通过AOM及AOM联合DSS建立C57BL/6J小鼠结肠癌诱导模型的对比研究
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摘要
目的探讨使用氧化偶氮甲烷(AOM)及AOM联合葡聚糖硫酸钠(DSS)中不同药物剂量、给药周期及暴露时间对C57BL/6J小鼠建立结肠癌诱导模型效果的影响。方法分别予低、中、高浓度AOM(10、15、20 mg/kg,每周1次,共4周,每组24只,AOM对照组24只)或AOM(10 mg/kg)联合DSS(一、二、三循环,小鼠数量分别为50、41、29只,DSS对照组40只)干预,对给药后不同时间点处死的小鼠结直肠进行大体与组织病理学评估。结果单独使用AOM可使小鼠结肠产生异常隐窝灶(ACF),随着AOM药物浓度和(或)暴露时间增加,ACF数量显著增加(P均<0. 05)。AOM联合DSS可使小鼠结肠形成腺瘤伴高级别上皮内瘤变,相比DSS一循环,DSS二、三循环可显著增加肿瘤发生率、平均成瘤数量、荷瘤小鼠平均成瘤数量及肿瘤体积(P均<0. 05或0. 008)。结论C57BL/6J小鼠结直肠ACF随AOM给药浓度及暴露天数增加而增加,AOM联合DSS可加快结直肠癌模型的发生,增加DSS循环可增加成瘤效率。
Objective To evaluate the effect of drug dose,cycle of drug administration and exposure time between azoxymethane( AOM) and AOM combined with dextran sodium sulfate( DSS) in the establishment of C57 BL/6 J mouse models with colonic carcinogenesis. Methods Mice were treated with subcutaneous administration of 10,15 or 20 mg/kg AOM once a week for 4 weeks( n = 24 for each dose group and control group),or with 10 mg/kg AOM followed by one,two,or three cycles of 2% DSS administration( n = 50,41 and 29 for each cycle group,and n = 24 for control group). The colon tissues were collected at different time points after drug administration for gross and histopathological examinations. Results Single use of AOM could yield aberrant crypt foci( ACF). The quantity of ACF was significantly increased along with the increasing AOM concentration and/or exposure time( all P < 0. 05). Adenomas with high-grade intraepithelial neoplasia were induced in mice treated with AOM in combination with DSS. Two or three cycles of DSS could significantly enhance the incidence of tumor,average quantity of tumor,average quantity of tumor in tumor-bearing mouse and average tumor volume compared with one cycle of DSS after AOM injection( all P < 0. 05 or 0. 008).Conclusions The quantity of colonic ACF is increased over the increasing AOM concentration and exposure time in C57 BL/6 J mice. Administration of AOM combined with DSS can accelerate the colonic carcinogenesis.Increasing the DSS cycle can enhance the efficiency of colonic carcinogenesis.
Objective To evaluate the effect of drug dose,cycle of drug administration and exposure time between azoxymethane( AOM) and AOM combined with dextran sodium sulfate( DSS) in the establishment of C57 BL/6 J mouse models with colonic carcinogenesis. Methods Mice were treated with subcutaneous administration of 10,15 or 20 mg/kg AOM once a week for 4 weeks( n = 24 for each dose group and control group),or with 10 mg/kg AOM followed by one,two,or three cycles of 2% DSS administration( n = 50,41 and 29 for each cycle group,and n = 24 for control group). The colon tissues were collected at different time points after drug administration for gross and histopathological examinations. Results Single use of AOM could yield aberrant crypt foci( ACF). The quantity of ACF was significantly increased along with the increasing AOM concentration and/or exposure time( all P < 0. 05). Adenomas with high-grade intraepithelial neoplasia were induced in mice treated with AOM in combination with DSS. Two or three cycles of DSS could significantly enhance the incidence of tumor,average quantity of tumor,average quantity of tumor in tumor-bearing mouse and average tumor volume compared with one cycle of DSS after AOM injection( all P < 0. 05 or 0. 008).Conclusions The quantity of colonic ACF is increased over the increasing AOM concentration and exposure time in C57 BL/6 J mice. Administration of AOM combined with DSS can accelerate the colonic carcinogenesis.Increasing the DSS cycle can enhance the efficiency of colonic carcinogenesis.
引文
[1] De Robertis M,Massi E,Poeta ML,Carotti S,Morini S,Cecchetelli L,Signori E,Fazio VM. The AOM/DSS murine model for the study of colon carcinogenesis:from pathways to diagnosis and therapy studies. J Carcinog,2011,10:9.
[2] Zheng R,Zeng H,Zhang S,Chen T,Chen W. National estimates of cancer prevalence in China,2011. Cancer Lett,2016,370(1):33-38.
[3]吕愈敏.大肠癌癌前病变研究进展.新医学,2003,34(7):405-407.
[4] Bissahoyo A,Pearsall RS,Hanlon K,Amann V,Hicks D,Godfrey VL,Threadgill DW. Azoxymethane is a genetic backgrounddependent colorectal tumor initiator and promoter in mice:effects of dose,route,and diet. Toxicol Sci,2005,88(2):340-345.
[5] Johnson RL,Fleet JC. Animal models of colorectal cancer.Cancer Metastasis Rev,2013,32(1-2):39-61.
[6] Hata K,Kubota M,Shimizu M,Moriwaki H,Kuno T,Tanaka T,Hara A,Hirose Y. Monosodium glutamate-induced diabetic mice are susceptible to azoxymethane-induced colon tumorigenesis. Carcinogenesis,2012,33(3):702-707.
[7] Saxena A,Shoeb M,Tammali R,Ramana KV,Srivastava SK.Aldose reductase inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL/Ks J-db/db mice. Cancer Lett,2014,355(1):141-147.
[8] Greten FR,Eckmann L,Greten TF,Park JM,Li ZW,Egan LJ,Kagnoff MF,Karin M. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell,2004,118(3):285-296.
[9] Tanaka T,Kohno H,Suzuki R,Yamada Y,Sugie S,Mori H. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci,2003,94(11):965-973.
[10] Neufert C,Becker C,Neurath MF. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat Protoc,2007,2(8):1998-2004.
[11]王磊,宋顺心,汪建平.结直肠癌实验研究现状及展望.中华实验外科杂志,2013,30(3):429-430.
[12]房静远.关注结直肠腺瘤的诊治研究.中华消化杂志,2010,30(7):433-435.
[13] Suzuki R,Kohno H,Sugie S,Nakagama H,Tanaka T. Strain differences in the susceptibility to azoxymethane and dextran sodium sulfate-induced colon carcinogenesis in mice. Carcinogenesis,2006,27(1):162-169.
[14] Tanaka T. Colorectal carcinogenesis:review of human and experimental animal studies. J Carcinog,2009,8:5.
[15] Araki Y,Mukaisyo K,Sugihara H,Fujiyama Y,Hattori T. Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. Oncol Rep,2010,24(4):869-874.
[16] Corpet DE,TachéS. Most effective colon cancer chemopreventive agents in rats:a systematic review of aberrant crypt foci and tumor data,ranked by potency. Nutr Cancer,2002,43(1):1-21.
[17] Ochiai M,Hippo Y,Izumiya M,Watanabe M,Nakagama H.Newly defined aberrant crypt foci as a marker for dysplasia in the rat colon. Cancer Sci,2014,105(8):943-950.
[2] Zheng R,Zeng H,Zhang S,Chen T,Chen W. National estimates of cancer prevalence in China,2011. Cancer Lett,2016,370(1):33-38.
[3]吕愈敏.大肠癌癌前病变研究进展.新医学,2003,34(7):405-407.
[4] Bissahoyo A,Pearsall RS,Hanlon K,Amann V,Hicks D,Godfrey VL,Threadgill DW. Azoxymethane is a genetic backgrounddependent colorectal tumor initiator and promoter in mice:effects of dose,route,and diet. Toxicol Sci,2005,88(2):340-345.
[5] Johnson RL,Fleet JC. Animal models of colorectal cancer.Cancer Metastasis Rev,2013,32(1-2):39-61.
[6] Hata K,Kubota M,Shimizu M,Moriwaki H,Kuno T,Tanaka T,Hara A,Hirose Y. Monosodium glutamate-induced diabetic mice are susceptible to azoxymethane-induced colon tumorigenesis. Carcinogenesis,2012,33(3):702-707.
[7] Saxena A,Shoeb M,Tammali R,Ramana KV,Srivastava SK.Aldose reductase inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL/Ks J-db/db mice. Cancer Lett,2014,355(1):141-147.
[8] Greten FR,Eckmann L,Greten TF,Park JM,Li ZW,Egan LJ,Kagnoff MF,Karin M. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell,2004,118(3):285-296.
[9] Tanaka T,Kohno H,Suzuki R,Yamada Y,Sugie S,Mori H. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci,2003,94(11):965-973.
[10] Neufert C,Becker C,Neurath MF. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat Protoc,2007,2(8):1998-2004.
[11]王磊,宋顺心,汪建平.结直肠癌实验研究现状及展望.中华实验外科杂志,2013,30(3):429-430.
[12]房静远.关注结直肠腺瘤的诊治研究.中华消化杂志,2010,30(7):433-435.
[13] Suzuki R,Kohno H,Sugie S,Nakagama H,Tanaka T. Strain differences in the susceptibility to azoxymethane and dextran sodium sulfate-induced colon carcinogenesis in mice. Carcinogenesis,2006,27(1):162-169.
[14] Tanaka T. Colorectal carcinogenesis:review of human and experimental animal studies. J Carcinog,2009,8:5.
[15] Araki Y,Mukaisyo K,Sugihara H,Fujiyama Y,Hattori T. Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. Oncol Rep,2010,24(4):869-874.
[16] Corpet DE,TachéS. Most effective colon cancer chemopreventive agents in rats:a systematic review of aberrant crypt foci and tumor data,ranked by potency. Nutr Cancer,2002,43(1):1-21.
[17] Ochiai M,Hippo Y,Izumiya M,Watanabe M,Nakagama H.Newly defined aberrant crypt foci as a marker for dysplasia in the rat colon. Cancer Sci,2014,105(8):943-950.