Investigação do possível elfeito quimioprotetor do zinco na carcinogênese do colón induzida pela 1,2-Dimetilhidrazina, em ratos Wistar machos

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Efeito protetor do açaí (Euterpeoleracea Martius) na promoção da carcinogênese de cólon em ratos Wistar

Pós-graduação em Patologia - FMB

Modulação da carcinogênese do cólon pelo cogumelo Agaricus Blazei no rato

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação do ecossistema microbiano de ratos wistar submetidos à carcinogênese química de cólon após o consumo de lactobacillus acidophilus crl 1014 e extrato aquoso

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Repercusões a longo prazo do padrão alimentar ocidental ocorrido durante a gestação, lactação e fase juvenil na susceptibilidade ao desenvolvimento de câncer do cólon em ratos

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

In vivo assessment of genotoxic, antigenotoxic and anticarcinogenic activities of Solanum lycocarpum fruits glycoalkaloidic extract

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Efeitos da ingestão de simbiótico e indol-3-carbinol sobre o processo de carcinogênese química de cólon em ratos Wistar alimentados com dieta contendo heme

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

High-fat diet causes an imbalance in the colonic serotonergic system promoting adipose tissue enlargement and dysplasia in rats

A high-fat (HF) diet, the serotonergic system and stromal elements have all been implicated in colon carcinogenesis. We investigated whether the colonic serotonergic system could play a main role in the development of colonic dysplasia and stromal reactivity in carcinogen-treated rats under HF diet. For this, dimethylhydrazine-treated rats were fed with standard diet and a HF diet. Fat distribution was quantified by computerized tomography exam, serotonergic activity was analyzed by high-performance liquid chromatography, gene expression, and immunohistochemistry, which along with histopathological technique enabled us to enumerate dysplasia, microvessels density, cell proliferation and COX-2 expression. We found that the HF diet induced an increase in the amount of viscera! adipose tissue, even without expressive changes in the average body weight. This was correlated with a loss of serotonergic balance in colon tissue. Moreover, the HF diet promoted dysplasia and microvessel density in association with increased proliferation and COX-2 expression within pericryptal colonic stroma. Our current findings suggest that a HF diet promotes the enlargement of adipose tissue via loss of control in colon serotonergic activity, which enhances colonic dysplasia by supporting microvessel development. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Prostacyclin-mediated activation of peroxisome proliferator-activated receptor δ in colorectal cancer

There is evidence from both genetic and pharmacologic studies to suggest that the cyclooxygenase-2 (COX-2) enzyme plays a causal role in the development of colorectal cancer. However, little is known about the identity or role of the eicosanoid receptor pathways activated by COX-derived prostaglandins (PG). We previously have reported that COX-2-derived prostacyclin promotes embryo implantation in the mouse uterus via activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) δ. In light of the recent finding that PPARδ is a target of β-catenin transactivation, it is important to determine whether this signaling pathway is operative during the development of colorectal cancer. Analysis of PPARδ mRNA in matched normal and tumor samples revealed that expression of PPARδ, similar to COX-2, is up-regulated in colorectal carcinomas. In situ hybridization studies demonstrate that PPARδ is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands. In contrast, expression of PPARδ mRNA in colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of PPARδ and COX-2 mRNA in serial sections suggested they were colocalized to the same region within a tumor. Finally, transient transfection assays established that endogenously synthesized prostacyclin (PGI2) could serve as a ligand for PPARδ. In addition, the stable PGI2 analog, carbaprostacyclin, and a synthetic PPARδ agonist induced transactivation of endogenous PPARδ in human colon carcinoma cells. We conclude from these observations that PPARδ, similar to COX-2, is aberrantly expressed in colorectal tumors and that endogenous PPARδ is transcriptionally responsive to PGI2. However, the functional consequence of PPARδ activation in colon carcinogenesis still needs to be determined.

Tributirina apresenta atividade quimiopreventiva quando administrada isoladamente, mas não em associação com a vitamina A, em ratos submetidos a modelo de carcinogênese de cólon

Avaliou-se a atividade quimiopreventiva da tributirina (TB), e da vitamina A (VA) administradas em associação ou não, antes, durante e após a iniciação em ratos submetidos a modelo de carcinogênese de cólon. Ratos Wistar receberam VA [1 mg/100 g de p.c (grupo VA)], tributirina [200 mg/100 g de p.c (grupo TB)] ou associação de VA com TB (grupo VA+TB). Ratos tratados com óleo de milho e maltodextrina serviram como controle (GC). Avaliou-se a presença de focos de criptas aberrantes (FCA) e sua localização nos cólons, além de danos e do padrão de metilação global do DNA na mucosa colônica. No cólon total, distal e proximal, o grupo TB apresentou menor (p<0,05) número de FCA com 4 ou mais criptas/cm2, considerados mais agressivos, em relação ao GC. Quanto aos danos no DNA, os grupos VA, TB e VA+TB apresentaram cometas de comprimentos menores (p<0,05) em comparação ao GC. Não houve diferenças estatisticamente significantes quanto ao padrão de metilação global do DNA. Assim, TB consiste em agente quimiopreventivo promissor da carcinogênese de cólon quando administrada isoladamente, mas não em associação com a VA. 15

Vitamine D et prévention du cancer colorectal associé à la colite ulcéreuse : modèles murins

Les patients atteints de maladies inflammatoires de l'intestin (MII) ont un risque accru de développer un cancer colorectal dû aux lésions épithéliales secondaires à l’inflammation chronique. La vitamine D (vD) régule NOD2, gène impliqué dans la réponse inflammatoire et dans la susceptibilité aux MII, et induit son expression dans les monocytes et dans l’épithélium intestinal. Dans ce projet, nous avons d’abord induit le cancer colorectal associé à la colite ulcéreuse (CAC) en administrant un traitement combiné d’azoxyméthane (AOM) et de dextran de sulfate de sodium (DSS) aux souris C57BL/6J. Par la suite, nous avons étudié l'effet d’une carence en vD3 sur le développement du CAC et évalué la capacité préventive d’une supplémentation en vD3 sur la tumorigenèse, et vérifié si cet effet est médié par NOD2, en utilisant les souris Nod2-/-. Les C57BL/6J et les Nod2-/-, ayant reçu une diète déficiente en vD3, étaient moins résistantes au CAC par rapport aux souris supplémentées. Le pourcentage de perte de poids, l’indice d’activation de la maladie (DAI), le taux de mortalité et le poids relatif du côlon (mg/cm) chez les souris déficientes en vD3 étaient plus élevés en comparaison avec celles supplémentées en vD3. Une augmentation du score d'inflammation et de la multiplicité tumorale corrélait avec une expression accentuée de l’Il6 dans les colonocytes des souris déficientes en vD3. La vD3 régulait l’expression génétique de Cyp24, Vdr et de gènes pro-inflammatoires chez les C57BL/6, comme chez les Nod2-/-. En conclusion, la supplémentation en vD3 peut prévenir le développement du CAC indépendamment de NOD2.

Vitamine D et prévention du cancer colorectal associé à la colite ulcéreuse : modèles murins

Les patients atteints de maladies inflammatoires de l'intestin (MII) ont un risque accru de développer un cancer colorectal dû aux lésions épithéliales secondaires à l’inflammation chronique. La vitamine D (vD) régule NOD2, gène impliqué dans la réponse inflammatoire et dans la susceptibilité aux MII, et induit son expression dans les monocytes et dans l’épithélium intestinal. Dans ce projet, nous avons d’abord induit le cancer colorectal associé à la colite ulcéreuse (CAC) en administrant un traitement combiné d’azoxyméthane (AOM) et de dextran de sulfate de sodium (DSS) aux souris C57BL/6J. Par la suite, nous avons étudié l'effet d’une carence en vD3 sur le développement du CAC et évalué la capacité préventive d’une supplémentation en vD3 sur la tumorigenèse, et vérifié si cet effet est médié par NOD2, en utilisant les souris Nod2-/-. Les C57BL/6J et les Nod2-/-, ayant reçu une diète déficiente en vD3, étaient moins résistantes au CAC par rapport aux souris supplémentées. Le pourcentage de perte de poids, l’indice d’activation de la maladie (DAI), le taux de mortalité et le poids relatif du côlon (mg/cm) chez les souris déficientes en vD3 étaient plus élevés en comparaison avec celles supplémentées en vD3. Une augmentation du score d'inflammation et de la multiplicité tumorale corrélait avec une expression accentuée de l’Il6 dans les colonocytes des souris déficientes en vD3. La vD3 régulait l’expression génétique de Cyp24, Vdr et de gènes pro-inflammatoires chez les C57BL/6, comme chez les Nod2-/-. En conclusion, la supplémentation en vD3 peut prévenir le développement du CAC indépendamment de NOD2.

Revisión sistemática utilidad de asa y calcio con o sin vitamina d en la prevención de cáncer colorrectal y la recurrencia de pólipos adenomatosos en paciente con riesgo de padecer esta patología

Introducción: El cáncer colorrectal es una patología con alto impacto en la salud pública, debido a su prevalencia, incidencia, severidad, costo e impacto en la salud mental y física del individuo y la familia. Ensayos clínicos realizados en pacientes con antecedente de infarto al miocardio que consumían ácido acetil salicílico (asa), calcio con y sin vitamina D, mostraron asociación entre el consumo de estos medicamentos y disminución en la incidencia en cáncer colorrectal y pólipos adenomatosos. Objetivo: Evaluar la literatura sobre el uso de asa, calcio con y sin vitamina D con relación a su impacto en la prevención del cáncer colorrectal y pólipos adenomatosos. Métodos: Se realizó revisión sistemática buscando ensayos clínicos realizados en pacientes con factores de riesgo para cáncer colorrectal y pólipos adenomatosos que usaron asa, calcio con y sin vitamina D fueron incluidos. Resultados: se escogieron 105 para la revisión sistemática. Conclusiones: Es necesario desarrollar más estudios que lleven a evaluar el efecto protector de la aspirina, calcio y vitamina D. En los artículos revisados la aspirina a dosis de 81 a 325 mg día se correlaciona con reducción de riesgo de aparición de CRC aunque la dosis ideal, el tiempo de inicio y la duración de la ingesta continua no son claros. Hacen falta estudios que comparen poblaciones con ingesta de asa a diferentes dosis.

MiR-1 Is a Tumor Suppressor in Thyroid Carcinogenesis Targeting CCND2, CXCR4, and SDF-1 alpha

Context: Micro-RNA have emerged as an important class of short endogenous RNA that act as posttranscriptional regulators of gene expression and are constantly deregulated inhumancancer. MiR-1 has been found down-regulated in lung, colon, and prostate cancer. Objectives: In this study, we investigated the possible role of miR-1 in thyroid carcinogenesis. Design: We have analyzed miR-1 expression in a panel of thyroid neoplasias including benign and malignant lesions and searched for miR-1 targets. Results: Our results show that miR-1 expression is drastically down-regulated in thyroid adenomas and carcinomas in comparison with normal thyroid tissue. Interestingly, miR-1 down-regulation was also found in thyroid hyperproliferative nonneoplastic lesions such as goiters. We identified the CCND2, coding for the cyclin D2 (CCND2) protein that favors the G1/S transition, CXCR4, and SDF-1 alpha genes, coding for the receptor for the stromal cell derived factor-1 (SDF-1)/CXCL12 chemokine and its ligand SDF-1/CXCL12, respectively, as miR-1 targets. An inverse correlation was found between miR-1 expression and CXC chemokine receptor 4 (CXCR4) and SDF-1 alpha protein levels in papillary and anaplastic thyroid carcinomas. Consistent with a role of the CCND2 protein in cell proliferation and CXCR4 and SDF-1 alpha proteins in cell invasion and metastasis, functional studies demonstrate that miR-1 is able to inhibit thyroid carcinoma cell proliferation and migration. Conclusions: These results indicate the involvement of miR-1 in thyroid cell proliferation and migration, validating a role of miR-1 down-regulation in thyroid carcinogenesis. (J Clin Endocrinol Metab 96: E1388-E1398, 2011)

The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: Functional and localization studies

In both animal models and humans, the first and obligatory step in the activation of arylamines is N-hydroxylation. This pathway is primarily mediated by the phase-I enzymes CYP1A1, CYP1A2 and CYP4B1. In the presence of flavonoids such as alpha-naphthoflavone and flavone, both CYP3A4 and CYP3A5 have also been shown to play a minor role in the activation of food-derived heterocyclic amines. The further activation of N-hydroxyarylamines by phase-II metabolism can involve both N,O-acetylation and N,O-sulfonation catalyzed by N-acetyltransferases (NAT1 and NAT2) and sulfotransferases, respectively. Using an array of techniques, we have been unable to detect constitutive CYP1A expression in any segments of the human gastrointestinal tract. This is in contrast to the rabbit where CYP1A1 protein was readily detectable on immunoblots in microsomes prepared from the small intestine. In humans, CYP3A3/3A4 expression was detectable in the esophagus and all segments of the small intestine. Northern blot analysis of eleven human colons showed considerable heterogeneity in CYP3A mRNA between individuals, with the presence of two mRNA species in same subjects. Employing the technique of hybridization histochemistry (also known as in situ hybridization), CYP4B1 expression was observed in some human colons but not in the liver or the small intestine. Hybridization histochemistry studies have also demonstrated variable NAT1 and NAT2 expression in the human gastrointestinal tract. NAT1 and NAT2 mRNA expression was detected in the human liver, small intestine, colon, esophagus, bladder, ureter, stomach and lung. Using a general aryl sulfotransferase riboprobe (HAST1), we have demonstrated marked sulfotransferase expression in the human colon, small intestine, lung, stomach and liver. These studies demonstrate that considerable variability exists in the expression of enzymes involved in the activation of aromatic amines in human tissues. The significance of these results in relation to a role for heterocyclic amines in colon cancer is discussed.