title: Different Susceptibilities between Apoe- and Ldlr-Deficient Mice to Inflammation-Associated Colorectal Carcinogenesis.
abstract: Hypercholesterolemia resulting in atherosclerosis is associated with an increased risk of ischemic heart disease and colorectal cancer (CRC). However, the roles of apoliprotein (Apo) E (Apoe) and low-density lipoprotein (Ldl) receptor (Ldlr) in colorectal carcinogenesis have not yet been investigated. In this study, we examined the susceptibility ofApoe-deficient andLdlr-deficient mice, which are genetic animal models of atherosclerosis to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. In Experiment 1, maleApoe-deficient (n= 20) and wild type (WT) mice (C57BL/6J,n= 21) were treated with a single intraperitoneal (i.p.) injection of AOM (10 mg/kg body weight) and then given 1.5% DSS in drinking water for seven days. They were maintained up to week 20 and sacrificed for the histopathological examination of colorectal tumors. The mRNA expression of cyclooxygenase (Cox)-2, inducible nitric oxide synthase (Nos2), tumor necrosis factor (Tnf)-αinterleukin (Il)-1β, andIl-6was assayed in the colorectal mucosa. In Experiment 2, maleLdlr-deficient (n= 14) and WT mice (C57BL/6J,n= 10) were given a single i.p. injection of AOM (10 mg/kg body weight) and then given 2% DSS in drinking water for seven days. They were sacrificed at week 20 to evaluate their colorectum histopathologically. In Experiment 1, the multiplicity of CRCs was significantly higher in theApoe-deficient mice (2.75 ± 1.48) than in the WT mice (0.62 ± 0.67). The serum lipoprotein levels in theApoe-deficient mice were also significantly higher than in the WT mice. In Experiment 2, the incidence (29%) and multiplicity (0.50 ± 0.94) of CRCs in theLdlrmice were significantly lower than in the WT mice (80% incidence and 3.10 ± 2.38 multiplicity). The mRNA expression of two inducible enzymes and certain pro-inflammatory cytokines in the colorectum of each genotype was greater than in the respective WT mice. The values in theApoe-deficient mice were much greater than in theLdlrmice. These findings suggest thatApoe-deficient mice showed increased susceptibility to inflammation-associated colorectal carcinogenesis due to their high reactivity to inflammatory stimuli.
authors: Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu City, Gifu 500-8513, Japan. takutt@gmhosp.gifu.gifu.jp.|Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan. takutt@gmhosp.gifu.gifu.jp.
authors: Takuji
authors: T
authors: Tanaka
authors: Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan. takeruoyama@staff.kanazawa-u.ac.jp.
authors: Takeru
authors: T
authors: Oyama
authors: Department of Pathology, Murakami Memorial Hospital, Asahi University, School of Dentistry, 3-23 Hashimoto-cho, Gifu City, Gifu 500-8523, Japan. sugie@murakami.asahi-u.ac.jp.
authors: Shigeyuki
authors: S
authors: Sugie
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan. shimim-gif@umin.ac.jp.
authors: Masahito
authors: M
authors: Shimizu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D001397:Azoxymethane / Q000633:toxicity; D063646:Carcinogenesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D001057:Apolipoproteins E; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008074:Lipoproteins; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D001397:Azoxymethane
keywords: Apoe; Ldl receptor; colorectal carcinogenesis; genetically altered mice; inflammation; serum lipid profiles