COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice.

Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.

Higher incidence of lung adenocarcinomas induced by DMBA in connexin 43 heterozygous knockout mice.

Gap junctions are communicating junctions which are important for tissue homeostasis, and their disruption is involved in carcinogenic processes. This study aimed to verify the influence of deletion of one allele of the Connexin 43 gene on cancer incidence in different organs. The 7, 12-dimethylbenzanthracene (DMBA) carcinogenic model, using hebdomadary doses by gavage of 9 mg per animal, was used to induce tumors in Connexin 43 heterozygous or wild-type mice. The experiment began in the eighth week of the mice life, and all of them were euthanized when reaching inadequate physical condition, or at the end of 53 weeks. No statistical differences occurred for weight gain and cancer survival time (P = 0.9853) between heterozygous and wild-type mice. Cx43⁺/⁻ mice presented significantly higher susceptibility to lung cancer (P = 0.0200) which was not evidenced for benign neoplasms (P = 0.3449). In addition, incidence of ovarian neoplasms was 2.5-fold higher in Cx43⁺/⁻ mice, although not statistically significant. Other organs showed a very similar cancer occurrence between Cx43 groups. The experiment strengthens the evidence of the relationship between Connexin 43 deficiency and carcinogenesis.

Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice: effects of alcohol and caffeine / Neoplasia pancreática intraepithelial e adenocarcinoma ductal induzidos pelo DMBA em camundongos. Efeitos do álcool e da cafeína

PURPOSE: To evaluate the effects of alcohol and caffeine in a pancreatic carcinogenesis mouse model induced by 7,12-dimethylbenzantracene (DMBA), according to the PanIN classification system. METHODS: 120 male, Mus musculus, CF-1 mice were divided into four groups. Animals received either water or caffeine or alcohol or alcohol + caffeine in their drinking water. In all animals, 1 mg of DMBA was implanted into the head of the pancreas. After 30 days, euthanasia was performed; excised pancreata were then fixed in formalin, stained with hematoxylin-eosin and categorized as follows: normal ducts, reactive hyperplasia, PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 or adenocarcinoma. RESULTS: PanIN lesions were verified in all groups. Adenocarcinoma was detected in 15 percent of animals in the caffeine group, 16.6 percent in the water group, 23.8 percent in the alcohol + caffeine group and 52.9 percent in the alcohol group (P<0.05). CONCLUSIONS: The experimental pancreatic carcinogenesis mouse model using DMBA effectively induces PanIN lesions and pancreatic adenocarcinoma. This study verified the association between alcohol use and pancreatic adenocarcinoma; caffeine did not present the same effect.(AU)

OBJETIVO: Avaliar os efeitos do álcool e da cafeína na carcinogênese pancreática induzida pelo 7,12-dimetilbenzantraceno (DMBA) em camundongos, descrevendo as lesões de acordo com a classificação das neoplasias pacreáticas intraepiteliais (PanIN). MÉTODOS: 120 camundogos machos, Mus musculus, CF-1 foram divididos em quatro grupos. Animais receberam água ou cafeína ou álcool ou álcool + cafeína para beber. Em todos animais, 1 mg de DMBA foi implantado na cabeça do pâncreas. Após 30 dias, eutanásia foi realizada, o pâncreas foi removido, fixado em formalina e corado com hematoxilina e eosina sendo classificado em: ductos normais, hiperplasia reativa, PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 ou adenocarcinoma. RESULTADOS: Neoplasias pancreáticas intraepiteliais foram encontradas em todos grupos. Adenocarcinoma foi detectado em 15 por cento dos animais do grupo cafeína, 16,6 por cento do grupo água, 23,8 por cento do grupo álcool + cafeína e 52,9 por cento do grupo álcool (P<0,05). CONCLUSÕES: O modelo experimental de carcinogênese pancreática em camundongos utilizando DMBA induz neoplasias pancreáticas intraepiteliais (PanIN) e adenocarcinoma pancreático. Este estudoverificou associação entre álcool e adenocarcinoma pancreático, enquanto a cafeína não demonstrou este efeito.(AU)

Ploidy analysis of field cancerization and cancer development in the hamster cheek pouch carcinogenesis model.

BACKGROUND: The hamster cheek-pouch carcinogenesis model is a well-known animal system that closely mimics the development of premalignant and malignant lesions in human oral cancer. Our aim was to numerically characterize the premalignant and malignant lesions and expressions of field cancerization in this model using ploidy as the end-point. METHODS: To study the DNA content and proliferation status of the cells in this model we assessed the Feulgen reaction and the immunohistochemical reaction for 5-bromo-2-deoxiuridine (BrdU) in different histological areas of serial tissue sections of the cheek pouches of animals injected with BrdU. RESULTS: Ploidy values were higher in cancerized epithelia with no unusual microscopic features (NUMF), in preneoplastic and tumor areas than in control epithelia. The aneuploidy index was higher in NUMF areas than in control and differed significantly from control in preneoplastic areas and carcinoma. CONCLUSIONS: The unexpected alteration in DNA content observed in NUMF epithelia is of great relevance as a biomarker of field cancerized areas.

Experimental study to test the potential tumor promotion effect of a tooth bleaching agent.

Carbamide Peroxide is routinely employed as a whitener for tooth enamel. Oral mucosa protection is recommended to avoid inflammatory reactions. Experimental work has demonstrated its irritative effect on gastric mucosa when swallowed. The activity of certain oxidizing agents as tumoral promoters has been demonstrated and associated to their capacity to induce hyperplasia. Within this context it seemed of interest to assess the possible action of carbamide peroxide as a tumoral promoter in oral mucosa with or without a precancerous condition. Its action was tested in 2 models which are highly sensitive to chemical cancerization: a) Dorsum skin or SENCAR mice treated with carbamide peroxide daily or twice a week with or without prior initiation with dimethylbenz(a)anthracene (DMBA). Control mice were submitted to the standard carcinogenesis protocol, i.e. initiation with DMBA and promotion with 12-O-tetradecanoyl phorbol acetate (TPA). b) Hamster cheek pouch submitted to topical application of carbamide peroxide 3 times a week with or without prior initiation with DMBA, hamster cheek pouch submitted to repeated topical application of DMBA as a complete carcinogen: application twice a week in the control group and identical treatment + 1 weekly application of carbamide peroxide to evaluate its capacity to enhance the process. The effects were assessed between 1 and 14 weeks of treatment at different intervals for the different experimental protocols. The control cases exhibited hyperplasia and tumor induction in keeping with the known sequence for both carcinogenesis models. None of the cases revealed a promoter or enhancer capacity of carbamide peroxide. These results indicate the lack of risk involved in the application of carbamide peroxide even in oral mucosa with a precancerous condition due to the action of initiation agents such as tobacco and alcohol.

Estudo das alteraçöes morfológicas causadas pela induçäo concomitante de DMBA e bebidas alcoólicas de alto teor na carcinogênese química bucal / Study of morphologic changes caused by concomitant induction of DMBA and heavy alcoholic drinks in oral chemical carcinogenesis

Realizou-se este trabalho com o objetivo de observar o comportamento biológico, macro e microscópico, da mucosa lingual lateral de hamsters sírios dourados Mesocricetus auratus após contato direto com bebidas de alto teor alcoólico (cachaça e uísque) associadas ao 9,10 dimetil 1,2-benzantraceno (DMBA). Sessenta animais foram divididos em três grupos experimentais: grupo 1 - DMBA + cachaça; grupo 2 - DMBA + uísque; grupo 3 - DMBA. Dez animais de cada grupo experimental foram sacrificados após 13 e 20 semanas. Os resultados mostraram que após 13 semanas ocorreu a formaçäo de alteraçöes displásicas em 70 por cento, 60 por cento e 80 por cento, na língua dos animais dos grupos 1, 2 e 3, respectivamente. Após 13 semanas, carcinomas de células escamosas papiliforme estavam presentes em todos os grupos experimentais sendo que em 30 por cento dos animais do grupo 1 os carcinomas eram pequenos (0,1-0,2cm); no grupo 2, 30 por cento dos animais apresentavam carcinomas pequenos e 10 por cento eram microinvasivos; no grupo 3 todos os carcinomas presentes eram microinvasivos (20 por cento). Após 20 semanas, ocorreu a formaçäo de alteraçöes displásicas em 10 por cento, 10 por cento e 30 por cento dos animais dos grupos 1, 2 e 3, respectivamente; carcinomas microinvasivos em 20 por cento dos animais do grupo 1; carcinomas de células escamosas papiliforme tamanho pequeno em 50 por cento, 30 por cento e 60 por cento dos animais dos grupos 1, 2 e 3, respectivamente; e os carcinomas de células escamosas papiliformes grandes (>0,5cm) em 20 por cento, 60 por cento e 10 por cento dos animais dos grupos 1, 2 e 3 respectivamente. Assim, pode-se concluir que as bebidas de alto teor alcoólico (cachaça e uísque) tem potencial carcinogênico promotor sobre a mucosa bucal e o uísque tem potencial carcinogênico de progressäo sobre a mucosa bucal

Estudo das alteraçöes morfológicas causadas pela induçäo concomitante de DMBA e bebidas alcoólicas de alto teor na carcinogênese química bucal / Study of morphologic changes caused by concomitant induction of DMBA and heavy alcoholic drinks in oral chemical carcinogenesis

Com o objetivo de observar o comportamento biológico, macro e microscópico, da mucosa lingual lateral de hamsters sírios dourados Mesocricetus auratus após contato direto com bebidas de alto teor alcoólico (cachaça e uísque) associadas ao 9,10 dimetil1,2-benzantraceno (DMBA) realizou-se este trabalho. Sessenta animais foram divididos em três grupos experimentais: grupo 1 - DMBA + cachaça; grupo 2 - DMBA + úisque; grupo 3 - DMBA. Dez animais de cada grupo experimental foram sacrificados após 13 e 20 semanas. Os resultados mostraram que após 13 semanas ocorreu a formaçäo de carcinomas de células escamosas papiliforme em todos os grupos experimentais sendo que em 30 por cento dos animais do grupo 1 os carcinomas eram pequenos (0,1-0,2 cm). No grupo 2, 40 por cento dos animais apresentavam carcinomas pequenos (30 por cento) ou microinvasivos) (10 por cento) e no grupo 3 todos os carcinomas presentes eram microinvasivos (20 por cento). Após 20 semanas, os carcinomas observados eram de grandes dimensöes (>0,5 cm) em 20 por cento, 60 por cento e 10 por cento dos animais dos grupos 1, 2 e 3 respectivamente. Assim, pode-se concluir que as bebidas de alto teor alcoólioco (cachaça e uísque) tem potencial carcinogênico promotor sobre a mucosa bucal e o uísque tem potencial carcinogênico de progressäo sobre a mucosa bucal

Estudo das alteraçöes morfológicas na carcinogênese química bucal comparando-se a induçäo pelo DMBA e bebidas alcoólicas de alto teor / Study of morphologic changes in the oral chemical carcinogenesis with induction by DMBA and heavy concentration of alcohol in alcoholic drinks

Com o objetivo de observar o comportamento biológico, macro e microscópio, da mucosa lingual lateral de hamsters sírios dourados Mesocricetus auratus após contato direto com bebidas alcoólicas de alto teor (cachaça e uísque) e de uma revisäo literária sobre o relacionamento álcool/câncer bucal, realizou-se este trabalho. Os animais foram divididos em três grupos experimentais, sendo estes subdivididos em dois períodos experimentais de 13 e 20 semanas, respectivamente. Os hamsters do Grupo I recebiam três aplicaçöes semanais de cachaça na borda lateral da língua, com o auxílio de pincel número zero. O Grupo II recebia aplicaçöes de uísque e o Grupo III aplicaçöes de 7,12 dimetil-benzantraceno (DMBA), sendo o grupo controle/positivo. As alteraçöes macro e microscópicas foram anotadas e avaliadas, constatando-se: 1) a induçäo à carcinogênese bucal pelo uso do DMBA na mucosa lingual lateral promoveu carcinomas em 50 por cento dos animais após 13 semanas e em 100 por cento dos animais após 20 semanas; 2) o tempo experimental influenciou na obtençäo de carcinomas DMBA/induzidos; 3) o uso da bebida alcoólica de alto teor näo foi suficiente para, isoladamente, iniciar a carcinogênese na mucosa lingual lateral; 4) as principais modificaçöes morfológicas no epitélio da mucosa lingual lateral de hamsters que indicam a carcinogênese säo: hiperplasia e hiperqueratose com projeçöes papiliformes...

AgNOR mark epithelial foci in malignant transformation in hamster cheek pouch carcinogenesis.

Hamster cheek pouch mucosa is an accepted model of oral carcinogenesis. We herein examined the value of morphometric evaluation of silver-stained nucleolar organizer regions (AgNOR) in the detection of epithelial foci in malignant transformation following dimethyl-1,2-benzanthracene-induced carcinogenesis of hamster cheek pouch. AgNOR-related parameters were analyzed at different stages of the process of carcinogenesis (control epithelium, epithelium with no unusual microscopic features, "dysplastic" epithelium, exophytic and endophytic carcinomas). Morphometric evaluation of AgNOR revealed incipient cellular alterations which were not evident in routine preparations and contributed to the characterization of different stages of carcinogenesis in this model.

Alteraciones del tejido conectivo subepitelial durante la carcinogénesis experimental: estudio estereológico / Stereological assessment of changes in subepitelial stroma during experimental carcinogenesis

El propósito de este estudio fué el de obtener información cuantitativa de los cambios del estroma subepitelial durante la carcinogénesis química experimental El carcinógeno DMBA fué aplicado localmente tres veces por semana durante cuatro semanas a la mucosa bucal (bolsa) y la palatina de veinte hamsters dorados machos, de cuatro a seis semanas de edad. A otros seis animales se les aplicó parafina líquida en sitios análogos, y diez animales no recibieron tratamiento. A las seis y doce semanas de iniciado el experimento, se tomaron muestras de tejido de paladar y mucosa bucal para microscopía de luz y electrónica, a cinco animales tratados con DMBA, a cinco no tratados y a tres tratados con parafina líquida. A las 21 semanas, la mucosa bucal de los animales tratados con dDMBA, mostró displasia epitelial o carcinoma escamocelular; la mucosa palatina no mostró cambios malignos o premalignos. Se tomaron fotomicrografías a un aumetno final de x14,210 de las secciones obtenidas de los bloques seleccionados al azar. Para calcular la densidad de volumen de colágeno, substancia intercelular, células del estroma y vasos sanguíneos, se aplicó la técnica de conteo de puntos. El analizador de imágenes proporcionó la densidad de volumen de las células del estroma y vasos sanguíneos. A las 6 y 12 semanas, la mucosa bucal tratada con DMBA mostró una disminución significativa de colágeno, un aumento significativo de substancia intercelular y un ligero aumento de vasos sanguíneos. A las 12 semanas hubo también un aumento significativo de las células del estroma. La mucosa palatina tratada con el carcinógeno no mostró cambios significativos en el estroma.

The psychophysiological mediators of stress as it relates to oncology in humans and animals

This study was designed to investigate the effect of stress on cancer development and treatment, and also to determine whether there is any cancer association personality profile. Human studies were supplemented by controlled animal studies. Twenty-nine male and female cancer subjects were studied along with twenty-nine controls. The animal study comprised ninety female Sprague-Dawley rats, which were divided into nine groups of ten. One group was treated with noise stress alone, while another group received no treatment at all. Three groups received the carcinogen 7,12-Dimethylbenz(a)anthracene together with either noise stress, cortisone acetate or 6-mercaptopurine and the rate of tumour growth in these animals was compared to a group that received only the carcinogen, and after tumour growth these animals were subjected to chemotherapy. In addition to the chemotherapy, one of these groups received noise stress and another cortisone acetate. The stress level of the humans and animals was determined by physiological and psychological tests where applicable. The results of the human study revealed that the level of stress among the cancer subjects was higher than among the controls. Even though in some cases cancer development occured after an event that may be considered stressful, it was not easy to conclude whether stress occurred before or after the cancer development. The controlled animal studies revealed, though, that stress alone could not induce tumour development in the observation period of 280 days. Stress, however, influenced tumour growth when the rats were treated with the carcinogen. The findings of this study also suggested that immunosuppression might play a vital role in cancer development. A cancer associated personality profile, depicting among other things a schizophrenic character, was also detected among the human cancer subjects. The treatment of the cancer subjects who had high stress levels was less successful, and this was substantiated by the results of the animal study, which showed that stressed decreased the life span of the animals receiving chemotherapy and stress. The findings of this study suggest that even though stress may not initiate tumour growth, stress influences the growth of potential tumour cells, and may interfere with the response to treatment (AU)

The psychophysiological mediators of stress as it relates to oncology in humans and animals

This study was designed to investigate the effect of stress on cancer development and treatment, and also to determine whether there is any cancer association personality profile. Human studies were supplemented by controlled animal studies. Twenty-nine male and female cancer subjects were studied along with twenty-nine controls. The animal study comprised ninety female Sprague-Dawley rats, which were divided into nine groups of ten. One group was treated with noise stress alone, while another group received no treatment at all. Three groups received the carcinogen 7,12-Dimethylbenz(a)anthracene together with either noise stress, cortisone acetate or 6-mercaptopurine and the rate of tumour growth in these animals was compared to a group that received only the carcinogen, and after tumour growth these animals were subjected to chemotherapy. In addition to the chemotherapy, one of these groups received noise stress and another cortisone acetate. The stress level of the humans and animals was determined by physiological and psychological tests where applicable. The results of the human study revealed that the level of stress among the cancer subjects was higher than among the controls. Even though in some cases cancer development occured after an event that may be considered stressful, it was not easy to conclude whether stress occurred before or after the cancer development. The controlled animal studies revealed, though, that stress alone could not induce tumour development in the observation period of 280 days. Stress, however, influenced tumour growth when the rats were treated with the carcinogen. The findings of this study also suggested that immunosuppression might play a vital role in cancer development. A cancer associated personality profile, depicting among other things a schizophrenic character, was also detected among the human cancer subjects. The treatment of the cancer subjects who had high stress levels was less successful, and this was substantiated by the results of the animal study, which showed that stressed decreased the life span of the animals receiving chemotherapy and stress. The findings of this study suggest that even though stress may not initiate tumour growth, stress influences the growth of potential tumour cells, and may interfere with the response to treatment.

Tamoxifeno como supresor de la carcinogenesis mamaria inducida por 7,12-dimetil-benzoantraceno y nitroso-metilurea, en ratas hembras con hiperprolactinemia provocada / Tamoxifen as a suppressor of mammary carcinogenesis induced by 7,12-dimetil-benzanthracene and methylnitrosourea, in female rats with induced hyperprolactinemia

El efecto del tamoxifeno sobre tumores mamarios inducidos con DMBA (7, 12-dimetil-benzoantraceno) y NMU (nitroso-metilurea) se analiza. De 7 lotes de ratas Sprague-Dayley, 4 (A-B-C-D) reciben adiconalmene sulpirida 0,5 mg/100g durante 5 días de la semana y hasta finalizar el experimento. Dos lotes (C-D) recibieron una sola inyección intraperitoneal de 900 microcuries por 100g de peso de I. Tres lotes (E-F-G) recibieron sólo I para activar secreción de prolactina, y de ellos, 2(F-G)recibieron tamoxifeno. Los tumores que se desarrollaron fueron todos del tupo adenocarcinoma papilífero. Los receptores hormonales estrogénicos fueron positivos. El estudio por microscopia electrónica mostró vacuolas acuosas grasosas en el citoplasma y la falta de organoides y mitocondrias en algunas células. Los lotes que recibieron tamoxifeno (F-G) no desarrollaron tumores

Tamoxifeno como supresor de la carcinogenesis mamaria inducida por 7,12-dimetil-benzoantraceno y nitroso-metilurea, en ratas hembras con hiperprolactinemia provocada / Tamoxifen as a suppressor of mammary carcinogenesis induced by 7,12-dimetil-benzanthracene and methylnitrosourea, in female rats with induced hyperprolactinemia

El efecto del tamoxifeno sobre tumores mamarios inducidos con DMBA (7, 12-dimetil-benzoantraceno) y NMU (nitroso-metilurea) se analiza. De 7 lotes de ratas Sprague-Dayley, 4 (A-B-C-D) reciben adiconalmene sulpirida 0,5 mg/100g durante 5 días de la semana y hasta finalizar el experimento. Dos lotes (C-D) recibieron una sola inyección intraperitoneal de 900 microcuries por 100g de peso de I. Tres lotes (E-F-G) recibieron sólo I para activar secreción de prolactina, y de ellos, 2(F-G)recibieron tamoxifeno. Los tumores que se desarrollaron fueron todos del tupo adenocarcinoma papilífero. Los receptores hormonales estrogénicos fueron positivos. El estudio por microscopia electrónica mostró vacuolas acuosas grasosas en el citoplasma y la falta de organoides y mitocondrias en algunas células. Los lotes que recibieron tamoxifeno (F-G) no desarrollaron tumores (AU)