Colorectal carcinoma development in inducible nitric oxide synthase‐deficient mice with dextran sulfate sodium‐induced ulcerative colitis

Molecular Carcinogenesis - Tập 46 Số 5 - Trang 341-353 - 2007
Darren N. Seril1, Jie Liao2, Guang‐Yu Yang2
1Department of Chemical Biology, Rutgers University, Piscataway, New Jersey
2Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Tóm tắt

AbstractThe overproduction of reactive oxygen and nitrogen species (RONS) may play an important role in ulcerative colitis (UC)‐associated carcinogenesis. In order to study the role of nitric oxide (NO) in UC‐associated colorectal carcinogenesis, the development of colorectal carcinoma was studied using the DSS‐induced and iron‐enhanced model of chronic UC in inducible nitric oxide synthase (iNOS)‐deficient mice. Female wild‐type C57BL/6 (iNOS+/+) and iNOS−/− mice were administered 1% DSS (w/v) through the drinking fluid for 15 DSS cycles and fed twofold iron‐enriched diet. Colorectal inflammation and mucosal ulceration of moderate severity were observed in both iNOS+/+ and iNOS−/− mice. Similar tumor incidence and multiplicity in the colon were observed that 15 out of 23 (65.2%) iNOS+/+ mice developed colorectal tumors with a tumor multiplicity of 1.47 ± 0.17 (mean ± SE) after 15 DSS cycles, and 13 out of 19 (68.4%) iNOS−/− mice developed colorectal tumors with a tumor multiplicity of 2.08 ± 0.21. Histopathologically, the tumors were confirmed to be well‐differentiated adenocarcinomas. Nitrotyrosine, an indicator of peroxynitrite‐caused protein modification, was detectable by immunohistochemistry in inflammatory cells and epithelial cells of the colon in iNOS+/+ and iNOS−/− mice, and no difference in staining intensity was observed between the two groups. Immunostaining for endothelial NOS (eNOS) was observed in lamina propria macrophages and colonic blood vessels, and eNOS protein levels were increased in the inflamed colon. These results show that there is no difference in UC‐associated cancer development in iNOS+/+ and iNOS−/− mice, and suggest that in the absence of iNOS, other factors, such as eNOS, may play a role in nitrosative stress and UC‐associated carcinogenesis in this model system. © 2006 Wiley‐Liss, Inc.

Từ khóa


Tài liệu tham khảo

10.1097/00000658-197812000-00018

10.3109/00365528708996463

10.1056/NEJM198706253162609

10.1056/NEJM199011013231802

10.1016/S0140-6736(94)92831-2

10.1016/0891-5849(92)90079-V

10.1016/0891-5849(95)94362-H

10.1023/A:1018849405922

10.1080/00365529850166897

10.1023/A:1018899222258

10.1093/carcin/19.5.711

10.1093/carcin/24.3.353

10.1016/S1054-3589(08)61081-9

10.1007/BF02388298

10.1007/BF02388303

10.1136/gut.36.5.718

10.1016/S0140-6736(95)90427-1

10.1016/S0016-5085(96)70055-0

10.1002/(SICI)1096-9896(199812)186:4<416::AID-PATH201>3.0.CO;2-U

10.1073/pnas.89.7.3030

10.1152/ajpgi.2001.281.3.G626

10.1053/gast.2001.20875

10.1016/S1567-5769(01)00102-3

Hussain SP, 1998, Molecular epidemiology of human cancer: Contribution of mutation spectra studies of tumor suppressor genes, Cancer Res, 58, 4023

Hussain SP, 2000, Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: A cancer‐prone chronic inflammatory disease, Cancer Res, 60, 3333

10.1016/0016-5085(90)90290-H

Hirono I, 1981, Induction of intestinal tumors in rats by dextran sulfate sodium, J Natl Cancer Inst, 66, 579

10.1136/gut.33.11.1521

10.1093/carcin/21.4.757

10.1023/A:1015362228659

10.1093/carcin/23.6.993

10.1073/pnas.92.23.10688

10.1152/ajpgi.1998.274.3.G544

10.1016/0016-5085(95)27512-6

Hogaboam CM, 1995, The selective beneficial effects of nitric oxide inhibition in experimental colitis, Am J Physiol, 268, G673

10.1136/gut.37.2.247

Mourelle M, 1996, Toxic dilatation of colon in a rat model of colitis is linked to an inducible form of nitric oxide synthase, Am J Physiol, 270, G425

10.1053/gast.1997.v112.pm9041266

10.1152/ajpgi.2000.279.1.G90

10.1136/gut.45.2.199

10.1046/j.1365-2036.2000.014s1026.x

10.1016/S0891-5849(01)00565-2

10.1016/S0014-2999(00)00926-2

10.1136/gut.45.6.864

10.1093/carcin/20.4.641

Ahn B, 2001, Suppression of intestinal polyposis in Apc(Min/+) mice by inhibiting nitric oxide production, Cancer Res, 61, 8357

10.1053/gast.2001.27994

Kisley LR, 2002, Genetic ablation of inducible nitric oxide synthase decreases mouse lung tumorigenesis, Cancer Res, 62, 6850

10.1152/ajprenal.2001.280.2.F193

10.1152/ajplung.1998.274.3.L360

10.1309/W7T9-HW9V-V94B-R9KM

10.1146/annurev.physiol.64.081501.155952

Wort SJ, 2001, Inducible nitric oxide synthase: A tissue‐specific affair?, Am J Physiol, 280, L387

10.1016/S0002-9440(10)65648-9

10.1073/pnas.93.23.13176

10.1152/ajpheart.1999.277.4.H1600

10.1016/S0008-6363(02)00287-0

10.1152/ajpheart.00383.2002

10.1002/path.1711710412

Thomsen LL, 1994, Nitric oxide synthase activity in human gynecological cancer, Cancer Res, 54, 1352

Cobbs CS, 1995, Expression of nitric oxide synthase in human central nervous system tumors, Cancer Res, 55, 727

10.1038/bjc.1995.274

Nakano S, 1996, Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide, Cancer Res, 56, 4027

Takahashi M, 1997, Increased expression of inducible and endothelial constitutive nitric oxide synthases in rat colon tumors induced by azoxymethane, Cancer Res, 57, 1233

Thông tin
Thông tin xuất bản

Molecular Carcinogenesis

Tập 46 Số 5

341-353

Thông tin tác giả