慢性萎缩性胃炎及胃癌前病变动物模型的总结应用与评述
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摘要
胃癌是目前在全球范围中发病率和死亡率较高的一种疾病,也是在全球医学界作为重点关注的疾病。胃癌的发生是一个多重阶段、多重因素的过程。大量流行病学、病理学和临床证据证实,慢性萎缩性胃炎(chronic atrophic gastritis,CAG)患者的胃癌罹患风险增高,CAG的患病率与胃癌死亡率高度相关。胃黏膜萎缩和肠上皮化生(特别是不完全型结肠化生)及异型增生是胃癌的癌前病变(precancerous lesions of gastric cancer,PLGC)的主要阶段。对CAG患者尤其是伴有肠化和异型增生者进行病情监测,对于早期胃癌的发现意义重大。CAG与PLGC作为在胃癌发生过程中的重要病理阶段意义非凡,近年来与此相关的深入临床及实验研究越来越多。迄今为止,动物实验是CAG与PLGC疾病实验方向的主要研究途径,所以造模方法的探索显得尤为关键,选择一个稳定可靠的模型是研究动物实验的首要因素。鉴于两种疾病的关联性,本文总结了近年来CAG与PLGC动物模型的建立方法,大致分为化学药物诱变法、物理方式刺激法、免疫造模法、幽门螺杆菌感染复制法以及手术造模法,对各种方法在之前实验中的应用分别举例,并加以笔者后续探索而且已经成功的实验造模方法,同时对各种方法的优缺点做简要评述,为今后CAG与PLGC实验中动物模型的建立和应用提供一定的参考。
Gastric cancer is a disease with high morbidity and mortality in the world,and also obtains attention in the global medicine. The occurrence of gastric cancer is a multi-stage and multi-factor process. A large number of epidemiological,pathological and clinical evidences have confirmed that the risk of gastric cancer in patients with chronic atrophic gastritis( CAG) is significantly correlated with the mortality of gastric cancer. Gastric mucosal atrophy,intestinal metaplasia( especially incomplete colonic metaplasia) and dysplasia are the main stages of precancerous lesions of precancerous lesions of gastric cancer( PLGC). Monitoring the condition of CAG patients,especially those with intestinal metaplasia and dysplasia,is of great significance for the discovery of early gastric cancer. CAG and PLGC are great significance in the pathological stage of gastric carcinogenesis. In recent years,more and more in-depth clinical and experimental studies have been carried out in this direction. So far,animal experiment is the main research way for CAG and PLGC disease,so it is very important to explore the modeling method. Choosing a stable and reliable model is the primary factor to study animal experiment. In view of the relationship between two diseases,this paper will summarize the methods of establishing animal models for CAG and PLGC in recent years, generally including chemical drug mutagenesis, physical stimulation, immune modeling,Helicobacter pylori infection replication and surgical modeling. Examples would be given for the application of various methods in the previous experiments,and the author would make a brief comment on the merits and demerits of these methods,which have been explored and successfully made by the author. This study would provide certain reference for the establishment and application of animal models in further CAG and PLGC experiments.
Gastric cancer is a disease with high morbidity and mortality in the world,and also obtains attention in the global medicine. The occurrence of gastric cancer is a multi-stage and multi-factor process. A large number of epidemiological,pathological and clinical evidences have confirmed that the risk of gastric cancer in patients with chronic atrophic gastritis( CAG) is significantly correlated with the mortality of gastric cancer. Gastric mucosal atrophy,intestinal metaplasia( especially incomplete colonic metaplasia) and dysplasia are the main stages of precancerous lesions of precancerous lesions of gastric cancer( PLGC). Monitoring the condition of CAG patients,especially those with intestinal metaplasia and dysplasia,is of great significance for the discovery of early gastric cancer. CAG and PLGC are great significance in the pathological stage of gastric carcinogenesis. In recent years,more and more in-depth clinical and experimental studies have been carried out in this direction. So far,animal experiment is the main research way for CAG and PLGC disease,so it is very important to explore the modeling method. Choosing a stable and reliable model is the primary factor to study animal experiment. In view of the relationship between two diseases,this paper will summarize the methods of establishing animal models for CAG and PLGC in recent years, generally including chemical drug mutagenesis, physical stimulation, immune modeling,Helicobacter pylori infection replication and surgical modeling. Examples would be given for the application of various methods in the previous experiments,and the author would make a brief comment on the merits and demerits of these methods,which have been explored and successfully made by the author. This study would provide certain reference for the establishment and application of animal models in further CAG and PLGC experiments.
引文
[1] Kuper H,Adami H O,Trichopoulos D. Infections as a major preventable cause of human cancer[J]. J Intern Med,2000,248(3):171-183.
[2] National Office for Cancer Prevention and Control.China report on cancer mortality-the third national sampling retrospective death survey[M]. Beijing:Peking Union Medical College Press,2010:52-62.
[3]张玉峰,刘新爱,叶坤英,等.参枳消萎汤对慢性萎缩性胃炎癌前病(肝胃气滞证)变转归的影响[J].中国实验方剂学杂志,2016,22(4):174-177.
[4] Park Y H,Kim N. Review of atrophic gastritis and intestinal metaplasia as a premalignant lesion of gastric cancer[J]. J Cancer Prev,2015,20(1):25-40.
[5]房静远,刘文忠,李兆申,等.中国慢性胃炎共识意见[J].现代消化及介入诊疗,2013,18(2):119-128.
[6] Che T C H,Fran9ois S,Bouchet S,et al. Early lesions induced in rat colon epithelium by N-methyl-N'-nitro-Nnitrosoguanidine[J]. Tissue Cell, 2010, 42(3):190-194.
[7]陈曦,赵亚红,张也青,等.胃复春的临床应用和现代研究进展[J].江西中医药,2016,47(9):77-80.
[8] LUO C, WU X G. Lycopene enhances antioxidant enzyme activities and immunity function in N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric cancer rats[J].Int J Mol Sci,2011,12(12):3340-3351.
[9] ZHU X,LIU S,ZHOU J,et al. Effect of astragalus polysaccharides on chronic atrophic gastritis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats[J]. Drug Res,2013,63(11):597-602.
[10]许伟光.加味生胃方治疗慢性萎缩性胃炎的临床观察与实验研究[D].广州:广州中医药大学,2016:25-26.
[11]刘更.低浓度MNNG激活内质网应激及其对表皮生长因子受体通路的影响[D].杭州:浙江大学,2005:14-16.
[12]袁孝兵.大鼠胃癌前病变模型的研究进展[J].安徽中医学院学报,2004,23(5):62-64.
[13] WANG X Y,WANG L L,ZHENG X,et al. Expression of p-STAT3 and vascular endothelial growth factor in MNNG-induced precancerous lesions and gastric tumors in rats[J]. World J Gastrointest Oncol,2016,8(3):305-313.
[14]周晶,黄柳向,喻斌,等. MNNG诱导胃癌前病变模型的探讨[J].中国中西医结合消化杂志,2016,24(11):888-890.
[15] Kandasamy M, Rosskopf M, Wagner K, et al.Reduction in subventricular zone-derived olfactory bulb neurogenesis in a rat model of Huntington's disease is accompanied by striatal invasion of neuroblasts[J].PLo S One,2015,10(2):e0116069.
[16]陈小野,邹世洁,佟彤,等.大鼠CAG证病结合模型胃黏膜病理研究[J].中医药学刊,2002,20(3):292-295.
[17] SHEN S,YUWEN Y,ZHANG Z,et al. Effect of Jinguo Weikang capsule on proto-oncogene expression of gastric mucosa in rats with gastric precancerous lesions[J]. Chin J Integr Med,2008,14(3):212-216.
[18] YANG Z, WANG C, CHEN J, et al. Effects of moxibustion on cell proliferative factors in gastric mucosa in rats with precancerous lesions of chronic atrophic gastritis[J]. Chinese Acupun Mox,2015,35(12):1269-1273.
[19] Uchiyama S, Saeki N, Ogawa K. Aberrant Eph B/ephrin-B expression in experimental gastric lesions and tumor cells[J]. World J Gastroenterol,2015,21(2):452-464.
[20]朱晓玲.氨水对大白鼠胃黏膜长期作用的组织学变化[J].中华消化杂志,1990,10(4):198-201.
[21] Tsukamoto T, Mizoshita T, Tatematsu M. Animal models of stomach carcinogenesis[J]. Toxicol Pathol,2007,35(5):636-648.
[22] ZHANG H, DING C, SUO Z, et al. Effect of Helicobacter pylori on cyclooxygenase-2 and inducible nitric oxide synthase in patients with gastric precancerous lesions and its clinical significance[J].Exp Ther Med,2015,9(6):2364-2368.
[23] Valenzuela M A,Canales J,Corvalán A H,et al.Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis[J]. World J Gastroenterol,2015,21(45):12742-12756.
[24]李俊青,李纯,刘希,等.参七消痞颗粒对慢性萎缩性胃炎大鼠血清GH,EGF,GAS的影响[J].中国实验方剂学杂志,2013,19(12):172-175.
[25] Den Hollander W J, Kuipers E J. Current pharmacotherapy options for gastritis[J]. Expert Opin Pharmacother,2012,13(18):2625-2636.
[26]宋春红,王海苹,宫明华,等.坐珠达西对MNNG致大鼠慢性萎缩性胃炎的作用[J].中国实验方剂学杂志,2014,20(20):142-144.
[27] XIE J R,SUN F,LIANG G Y. Effects of xinwei granule on STAT3 and p-STAT3 signal pathway in rats with precancerous lesion of gastric cancer[J]. Chin J Integr Trad West Med,2013,33(1):65-70.
[28]罗伟,刘春雷,王军英,等.针刺与智能通络治疗仪联合应用对慢性萎缩性胃炎大鼠胃电节律及胃黏膜组织前列腺素E2、前列腺素F2α的影响[J].针刺研究,2014,39(6):482-486.
[29]范英昌,张斌,胡利明,等.大鼠脾气虚型慢性萎缩性胃炎动物模型的实验研究——胃黏膜病理形态及超微结构改变的研究[J].天津医药,1994,22(2):86-88.
[30]邵雪辉,王建国,戴杰,等.大鼠慢性萎缩性胃炎模型的建立[J].张家口医学院学报,2002,19(2):11-13.
[31]周杰.黄芪多糖治疗慢性萎缩性胃炎和胃癌癌前病变的机制研究[D].南京:南京中医药大学,2013:4-7.
[32]金东明,吴巍,孙树权,等.改良半夏泻心汤治疗慢性萎缩性胃炎实验研究[J].长春中医学院学报,2001,17(3):41-42.
[33]李兆申,全山丛.综合法制作大鼠萎缩性胃炎模型的实验研究[J].中华医学杂志,1992,72(2):81-83.
[34]张淑芹,赵林山,郑继奎,等.慢性萎缩性胃炎动物模型的复制[J].哈尔滨师范大学:自然科学学报,2001,17(6):81-83.
[35]赵敏,张占海,危北海,等.胃安素防治慢性萎缩性胃炎及胃癌前病变的实验病理研究[J].中国中西医结合脾胃杂志,1996,4(4):225-229.
[36]姚永莉.幽门螺杆菌感染与胃癌形成的动物实验研究[D].北京:第一军医大学南方医院全军消化内科研究所,2001.
[37]孟捷.慢性萎缩性胃炎证候规律探讨和消痞颗粒治疗慢性萎缩性胃炎癌前病变的机理研究[D].北京:北京中医药大学,2005.
[38] PENG L, XIE Y, WANG C, et al. Moxibustion alleviates gastric precancerous lesions in rats by promoting cell apoptosis and inhibiting proliferationrelated oncogenes[J]. Afr J Tradit Complement Altern Med,2017,14(2):148-160.
[39] JIANG X Y, QIAN L P, ZHENG X J, et al.Interventional effect of Ginkgo biloba extract on the progression of gastric precancerous lesions in rats[J]. J Dig Dis,2009,10(4):293-299.
[40]李美丽,朱西杰,李卫强,等.复方蜥蜴散不同微粒组合剂对胃癌前病变模型大鼠Bcl-2和Survivin表达的影响[J].中国实验方剂学杂志,2014,20(15):150-153.
[41]谢晶日,王业莉,张扬,等.复合造模法建立大鼠胃癌前病变模型的实验研究[J].中华中医药学刊,2013,31(11):2341-2342.
[42]李岩.中药不同组方对胃癌前病变模型大鼠胃黏膜组织细胞凋亡的影响[D].沈阳:辽宁中医药大学,2010.
[43]孙丽群.加味左金丸治疗大鼠胃癌前病变的实验研究和机理探讨[D].武汉:湖北中医学院,2005:28-29.
[44]谢晶日,孙芳,梁国英.胃癌前病变动物模型的研究进展[J].中华中医药学刊,2012,30(11):2377-2379.
[45]蒋时红,刘旺根,张文娴,等. 3种中医治法对胃癌前病变大鼠胃黏膜细胞增殖的影响[J].中华中医药杂志,2011,26(10):2423-2425.
[46]魏玥,杨晋翔,杨会敏,等.益气化瘀解毒法对慢性萎缩性胃炎伴异型增生大鼠干预的实验研究[J].胃肠病学和肝病学杂志,2011,20(10):916-919.
[47] Watanabe H. Experimentally induced intestinal metaplasia in Wistar rats by X-ray irradiation[J].Gastroenterology,1978,75(5):796-799.
[48]蔺焕萍,王小平,付倩,等.参佛胃康对大鼠慢性萎缩性胃炎及胃癌前病变逆转作用的研究[J].现代肿瘤医学,2012,20(2):266-269.
[49]王睿斌.幽门螺杆菌感染与胃癌前病变及胃癌形成的关系动物试验研究[D].长春:吉林大学,2004:44-46.
[50] SHI X Y, ZHAO F Z, DAI X, et al. Effect of jianpiyiwei capsule on gastric precancerous lesions in rats[J]. World J Gastroenterol, 2002, 8(4):608-612.
[51]高绍芳,王彦刚,李佃贵,等.化浊解毒和胃方对胃癌前病变大鼠血管生成机制的影响[J].中国中西医结合杂志,2013,33(11):1515-1519.
[2] National Office for Cancer Prevention and Control.China report on cancer mortality-the third national sampling retrospective death survey[M]. Beijing:Peking Union Medical College Press,2010:52-62.
[3]张玉峰,刘新爱,叶坤英,等.参枳消萎汤对慢性萎缩性胃炎癌前病(肝胃气滞证)变转归的影响[J].中国实验方剂学杂志,2016,22(4):174-177.
[4] Park Y H,Kim N. Review of atrophic gastritis and intestinal metaplasia as a premalignant lesion of gastric cancer[J]. J Cancer Prev,2015,20(1):25-40.
[5]房静远,刘文忠,李兆申,等.中国慢性胃炎共识意见[J].现代消化及介入诊疗,2013,18(2):119-128.
[6] Che T C H,Fran9ois S,Bouchet S,et al. Early lesions induced in rat colon epithelium by N-methyl-N'-nitro-Nnitrosoguanidine[J]. Tissue Cell, 2010, 42(3):190-194.
[7]陈曦,赵亚红,张也青,等.胃复春的临床应用和现代研究进展[J].江西中医药,2016,47(9):77-80.
[8] LUO C, WU X G. Lycopene enhances antioxidant enzyme activities and immunity function in N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric cancer rats[J].Int J Mol Sci,2011,12(12):3340-3351.
[9] ZHU X,LIU S,ZHOU J,et al. Effect of astragalus polysaccharides on chronic atrophic gastritis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats[J]. Drug Res,2013,63(11):597-602.
[10]许伟光.加味生胃方治疗慢性萎缩性胃炎的临床观察与实验研究[D].广州:广州中医药大学,2016:25-26.
[11]刘更.低浓度MNNG激活内质网应激及其对表皮生长因子受体通路的影响[D].杭州:浙江大学,2005:14-16.
[12]袁孝兵.大鼠胃癌前病变模型的研究进展[J].安徽中医学院学报,2004,23(5):62-64.
[13] WANG X Y,WANG L L,ZHENG X,et al. Expression of p-STAT3 and vascular endothelial growth factor in MNNG-induced precancerous lesions and gastric tumors in rats[J]. World J Gastrointest Oncol,2016,8(3):305-313.
[14]周晶,黄柳向,喻斌,等. MNNG诱导胃癌前病变模型的探讨[J].中国中西医结合消化杂志,2016,24(11):888-890.
[15] Kandasamy M, Rosskopf M, Wagner K, et al.Reduction in subventricular zone-derived olfactory bulb neurogenesis in a rat model of Huntington's disease is accompanied by striatal invasion of neuroblasts[J].PLo S One,2015,10(2):e0116069.
[16]陈小野,邹世洁,佟彤,等.大鼠CAG证病结合模型胃黏膜病理研究[J].中医药学刊,2002,20(3):292-295.
[17] SHEN S,YUWEN Y,ZHANG Z,et al. Effect of Jinguo Weikang capsule on proto-oncogene expression of gastric mucosa in rats with gastric precancerous lesions[J]. Chin J Integr Med,2008,14(3):212-216.
[18] YANG Z, WANG C, CHEN J, et al. Effects of moxibustion on cell proliferative factors in gastric mucosa in rats with precancerous lesions of chronic atrophic gastritis[J]. Chinese Acupun Mox,2015,35(12):1269-1273.
[19] Uchiyama S, Saeki N, Ogawa K. Aberrant Eph B/ephrin-B expression in experimental gastric lesions and tumor cells[J]. World J Gastroenterol,2015,21(2):452-464.
[20]朱晓玲.氨水对大白鼠胃黏膜长期作用的组织学变化[J].中华消化杂志,1990,10(4):198-201.
[21] Tsukamoto T, Mizoshita T, Tatematsu M. Animal models of stomach carcinogenesis[J]. Toxicol Pathol,2007,35(5):636-648.
[22] ZHANG H, DING C, SUO Z, et al. Effect of Helicobacter pylori on cyclooxygenase-2 and inducible nitric oxide synthase in patients with gastric precancerous lesions and its clinical significance[J].Exp Ther Med,2015,9(6):2364-2368.
[23] Valenzuela M A,Canales J,Corvalán A H,et al.Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis[J]. World J Gastroenterol,2015,21(45):12742-12756.
[24]李俊青,李纯,刘希,等.参七消痞颗粒对慢性萎缩性胃炎大鼠血清GH,EGF,GAS的影响[J].中国实验方剂学杂志,2013,19(12):172-175.
[25] Den Hollander W J, Kuipers E J. Current pharmacotherapy options for gastritis[J]. Expert Opin Pharmacother,2012,13(18):2625-2636.
[26]宋春红,王海苹,宫明华,等.坐珠达西对MNNG致大鼠慢性萎缩性胃炎的作用[J].中国实验方剂学杂志,2014,20(20):142-144.
[27] XIE J R,SUN F,LIANG G Y. Effects of xinwei granule on STAT3 and p-STAT3 signal pathway in rats with precancerous lesion of gastric cancer[J]. Chin J Integr Trad West Med,2013,33(1):65-70.
[28]罗伟,刘春雷,王军英,等.针刺与智能通络治疗仪联合应用对慢性萎缩性胃炎大鼠胃电节律及胃黏膜组织前列腺素E2、前列腺素F2α的影响[J].针刺研究,2014,39(6):482-486.
[29]范英昌,张斌,胡利明,等.大鼠脾气虚型慢性萎缩性胃炎动物模型的实验研究——胃黏膜病理形态及超微结构改变的研究[J].天津医药,1994,22(2):86-88.
[30]邵雪辉,王建国,戴杰,等.大鼠慢性萎缩性胃炎模型的建立[J].张家口医学院学报,2002,19(2):11-13.
[31]周杰.黄芪多糖治疗慢性萎缩性胃炎和胃癌癌前病变的机制研究[D].南京:南京中医药大学,2013:4-7.
[32]金东明,吴巍,孙树权,等.改良半夏泻心汤治疗慢性萎缩性胃炎实验研究[J].长春中医学院学报,2001,17(3):41-42.
[33]李兆申,全山丛.综合法制作大鼠萎缩性胃炎模型的实验研究[J].中华医学杂志,1992,72(2):81-83.
[34]张淑芹,赵林山,郑继奎,等.慢性萎缩性胃炎动物模型的复制[J].哈尔滨师范大学:自然科学学报,2001,17(6):81-83.
[35]赵敏,张占海,危北海,等.胃安素防治慢性萎缩性胃炎及胃癌前病变的实验病理研究[J].中国中西医结合脾胃杂志,1996,4(4):225-229.
[36]姚永莉.幽门螺杆菌感染与胃癌形成的动物实验研究[D].北京:第一军医大学南方医院全军消化内科研究所,2001.
[37]孟捷.慢性萎缩性胃炎证候规律探讨和消痞颗粒治疗慢性萎缩性胃炎癌前病变的机理研究[D].北京:北京中医药大学,2005.
[38] PENG L, XIE Y, WANG C, et al. Moxibustion alleviates gastric precancerous lesions in rats by promoting cell apoptosis and inhibiting proliferationrelated oncogenes[J]. Afr J Tradit Complement Altern Med,2017,14(2):148-160.
[39] JIANG X Y, QIAN L P, ZHENG X J, et al.Interventional effect of Ginkgo biloba extract on the progression of gastric precancerous lesions in rats[J]. J Dig Dis,2009,10(4):293-299.
[40]李美丽,朱西杰,李卫强,等.复方蜥蜴散不同微粒组合剂对胃癌前病变模型大鼠Bcl-2和Survivin表达的影响[J].中国实验方剂学杂志,2014,20(15):150-153.
[41]谢晶日,王业莉,张扬,等.复合造模法建立大鼠胃癌前病变模型的实验研究[J].中华中医药学刊,2013,31(11):2341-2342.
[42]李岩.中药不同组方对胃癌前病变模型大鼠胃黏膜组织细胞凋亡的影响[D].沈阳:辽宁中医药大学,2010.
[43]孙丽群.加味左金丸治疗大鼠胃癌前病变的实验研究和机理探讨[D].武汉:湖北中医学院,2005:28-29.
[44]谢晶日,孙芳,梁国英.胃癌前病变动物模型的研究进展[J].中华中医药学刊,2012,30(11):2377-2379.
[45]蒋时红,刘旺根,张文娴,等. 3种中医治法对胃癌前病变大鼠胃黏膜细胞增殖的影响[J].中华中医药杂志,2011,26(10):2423-2425.
[46]魏玥,杨晋翔,杨会敏,等.益气化瘀解毒法对慢性萎缩性胃炎伴异型增生大鼠干预的实验研究[J].胃肠病学和肝病学杂志,2011,20(10):916-919.
[47] Watanabe H. Experimentally induced intestinal metaplasia in Wistar rats by X-ray irradiation[J].Gastroenterology,1978,75(5):796-799.
[48]蔺焕萍,王小平,付倩,等.参佛胃康对大鼠慢性萎缩性胃炎及胃癌前病变逆转作用的研究[J].现代肿瘤医学,2012,20(2):266-269.
[49]王睿斌.幽门螺杆菌感染与胃癌前病变及胃癌形成的关系动物试验研究[D].长春:吉林大学,2004:44-46.
[50] SHI X Y, ZHAO F Z, DAI X, et al. Effect of jianpiyiwei capsule on gastric precancerous lesions in rats[J]. World J Gastroenterol, 2002, 8(4):608-612.
[51]高绍芳,王彦刚,李佃贵,等.化浊解毒和胃方对胃癌前病变大鼠血管生成机制的影响[J].中国中西医结合杂志,2013,33(11):1515-1519.