition, serum gastrin levels were analyzed. Hp infection induced significant increase in the development of ECL lesions in the glandular stomach, as well as serum gastrin levels as compared with non-infected MGs, while Hp eradication was associated with significant alleviation. The development of ECL lesions in the glandular stomach strongly correlated with titers of anti-Hp antibodies and serum gastrin levels in MGs. In conclusion, Hp infection induces carcinoid development, and Hp eradication prevents its occurrence in the glandular MG stomach, this being strongly linked with reduction in serum gastrin levels.
Assuntos
Tumor Carcinoide/etiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/patogenicidade , Neoplasias Gástricas/etiologia , Animais , Antibacterianos/farmacologia , Tumor Carcinoide/patologia , Tumor Carcinoide/prevenção & controle , Celulas Tipo Enterocromafim/patologia , Gastrinas/sangue , Gerbillinae , Helicobacter pylori/efeitos dos fármacos , Hiperplasia , Masculino , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controleRESUMO
A case of adenocarcinoma with chief cell differentiation, a novel entity in the stomach, is presented. An 82-year-old woman who had undergone distal gastrectomy, was scheduled for upper gastrointestinal endoscopy to clarify mechanical ileus. A protruding tumor 16 x 14 x 9 mm in size was found in the cardia of the remnant stomach. Histological examination indicated a well-differentiated tubular adenocarcinoma composed of basophilic columnar or cuboidal cells with occasional coarse eosinophilic granules. Immunohistochemical analysis revealed strong expression of pepsinogens I and II and Runt-related transcription factor gene 3 (RUNX3), characteristic for chief cells, and MUC6 typical for mucous neck cells. However, the tumor cells were negative for the proton pump alpha subunit, a marker for parietal cells. Cdx2 and defensin-5 were not present, confirming the lack of an intestinal phenotype. The cancer cells shared characteristics of a chief cell and a mucous neck cell, resembling an ancestor of these two cell types, so-called 'primitive chief cell' in fundic gland. In line with these data, the cancer was diagnosed as an adenocarcinoma with chief cell differentiation.
Assuntos
Adenocarcinoma/patologia , Celulas Principais Gástricas/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/química , Adenocarcinoma/cirurgia , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Cárdia/patologia , Celulas Principais Gástricas/química , Feminino , Humanos , Neoplasias Gástricas/química , Neoplasias Gástricas/cirurgiaRESUMO
Helicobacter pylori (H. pylori) infection causes chronic gastritis and is also related to gastric carcinoma. The present study focused on severity of H. pylori-induced gastritis as a determinant of carcinogenesis. Seven-week-old male Mongolian gerbils were inoculated with H. pylori at experimental weeks 0, 12, or 18, then given N-methyl-N-nitorosourea (MNU) from weeks 20-40. At week 70, stomachs were then excised for histological examination 70, 58, or 52 weeks after H. pylori inoculation, respectively (Groups A, B, and C for long-, middle-, and short-term). The respective incidences of glandular stomach adenocarcinomas were 65.0% (13/20), 20.0% (2/10), and 23.0% (3/13) (P<0.05). Higher scores of infiltration of inflammatory cells, hyperplasia, intestinal metaplasia and mucosal bromodeoxyuridine (BrdU) labeling index in antrum and corpus mucosa, were seen in group A than B or C (P<0.05) and serum anti-H. pylori IgG titer and gastrin levels were also significantly higher, along with mRNA levels for mucosal interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The results demonstrated the term and severity of H. pylori infection to play important roles in gastric carcinogenesis, with essential involvement of chronic inflammation, especially increased rates of cell proliferation, in H. pylori-associated carcinogenesis.
Assuntos
Adenocarcinoma/microbiologia , Mucosa Gástrica/microbiologia , Gastrite/complicações , Infecções por Helicobacter/complicações , Helicobacter pylori , Neoplasias Gástricas/microbiologia , Adenocarcinoma/metabolismo , Animais , Mucosa Gástrica/metabolismo , Gastrite/microbiologia , Gerbillinae , Interleucina-1beta/metabolismo , Masculino , Fator de Necrose Tumoral alfa/metabolismoRESUMO
p53 knockout mice are now being frequently used to identify the carcinogenic potential of chemicals, thus it is important to precisely assess the susceptibility of the animals to various test chemicals. In the present study the susceptibility of p53 nullizygous((-/-)), heterozygous((+/-)), and wild-type((+/+)) mice to 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was investigated. Mice of all three genotypes were first fed a diet containing 100 or 300 p.p.m. IQ for 15 weeks in a short-term experiment. p53((+/-)) and ((+/+)) mice were then treated with IQ for 40 weeks and maintained without further treatment for an additional 12 weeks in the long-term experiment. In the forestomach, the incidence of squamous cell hyperplasia was significantly higher in p53((-/-)) than in ((+/-)) and ((+/+)) mice at 15 weeks and higher in ((+/-)) mice than ((+/+)) mice with long-term IQ treatment, indicating an elevated susceptibility of p53 knockout mice. In contrast, in the liver, various hepatocellular lesions developed mainly in female mice with long-term IQ exposure but no significant differences were evident between p53 knockout and wild-type mice, indicating a lack of elevated susceptibility in the knockout animals. Furthermore, polymerase chain reaction-single strand conformation polymorphism and sequencing analysis revealed relatively high (13/30) and low (1/15) incidences of p53 mutations (exons 5-8) in squamous cell hyperplasia and hepatocellular tumors, respectively. These results clearly indicate that the susceptibility of p53 knockout mice is organ-dependent, coinciding to some extent with the likelihood of p53 gene alteration in the induced tumors.
Assuntos
Carcinoma de Células Escamosas/induzido quimicamente , Suscetibilidade a Doenças , Genes p53 , Neoplasias Hepáticas Experimentais/induzido quimicamente , Quinolinas/toxicidade , Neoplasias Gástricas/induzido quimicamente , Animais , Testes de Carcinogenicidade , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/genética , Feminino , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos , Camundongos Knockout , Mutação , Especificidade de Órgãos , Quinolinas/administração & dosagem , Neoplasias Gástricas/genética , Fatores de TempoRESUMO
Intestinal metaplasia has been investigated extensively as a possible premalignant condition for stomach cancer but its pathogenesis is still not fully understood. In the present study, we examined the relationship between endocrine and mucous cell marker expression periodically after Helicobacter pylori infection in the Mongolian gerbil model. The numbers of chromogranin A (CgA)-positive, gastrin-positive and gastric inhibitory polypeptide (GIP)-positive cells in H. pylori-infected groups was increased significantly compared with the non-infected case. However, CgA-positive and gastrin-positive cells then decreased from 50 through 100 experimental weeks after H. pylori infection, whereas GIP-positive cells increased. Coexistence of gastrin-positive and GIP-positive cells was detected in the same gastric and intestinal mixed phenotypic glandular-type glands. In conclusion, the endocrine cell phenotype is in line with that of the mucous counterpart in the glands of H. pylori-infected Mongolian gerbil stomach, supporting the concept that development of intestinal metaplasia is due to the abnormal differentiation of a stem cell.