RESUMO
Animal models are important for the development of novel therapies for esophageal cancer. Histone deacetylase 1 (HDAC1)/metastasis-associated gene (MTA1) complexes inhibit p53 acetylation and thus, inhibit p53-induced apoptosis. The aim of the present study was to evaluate HDAC1 and MTA1 expression in esophageal carcinogenesis in rats. The rats underwent a total gastrectomy followed by esophagojejunostomy to induce chronic duodenal content reflux esophagitis. The rats were sacrificed sequentially at 20, 30, 40 and 50 weeks post-surgery and the esophagi were examined. Immunohistochemical analysis was conducted to assess the expression and localization of HDAC1 and MTA1. At 20 weeks post-surgery, squamous proliferative hyperplasia and Barrett's metaplasia (BM) were observed. While, adenocarcinoma-associated BM and squamous cell carcinoma were observed at 30-50 weeks post-surgery. The nuclear expression of HDAC1 and MTA1 was observed in all of the stages of squamous carcinogenesis and adenocarcinogenesis, although not in the normal esophageal epithelium. The expression of HDAC1 and MTA1 may be involved in duodenoesophageal reflux-induced neoplastic transformation of the esophageal mucosa into cancer cells with squamous and adeno differentiation.
RESUMO
BACKGROUND AND AIMS: Chronic inflammation has been demonstrated to correlate with tumor onset and progression. Tumor-associated macrophages (TAMs) play an important role in inflammatory tumor microenvironment. We hypothesized that an inflammatory microenvironment around TAMs may promote the development of esophageal carcinomas when induced by duodenal content reflux without carcinogens. ANIMALS AND METHODS: A total gastrectomy followed by esophagojejunostomy was performed on rats in order to induce chronic duodenal content reflux esophagitis. The animals were sacrificed sequentially, at the 20th, 30th, 40th and 50th week after surgery, and their esophagi were examined. The primary antibodies against CD68, CD163, pStat3 and Foxp3 were used. Expression and localization of infiltrated cells was assessed by immunohistochemical analysis. RESULTS: At 20-weeks' post-surgery, squamous proliferative hyperplasia (PHP) and Barrett's metaplasia (BM) were observed. Adenocarcinoma (ADC) associated with BM, and squamous cell carcinoma (SCC) were observed 30-50 weeks' post-surgery. Numerous CD68 and pStat3-positive cells were identified surrounding PHP and BM after 20 weeks, and around ADC and SCC after 30 weeks. Moderate infiltration of CD163-positive macrophages was seen with BM, ADC, and SCC after 30 weeks. However, very few Foxp3-positive cells were observed around ADC and SCC. CONCLUSION: Macrophages infiltrate the esophagus and activate the pStat3 pathway in stromal cells and epithelium. M2 phenotype macrophages infiltrate following infiltration of M1 macrophage and contribute to tumor development through regulatory T cells (Tregs). The involvement of immune cells such as TAMs and Tregs in the inflammatory microenvironment promotes esophageal carcinogenesis.
Assuntos
Adenocarcinoma/patologia , Carcinogênese/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Esofagite Péptica/patologia , Esôfago/patologia , Inflamação/patologia , Microambiente Tumoral , Adenocarcinoma/química , Animais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Esôfago de Barrett/patologia , Carcinogênese/química , Carcinoma de Células Escamosas/química , Modelos Animais de Doenças , Células Epiteliais/química , Neoplasias Esofágicas/química , Fatores de Transcrição Forkhead/análise , Gastrectomia , Macrófagos/química , Masculino , Metaplasia , Fosforilação , Ratos , Receptores de Superfície Celular/análise , Fator de Transcrição STAT3/análise , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células Estromais/química , Linfócitos T ReguladoresRESUMO
The incidence of esophageal cancer continues to rise in the Western world. Prior studies have suggested that gastroduodenal content reflux from gastroesophageal reflux disease induces the inflammation-mediated progression from hyperplasia to metaplasia, and to adenocarcinoma. We further investigated the sequential development of esophageal adenocarcinoma (EADC) with the use of an established surgical rat model. The present paper will describe the impact of the inflammation-metaplasia-adenocarcinoma sequence and chemoprevention in surgical rat models. A clinically relevant rat reflux model was used to investigate the cause of carcinogenesis, the sequential development of adenocarcinoma and chemoprevention with the use of a proton pump inhibitor. We found that duodenal reflux plays an important role in the inflammation-induced transformation of esophageal mucosa to adenocarcinoma. We were able to inhibit this transformation with rabeprazole, a proton pump inhibitor. Duodenal reflux promotes inflammation in the esophagus. The inflammation-metaplasia-adenocarcinoma sequence is important in the progression and development of EADC. Carcinogenesis can be prevented with chemoprevention agents such as rabeprazole. These results will need to be validated in clinical trials.
Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Esôfago/patologia , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Adenocarcinoma/fisiopatologia , Adenocarcinoma/prevenção & controle , Animais , Modelos Animais de Doenças , Progressão da Doença , Duodeno/fisiopatologia , Epitélio/patologia , Neoplasias Esofágicas/fisiopatologia , Neoplasias Esofágicas/prevenção & controle , Metaplasia , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Rabeprazol , RatosRESUMO
The mechanism through which each histological type of carcinoma arises from the esophageal mucosa remains unknown. This study was designed to investigate whether there is an association between the severity of duodeno-esophageal reflux and the histological type of esophageal cancer. A series of 120 male Fischer rats, weighing â¼180 g, were randomized to receive one of the following procedures: duodeno-forestomach reflux (DFR) with reduced exposure to duodenal contents, duodeno-esophageal reflux (DER) with increased exposure to duodenal contents and three control operations (DFR, DER control and sham). The reflux of bile was estimated with (99m)Tc-PMT scintigraphy. All animals were fed a standard diet without carcinogen. The esophageal mucosa was assessed 50 weeks after surgery for carcinoma. The median scanned fraction rate of duodeno-esophageal reflux was significantly lower for the rodents in the DFR group than those in the DER group. Five of 28 rodents in the DFR group and 17 of the 22 rodents in the DER group developed esophageal carcinoma. None of the controls developed carcinoma. The five rodents in the DFR group developed SCC. Of 22 esophageal carcinomas for the DER group, nine were SCC, 12 ADC and one was adenosquamous carcinoma. The fraction of esophageal SCC for the DFR group was significantly higher than that for the DER group, while the fraction of esophageal ADC for the DFR group was significantly lower than that for the DER group. These observations suggest that the severity of duodeno-esophageal reflux in rodents is related to the development of different histological types of esophageal carcinoma.
Assuntos
Adenocarcinoma/etiologia , Carcinoma Adenoescamoso/etiologia , Carcinoma de Células Escamosas/etiologia , Refluxo Duodenogástrico/complicações , Neoplasias Esofágicas/etiologia , Refluxo Gastroesofágico/complicações , Conteúdo Gastrointestinal , Adenocarcinoma/patologia , Animais , Carcinoma Adenoescamoso/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Masculino , Ratos , Ratos WistarRESUMO
Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation-metaplasia-dysplasia-adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett's esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents.
Assuntos
Adenocarcinoma/prevenção & controle , Antineoplásicos , Progressão da Doença , Neoplasias Esofágicas/prevenção & controle , Refluxo Gastroesofágico/complicações , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Adenocarcinoma/etiologia , Animais , Anti-Inflamatórios , Antioxidantes , Esôfago de Barrett/complicações , Esôfago de Barrett/tratamento farmacológico , Neoplasias Esofágicas/etiologia , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Fatores Imunológicos , Lansoprazol , Neutrófilos/imunologia , Omeprazol , Inibidores da Bomba de Prótons/efeitos adversos , RabeprazolRESUMO
BACKGROUND: The role of proton pump inhibitors in Barrett's metaplasia and esophageal adenocarcinoma has been an area of controversy. AIMS: We evaluated the effectiveness of the proton pump inhibitor rabeprazole as a chemoprevention agent in a surgical rat reflux model of esophageal cancer. METHODS: The rat reflux model was created by performing a jejuno-esophagostomy on Sprague-Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. Rabeprazole sodium (Eisai, Tokyo, Japan) was dissolved in 0.9% physiological saline to a desired concentration of 1.5% (W/V). Beginning 4 weeks post-surgery, all animals were administered either 0.2 ml per 100 g body weight injections of rabeprazole or equivalent injections of saline 3 days per week into the subcutaneous tissue of the back. Forty animals were killed 40 weeks after surgery and their esophagi were examined. Of these, 23 were included in the control group, while the remaining 17 were subjected to rabeprazole. RESULTS: While 74% (17/23) of the controls developed esophageal cancer, animals administered rabeprazole had an incidence of cancer of 29% (5/17) (p < 0.05, Fisher's exact test). Barrett's metaplasia was found on 100% (23/23) of the rats in the placebo group, but there was a protective effect in the rabeprazole group with 65% (11/17) of the rats displaying signs of Barrett's metaplasia (p < 0.05, Fisher's exact test). All of the rats developed proliferative hyperplasia. CONCLUSIONS: Rabeprazole protected against the development of esophageal cancer in a clinically relevant surgical reflux model. Rabeprazole warrants further investigation for potential clinical use as a chemoprevention agent.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Antiulcerosos/farmacologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/prevenção & controle , Refluxo Gastroesofágico/complicações , Animais , Neoplasias Esofágicas/mortalidade , Masculino , Rabeprazol , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: We developed and evaluated a GM-CSF whole-cell tumor vaccine for esophageal cancer. EXPERIMENTAL DESIGN: Cell lines derived from surgically induced rat reflux esophageal tumors were passaged in vitro and transfected with GM-CSF. First, the GM-CSF whole cell vaccine was evaluated against subcutaneously transplanted esophageal tumor cells. In a subsequent study, the vaccine was tested to see if it could reduce the incidence of cancer in the surgical reflux model. RESULTS: While subcutaneously transplanted tumor cells produced lasting tumors in PBS non-vaccinated placebo rats, transplanted tumors regressed and were immunologically rejected in animals vaccinated prior to implantation. In the surgical reflux model, the vaccine reduced the incidence of cancer from 17/23 (74%) in the controls to 6/16 (38%) in the vaccinated animals (P = 0.046). CONCLUSIONS: The GM-CSF whole cell tumor vaccine effectively promoted a strong immune response against subcutaneously transplanted tumors and protected animals from developing esophageal cancer in the reflux model.
Assuntos
Adenocarcinoma/prevenção & controle , Esôfago de Barrett/complicações , Vacinas Anticâncer/uso terapêutico , Neoplasias Esofágicas/prevenção & controle , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/patologia , Esofagite Péptica/complicações , Esofagostomia , Ratos , Ratos Sprague-Dawley , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND & AIMS: We developed a granulocyte-macrophage-colony-stimulating factor (GM-CSF) tumor vaccine for esophageal cancer. We evaluated the effectiveness of the vaccine as a prevention option in a surgical reflux rat model of esophageal cancer. METHODS: A surgical model involving a jejuno-esophagostomy was used to create Barrett's esophagus and esophageal cancer in rats. No carcinogen exposure was utilized. Cell lines derived from these tumors were stably passaged in vitro. GM-CSF-secreting tumor cells were generated using stable transfection. All rats underwent a total gastrectomy, followed by a jejuno-esophagostomy. The surgery promoted the reflux of duodenal contents into the esophagus. All animals were administered either a GM-CSF secreting whole cell vaccine or a phosphate-buffered saline (PBS) placebo injection 4, 6, 14, and 16 weeks post-surgery. RESULTS: While 15 of 16 animals in the non-vaccinated placebo group developed esophageal cancer, 94% (15 of 16), animals in the vaccine group had an incidence of cancer of 25% (4 of 16) (p<0.05). Barrett's esophagus was seen in 100% (16 of 16) of the controls and 83% (13 of 16) of the vaccinated animals. CONCLUSIONS: A GM-CSF-secreting whole cell tumor vaccine impeded esophageal tumor growth, but not the development of Barrett's esophagus, in a clinically relevant surgical reflux model.