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Takuji Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • use of a chemically induced Colon Carcinogenesis prone apc mutant rat in a chemotherapeutic bioassay
    BMC Cancer, 2012
    Co-Authors: Kazuto Yoshimi, Takuji Tanaka, Tadao Serikawa, Takao Hashimoto, Yusuke Niwa, Kazuya Hata, Takashi Kuramoto
    Abstract:

    Background Chemotherapeutic bioassay for colorectal cancer (CRC) with a rat model bearing chemically-induced CRCs plays an important role in the development of new anti-tumor drugs and regimens. Although several protocols to induce CRCs have been developed, the incidence and number of CRCs are not much enough for the efficient bioassay. Recently, we established the very efficient system to induce CRCs with a chemically induced-Colon Carcinogenesis-prone Apc-mutant rat, Kyoto Apc Delta (KAD) rat. Here, we applied the KAD rat to the chemotherapeutic bioassay for CRC and showed the utility of the KAD rat.

  • dietary astaxanthin inhibits colitis and colitis associated Colon Carcinogenesis in mice via modulation of the inflammatory cytokines
    Chemico-Biological Interactions, 2011
    Co-Authors: Nana Mikami, Masashi Hosokawa, Kazuo Miyashita, Yumiko Yasui, Takuji Tanaka
    Abstract:

    Astaxanthin (AX) is one of the marine carotenoid pigments, which possess powerful biological antioxidant, anti-inflammatory and anti-cancer properties. The purpose of this study is to investigate possible inhibitory effect of AX against inflammation-related mouse Colon Carcinogenesis and dextran sulfate sodium (DSS)-induced colitis in male ICR mice. We conducted two different experiments. In the first experiment, we evaluated the effects of AX at three dose levels, 50, 100 and 200 ppm in diet, on colitis-associated Colon Carcinogenesis induced by azoxymethane (AOM)/DSS in mice. In the second, the effects of the AX (100 and 200 ppm) in diet on DSS-induced colitis were determined. We found that dietary AX significantly inhibited the occurrence of Colonic mucosal ulcers, dysplastic crypts, and Colonic adenocarcinoma at week 20. AX-feeding suppressed expression of inflammatory cytokines, including nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, inhibited proliferation, and induced apoptosis in the Colonic adenocarcinomas. Feeding with 200 ppm AX, but not 100 ppm, significantly inhibited the development of DSS-induced colitis. AX feeding (200 ppm in diet) also lowered the protein expression of NF-κB, and the mRNA expression of inflammatory cytokines, including IL-1β, IL-6, and cyclooxygenase (COX)-2. Our results suggest that the dietary AX suppresses the colitis and colitis-related Colon Carcinogenesis in mice, partly through inhibition of the expression of inflammatory cytokine and proliferation. Our findings suggest that AX is one of the candidates for prevention of colitis and inflammation-associated Colon Carcinogenesis in humans.

  • enhanced colitis associated Colon Carcinogenesis in a novel apc mutant rat
    Cancer Science, 2009
    Co-Authors: Kazuto Yoshimi, Takuji Tanaka, Akiko Takizawa, Megumi Kato, Masumi Hirabayashi, Tomoji Mashimo, Tadao Serikawa, Takashi Kuramoto
    Abstract:

    To establish an efficient rat model for colitis-associated colorectal cancer, azoxymethane and dextran sodium sulfate (AOM/DSS)induced Colon Carcinogenesis was applied to a novel adenomatous polyposis coli (Apc) mutant, the Kyoto Apc Delta (KAD) rat. The KAD rat was derived from ethylnitrosourea mutagenesis and harbors a nonsense mutation in the Apc gene (S2523X). The truncated APC of the KAD rat was deduced to lack part of the basic domain, an EB1-binding domain, and a PDZ domain, but retained an intact b-catenin binding region. KAD rats, homozygous for the Apc mutation on a genetic background of the F344 rat, showed no spontaneous tumors in the gastrointestinal tract. At 5 weeks of age, male KAD rats were given a single subcutaneous administration of AOM (20 mg/kg, bodyweight). One week later, they were given DSS (2% in drinking water) for 1 week. At week 15, the incidence and multiplicity of Colon tumors developed in the KAD rat were remarkably severe compared with those in the F344 rat: 100 versus 50% in incidence and 10.7 ± 3.5 versus 0.8 ± 1.0 in multiplicity. KAD tumors were dominantly distributed in the rectum and distal Colon, resembling human colorectal cancer. Accumulation of b-catenin protein and frequent b-catenin mutations were prominent features of KAD Colon tumors. To our knowledge, AOM/DSSinduced Colon Carcinogenesis using the KAD rat is the most efficient to induce Colon tumors in the rat, and therefore would be available as an excellent model for human colitis-associated CRC. (Cancer Sci 2009; 100: 2022‐2027)

  • mouse models for the study of Colon Carcinogenesis
    Carcinogenesis, 2008
    Co-Authors: Daniel W Rosenberg, Charles Giardina, Takuji Tanaka
    Abstract:

    The study of experimental Colon Carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced Colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma–carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer.

  • sphingosine kinase 1 is up regulated in Colon Carcinogenesis
    The FASEB Journal, 2006
    Co-Authors: Toshihiko Kawamori, Walid Osta, Korey R Johnson, Michael J Wargovich, Takuji Tanaka, Benjamin J Pettus, Yusuf A Hannun, Jacek Bielawski, Lina M Obeid
    Abstract:

    SPECIFIC AIMSThe sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) pathway has been implicated in cell growth, apoptosis, angiogenesis, and induction of cyclooxygenase-2 (COX-2). Increased expression of COX-2 and production of PGE2 have been implicated in Colon Carcinogenesis. Therefore, we examined the potential role of SK1 in COX-2 expression during Colon Carcinogenesis. The expression of SK1 and COX-2 in Colon tumors induced by azoxymethane (AOM) in male F344 rats was examined by immunohistochemical and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. The existence of a potential mechanistic link between SK1 and COX-2 expression in Colon Carcinogenesis was examined by analysis of COX-2 expression and PGE2 production in HT-29 human Colon cancer cells after SK1 down-regulation by small interfering RNA (siRNA) and in RIE-1 rat normal intestinal epithelial cells after SK1 overexpression by gene transfection.PRINCIPAL FINDINGS1. The expression of SK1 and COX-2 is up-regula...

Chung S Yang - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3433 il11 promotes the phip dss induced Colon Carcinogenesis
    Cancer Research, 2019
    Co-Authors: Hong Wang, David J Wang, Yuhai Sun, Xu Yang, Chung S Yang
    Abstract:

    Inflammation of the large intestine, such as colitis, is known to increase the risk of colorectal cancer in human. The colitis induced by dextran sodium sulfite (DSS) has been shown to promote carcinogen- and genetic-induced Colon tumorigenesis in rodent models. In a CYP1A-humanized (hCYP1A) mouse Colon cancer model that we developed to study dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), DSS-induced colitis was required for Colon tumor development after the PhIP treatment. Nevertheless, the mechanism for DSS-induced colitis to promote Carcinogenesis is not clear. To uncover the key cancer promotion factor induced by colitis is important in understanding the mechanism of Colon cancer development. By investigating the gene expression profiles of PhIP/DSS-induced Colon tumors and normal Colon epithelium, we found that cytokine IL11 was significantly upregulated in all tumors. The elevated levels of IL11 are also found in the human Colon cancer genomic data available in The Cancer Genome Atlas (TCGA), suggesting an important role of IL11 in human Colon cancer. Consistently, the activation/phosphorylation of STAT3, a key downstream factor of IL11 signaling, was also positively identified in tumors but not the normal adjacent tissues. To investigate the role of IL11 signaling, we generated hCYP1A:IL11Rα1-/- mice for investigating the role of IL11 signaling in PhIP/DSS-induced Carcinogenesis by crossing the IL11Rα1-/- mice with hCYP1A mice. These mice are infertile as the phenotype reported previously for the IL11Rα1 knockout mice, and need to be maintained through the breeding by the heterozygous. The experimental mice were maintained on the AIN93M diet. We found that the tumor incidence was reduced by 51.0% in hCYP1A:IL11Rα1+/- mice and 80.0% in hCYP1A:IL11Rα1-/- mice, suggesting that IL11 signaling plays critical roles in PhIP/DSS-induced Colon Carcinogenesis. By immunohistochemical staining for pSTAT3, we found the pSTAT3 staining in the colitis epithelial tissues induced by the DSS treatment in both heterozygous and homozygous mice were significantly reduced; whereas the tissues from the wildtype mice displayed strong positive staining in the nucleus. IL11 signaling could be a potential therapeutic target for Colon cancer prevention. (supported by the John L. Colaizzi Chair Endowment Fund and GI Pilot Study from Rutgers Cancer Institute of New Jersey Cancer Center Support Grant P30CA072720) Citation Format: Hong Wang, David Wang, Yuhai Sun, Xu Yang, Chung S. Yang. IL11 promotes the PhIP/DSS-induced Colon Carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3433.

  • from the cover phip dss induced Colon Carcinogenesis in cyp1a humanized mice and the possible role of lgr5 stem cells
    Toxicological Sciences, 2017
    Co-Authors: Jayson X Chen, Anna Liu, Hong Wang, Lanjing Zhang, Kenneth R Reuhl, Chung S Yang
    Abstract:

    In the past decades, experimental rodent models developed to study the pathogenesis of human colorectal cancer (CRC) generally employed synthetic chemical carcinogens or genetic manipulation. Our lab, in order to establish a more physiologically relevant CRC model, recently developed a Colon Carcinogenesis model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS)-induced colitis in the cytochrome P450 1A-humanized (hCYP1A) mice. The resulting Colon tumors shared many histologic and molecular features of human Colon cancer. In this study, we characterized the early stages of PhIP/DSS-induced Colon Carcinogenesis. We found that PhIP/DSS treatments caused rapid destruction of the Colon mucosa with severe inflammation, followed by the presence of reactive changes and low-grade dysplastic lesions, and then manifestation of high-grade dysplastic lesions and finally adenocarcinomas. Molecular analysis of the early time-points (ie, days 1, 3, 7, 11, 14, and 21 after DSS exposure) indicates Ctnnb1/β-catenin mutations and β-catenin nuclear accumulation in the high-grade dysplastic lesions, but not low-grade dysplastic lesions or adjacent normal tissues. In addition, we investigated the role of Lgr5+ Colon stem cells in the PhIP/DSS-induced Colon Carcinogenesis and found the presence of Lgr5-enhance green fluorescent protein-expressing cells amidst some ulcerated mucosa, high-grade dysplastic lesions and adenocarcinomas, suggesting a possible role of Lgr5+ stem cells in this dietary carcinogen-induced, inflammation-promoted Colon Carcinogenesis model. Overall, the findings suggest that PhIP/DSS-induced Colon Carcinogenesis is likely initiated by dominant active Ctnnb1/β-catenin mutation in residual epithelial cells, which when promoted by colitis, developed into high-grade dysplasia and adenocarcinoma.

  • abstract 2814 inhibition of phip dss induced Colon Carcinogenesis by different forms of tocopherols in cyp1a humanized mice
    Cancer Research, 2015
    Co-Authors: Chung S Yang, Anna B Liu, Hong Wang, Jayson X Chen, Marlon A Lee, Chunfang Zhao, Yingyi Kuo, Eric Chi, Nanjoo Suh
    Abstract:

    Tocopherols (T), which exist as α-, β-, γ-, and δ-T are important dietary antioxidants. Our previous studies have demonstrated that a mixture of tocopherols (γ-TmT), δ-T, and γ-T effectively inhibited Colon Carcinogenesis in AOM/DSS-treated mice or AOM-treated rats. However, the effects of different forms of tocopherols on Carcinogenesis in animal models and in humans remain controversial. In the present study, we investigated the inhibitory effects of α-T, γ-T, and δ-T on Colon Carcinogenesis induced by a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS) in CYP1A-humanized (hCYP1A) mice. At 5-6 weeks age, male hCYP1A mice were fed the AIN93M diet or diet supplemented with 0.2% α-T, γ-T, or δ-T for 1 week before PhIP treatment (2x 100mg/kg b.w., 3 days apart), which was followed by DSS (1.5% in drinking water for 4 days) treatment. The mice were sacrificed 10 weeks after the first dose of PhIP. Significant inhibition of Colon tumor incidences was caused by dietary δ-T and γ-T, but not by α-T. In addition, oxidative and nitrosative stress markers (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory stress markers (i.e., PGE2, LTB4, NFκB and p-STAT3) were significantly reduced by δ-T. Dietary treatment with δ-T and γ-T significantly increased the δ-T and γ-T levels, respectively, in the blood and tissues, but their levels were still lower than the levels of α-T. However, the levels of their side-chain degradation metabolites (δ-T and γ-T forms of carboxyethyl hydroxychroman and carboxymethylbutyl hydroxychroman) were much higher than their parent tocopherols in blood and tissues. Altogether, we demonstrated the inhibitory effects of δ-T and γ-T in a dietary carcinogen-induced Colon Carcinogenesis model. The inhibition is possibly due to the antioxidative, reactive nitrogen species-trapping, and anti-inflammatory activities δ-T and γ-T. (Supported by NIH grants F31CA168333, RO1CA120915 and RO1AT007036 as well as shared facilities funded by CA72720 and ES05022) Citation Format: Chung S. Yang, Jayson X. Chen, Anna B. Liu, Hong Wang, Marlon Lee, Siyuan Yu, Chunfang Zhao, Ying-Yi Kuo, Eric Chi, Nanjoo Suh. Inhibition of PhIP/DSS-induced Colon Carcinogenesis by different forms of tocopherols in CYP1A-humanized mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2814. doi:10.1158/1538-7445.AM2015-2814

  • inhibition effect of vitamine e δ tocotrienol on phip dss induced Colon Carcinogenesis in cyp1a humanized mice lb325
    The FASEB Journal, 2014
    Co-Authors: Yukuo Chen, Connie Cheung, Anna Liu, Maojung Lee, Hong Wang, Chung S Yang
    Abstract:

    Our previous research indicated that combination of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant heterocyclic amine produced during the cooking of meats and fish, with dextran sodium sulfate (DSS) rapidly induced Colon Carcinogenesis in transgenic CYP1A-humanized mice (hCYP1A-mice). Herein, we modulated the dosage of DSS (0.8-1.5%) to establish a suitable model for cancer prevention research and to evaluate the inhibition effect of δ-tocotrienol (δ-T3) on Colon Carcinogenesis. The treatment with 200 mg/kg PhIP, followed by 1% DSS in the drinking water for 7 days moderately induced Colon Carcinogenesis in hCYP1A-mice with a tumor multiplicity of 4.17 ± 0.58 at week 8. Tumor multiplicity was reduced in 0.025% and 0.5% δ-T3 treatment groups by 49% (P < 0.05) and 58% (P < 0.01), respectively. Supplementation with δ-T3 also increased the respective levels of tocotrienol in the serum and Colon tissues. These results demonstrate the inhibitory effect of δ-T3 against Colon carcinogene...

  • δ and γ tocopherols but not α tocopherol inhibit Colon Carcinogenesis in azoxymethane treated f344 rats
    Cancer Prevention Research, 2012
    Co-Authors: Fei Guan, Yukuo Chen, Guangxun Li, Zhihong Yang, Weichung Shih, Chung S Yang
    Abstract:

    The cancer preventive activity of vitamin E has been extensively discussed, but the activities of specific forms of tocopherols have not received sufficient attention. Herein, we compared the activities of δ-tocopherol (δ-T), γ-T and α-T in a Colon Carcinogenesis model. Male F344 rats, 7 weeks old, were given 2 weekly subcutaneous injections of azoxymethane (AOM) each at a dose of 15 mg/kg body weight. Starting 1 week before the AOM injection, the animals were maintained on a modified AIN76A diet, or the same diet containing 0.2% of δ-T, γ-T, α-T or a γ-T-rich mixture of tocopherols (γ-TmT), until the termination of the experiment at 8 weeks after the second AOM injection. δ-T treatment showed the strongest inhibitory effect, decreasing the numbers of aberrant crypt foci by 62%. γ-T and γ-TmT were also effective, but α-T was not. Immunohistochemical analysis showed that δ-T and γ-T treatments reduced the levels of 4-hydroxynonenal and nitrotyrosine and the expression of cyclin D1 in the Colon, preserved the expression of PPAR-γ, and decreased the serum levels of prostaglandin E2 and 8-isoprostane. Supplementation with 0.2% δ-T, γ-T or α-T increased the respective levels of tocopherols and their side-chain degradation metabolites in the serum and Colon tissues. Rather high concentrations of δ-T and γ-T and their metabolites were found in Colon tissues. Our study provides the first evidence for the much higher cancer preventive activity of δ-T and γ-T than α-T in a chemically-induced Colon Carcinogenesis model. It further suggests that δ-T is more effective than γ-T.

Shigeyuki Sugie - One of the best experts on this subject based on the ideXlab platform.

  • suppression of colitis related mouse Colon Carcinogenesis by a cox 2 inhibitor and ppar ligands
    BMC Cancer, 2005
    Co-Authors: Hiroyuki Kohno, Rikako Suzuki, Shigeyuki Sugie, Takuji Tanaka
    Abstract:

    Background It is generally assumed that inflammatory bowel disease (IBD)-related Carcinogenesis occurs as a result of chronic inflammation. We previously developed a novel colitis-related mouse Colon Carcinogenesis model initiated with azoxymethane (AOM) and followed by dextran sodium sulfate (DSS). In the present study we investigated whether a cyclooxygenase (COX)-2 inhibitor nimesulide and ligands for peroxisome proliferator-activated receptors (PPARs), troglitazone (a PPARγ ligand) and bezafibrate (a PPARα ligand) inhibit colitis-related Colon Carcinogenesis using our model to evaluate the efficacy of these drugs in prevention of IBD-related Colon Carcinogenesis.

  • strain differences in the susceptibility to azoxymethane and dextran sodium sulfate induced Colon Carcinogenesis in mice
    Carcinogenesis, 2005
    Co-Authors: Rikako Suzuki, Shigeyuki Sugie, Hitoshi Nakagama, Hiroyuki Kohno, Takuji Tanaka
    Abstract:

    Proc Amer Assoc Cancer Res, Volume 46, 2005 3891 We have recently developed a mouse model for colitis-related Colon Carcinogenesis by combined treatment with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male ICR mice. However, strain difference in sensitivity to AOM/DSS-induced Colon Carcinogenesis in mice is unknown. The current study was conducted to define and utilize a mouse strain difference in sensitivity to AOM/DSS-induced Colon Carcinogenesis to elucidate the role of initiation event by AOM and inflammation induced by DSS using four different strains of mice, Balb/cAnCrj (moderately or highly sensitive to AOM and moderately sensitive to DSS), C3H/HeNCrj (low or moderately sensitive to AOM and high sensitive to DSS), C57BL/6Ncrj (low or moderately sensitive to AOM and moderately susceptibility to DSS), and DBA/2Ncrj (moderately sensitive to AOM and resistant to DSS). Animals were given a single intraperitoneal injection of AOM (10 mg/kg body weight), followed by 1% DSS (w/v) in drinking water for 4 days, and then received no further treatment up to 16 weeks. At week 18, all mice were sacrificed and histopathological analysis of their Colon was performed. The incidence of Colonic adenocarcinoma was 100% with a multiplicity (/mouse) of 7.7±4.3 in Balb/cAnCrj and 50% with a multiplicity of 1.0±1.2 in C57BL/6Ncrj. On the other hand, only a few Colonic adenomas developed in C3H/HeNCrj (29% incidence with a multiplicity of 0.7±1.5) and DBA/2Ncrj (20% incidence with a multiplicity of 0.2±0.4). The inflammation scores in C3H/HeNCrj and Balb/cAnCrj mice were relatively higher than those found in C57BL/6Ncrj and DBA/2Ncrj mice. Our results indicate a strain difference in sensitivity to AOM/DSS-induced Colon Carcinogenesis and the difference may be related to the sensitivity to AOM rather than DSS.

  • strain differences in the susceptibility to azoxymethane and dextran sodium sulfate induced Colon Carcinogenesis in mice
    Carcinogenesis, 2005
    Co-Authors: Rikako Suzuki, Shigeyuki Sugie, Hitoshi Nakagama, Hiroyuki Kohno, Takuji Tanaka
    Abstract:

    We have recently developed a mouse model for colitis-related Colon Carcinogenesis by a combined treatment with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male ICR mice. However, strain differences in the sensitivity to AOM/DSS-induced Colon Carcinogenesis in mice have yet to be elucidated. The aim of this study was to determine the presence of any genetically determined differences in sensitivity to our model of Colon Carcinogenesis in four inbred strains of mice. Male Balb/c, C3H/HeN, C57BL/6N and DBA/2N mice were given a single intraperitoneal injection of AOM (10 mg/kg body wt), followed by 1% DSS (w/v) in drinking water for 4 days, and thereafter they received no further treatment for up to 16 weeks. At the end of the study (Week 18), all mice were killed and a histopathological analysis of their Colon was performed. The incidence of Colonic adenocarcinoma was 100% with a multiplicity (no. of tumors/mouse) of 7.7+/-4.3 in the Balb/c mice and 50% with a multiplicity of 1.0+/-1.2 in the C57BL/6N mice. On the other hand, only a few Colonic adenomas, but no adenocarcinomas, developed in the C3H/HeN mice (29% incidence with a multiplicity of 0.7+/-1.5) and the DBA/2N mice (20% incidence with a multiplicity of 0.2+/-0.4). The inflammation and immunohistochemical nitrotyrosine-positivity scores of the mice treated with AOM and DSS in the decreasing order were as follows: C3H/HeN>Balb/c>DBA/2N>C57BL/6N and Balb/c>C57BL/6N>C3H/HeN>DBA/2N, respectively. Our results thus indicated the presence of strain differences in the susceptibility to AOM/DSS-induced Colonic tumorigenesis. These differences may have been directly influenced by the response to nitrosation stress due to the inflammation caused by DSS.

  • a novel inflammation related mouse Colon Carcinogenesis model induced by azoxymethane and dextran sodium sulfate
    Cancer Science, 2003
    Co-Authors: Takuji Tanaka, Rikako Suzuki, Shigeyuki Sugie, Yasuhiro Yamada, Hiroyuki Kohno
    Abstract:

    To develop an efficient animal model for colitis-related Carcinogenesis, male Crj: CD-1 (ICR) mice were given a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic Colonic carcinogen, azoxymethane (AOM), and a 1-week oral exposure (2% in drinking water) to a non-genotoxic carcinogen, dextran sodium sulfate (DSS), under various protocols. At week 20, Colonic neoplasms (adenocarcinomas, 100% incidence with 5.60±2.42 multiplicity; and adenomas, 38% incidence with 0.20±0.40 multiplicity) with dysplastic lesions developed in mice treated with AOM followed by DSS. Protocols in which AOM was given during or after DSS administration induced a few tubular adenomas or no tumors in the Colon. Immunohistochemical investigation of such dysplasias and neoplasms revealed that all lesions were positive for β-catenin, cyclooxygenase-2 and inducible nitric oxide synthase, but did not show p53 immunoreactivity. The results indicate that 1-week administration of 2% DSS after initiation with a low dose of AOM exerts a powerful tumor-promoting activity in Colon Carcinogenesis in male ICR mice, and may provide a novel mouse model for investigating colitis-related Colon Carcinogenesis and for identifying xenobiotics with modifying effects.

  • silymarin a naturally occurring polyphenolic antioxidant flavonoid inhibits azoxymethane induced Colon Carcinogenesis in male f344 rats
    International Journal of Cancer, 2002
    Co-Authors: Hiroyuki Kohno, Kunihiro Kawabata, Shigeyuki Sugie, Takuji Tanaka, Yoshinobu Hirose, Hiroyuki Tsuda
    Abstract:

    The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced Colon Carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced Colonic ACF, being putative precursor lesions for Colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on Colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and Colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced Colon Carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of Colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced Colon Carcinogenesis reduced the incidence and multiplicity of Colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. β-Glucuronidase activity, PGE2 level and polyamine content were decreased in Colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced Colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human Colon cancer. © 2002 Wiley-Liss, Inc.

Hiroyuki Kohno - One of the best experts on this subject based on the ideXlab platform.

  • suppression of colitis related mouse Colon Carcinogenesis by a cox 2 inhibitor and ppar ligands
    BMC Cancer, 2005
    Co-Authors: Hiroyuki Kohno, Rikako Suzuki, Shigeyuki Sugie, Takuji Tanaka
    Abstract:

    Background It is generally assumed that inflammatory bowel disease (IBD)-related Carcinogenesis occurs as a result of chronic inflammation. We previously developed a novel colitis-related mouse Colon Carcinogenesis model initiated with azoxymethane (AOM) and followed by dextran sodium sulfate (DSS). In the present study we investigated whether a cyclooxygenase (COX)-2 inhibitor nimesulide and ligands for peroxisome proliferator-activated receptors (PPARs), troglitazone (a PPARγ ligand) and bezafibrate (a PPARα ligand) inhibit colitis-related Colon Carcinogenesis using our model to evaluate the efficacy of these drugs in prevention of IBD-related Colon Carcinogenesis.

  • strain differences in the susceptibility to azoxymethane and dextran sodium sulfate induced Colon Carcinogenesis in mice
    Carcinogenesis, 2005
    Co-Authors: Rikako Suzuki, Shigeyuki Sugie, Hitoshi Nakagama, Hiroyuki Kohno, Takuji Tanaka
    Abstract:

    Proc Amer Assoc Cancer Res, Volume 46, 2005 3891 We have recently developed a mouse model for colitis-related Colon Carcinogenesis by combined treatment with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male ICR mice. However, strain difference in sensitivity to AOM/DSS-induced Colon Carcinogenesis in mice is unknown. The current study was conducted to define and utilize a mouse strain difference in sensitivity to AOM/DSS-induced Colon Carcinogenesis to elucidate the role of initiation event by AOM and inflammation induced by DSS using four different strains of mice, Balb/cAnCrj (moderately or highly sensitive to AOM and moderately sensitive to DSS), C3H/HeNCrj (low or moderately sensitive to AOM and high sensitive to DSS), C57BL/6Ncrj (low or moderately sensitive to AOM and moderately susceptibility to DSS), and DBA/2Ncrj (moderately sensitive to AOM and resistant to DSS). Animals were given a single intraperitoneal injection of AOM (10 mg/kg body weight), followed by 1% DSS (w/v) in drinking water for 4 days, and then received no further treatment up to 16 weeks. At week 18, all mice were sacrificed and histopathological analysis of their Colon was performed. The incidence of Colonic adenocarcinoma was 100% with a multiplicity (/mouse) of 7.7±4.3 in Balb/cAnCrj and 50% with a multiplicity of 1.0±1.2 in C57BL/6Ncrj. On the other hand, only a few Colonic adenomas developed in C3H/HeNCrj (29% incidence with a multiplicity of 0.7±1.5) and DBA/2Ncrj (20% incidence with a multiplicity of 0.2±0.4). The inflammation scores in C3H/HeNCrj and Balb/cAnCrj mice were relatively higher than those found in C57BL/6Ncrj and DBA/2Ncrj mice. Our results indicate a strain difference in sensitivity to AOM/DSS-induced Colon Carcinogenesis and the difference may be related to the sensitivity to AOM rather than DSS.

  • strain differences in the susceptibility to azoxymethane and dextran sodium sulfate induced Colon Carcinogenesis in mice
    Carcinogenesis, 2005
    Co-Authors: Rikako Suzuki, Shigeyuki Sugie, Hitoshi Nakagama, Hiroyuki Kohno, Takuji Tanaka
    Abstract:

    We have recently developed a mouse model for colitis-related Colon Carcinogenesis by a combined treatment with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male ICR mice. However, strain differences in the sensitivity to AOM/DSS-induced Colon Carcinogenesis in mice have yet to be elucidated. The aim of this study was to determine the presence of any genetically determined differences in sensitivity to our model of Colon Carcinogenesis in four inbred strains of mice. Male Balb/c, C3H/HeN, C57BL/6N and DBA/2N mice were given a single intraperitoneal injection of AOM (10 mg/kg body wt), followed by 1% DSS (w/v) in drinking water for 4 days, and thereafter they received no further treatment for up to 16 weeks. At the end of the study (Week 18), all mice were killed and a histopathological analysis of their Colon was performed. The incidence of Colonic adenocarcinoma was 100% with a multiplicity (no. of tumors/mouse) of 7.7+/-4.3 in the Balb/c mice and 50% with a multiplicity of 1.0+/-1.2 in the C57BL/6N mice. On the other hand, only a few Colonic adenomas, but no adenocarcinomas, developed in the C3H/HeN mice (29% incidence with a multiplicity of 0.7+/-1.5) and the DBA/2N mice (20% incidence with a multiplicity of 0.2+/-0.4). The inflammation and immunohistochemical nitrotyrosine-positivity scores of the mice treated with AOM and DSS in the decreasing order were as follows: C3H/HeN>Balb/c>DBA/2N>C57BL/6N and Balb/c>C57BL/6N>C3H/HeN>DBA/2N, respectively. Our results thus indicated the presence of strain differences in the susceptibility to AOM/DSS-induced Colonic tumorigenesis. These differences may have been directly influenced by the response to nitrosation stress due to the inflammation caused by DSS.

  • a novel inflammation related mouse Colon Carcinogenesis model induced by azoxymethane and dextran sodium sulfate
    Cancer Science, 2003
    Co-Authors: Takuji Tanaka, Rikako Suzuki, Shigeyuki Sugie, Yasuhiro Yamada, Hiroyuki Kohno
    Abstract:

    To develop an efficient animal model for colitis-related Carcinogenesis, male Crj: CD-1 (ICR) mice were given a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic Colonic carcinogen, azoxymethane (AOM), and a 1-week oral exposure (2% in drinking water) to a non-genotoxic carcinogen, dextran sodium sulfate (DSS), under various protocols. At week 20, Colonic neoplasms (adenocarcinomas, 100% incidence with 5.60±2.42 multiplicity; and adenomas, 38% incidence with 0.20±0.40 multiplicity) with dysplastic lesions developed in mice treated with AOM followed by DSS. Protocols in which AOM was given during or after DSS administration induced a few tubular adenomas or no tumors in the Colon. Immunohistochemical investigation of such dysplasias and neoplasms revealed that all lesions were positive for β-catenin, cyclooxygenase-2 and inducible nitric oxide synthase, but did not show p53 immunoreactivity. The results indicate that 1-week administration of 2% DSS after initiation with a low dose of AOM exerts a powerful tumor-promoting activity in Colon Carcinogenesis in male ICR mice, and may provide a novel mouse model for investigating colitis-related Colon Carcinogenesis and for identifying xenobiotics with modifying effects.

  • silymarin a naturally occurring polyphenolic antioxidant flavonoid inhibits azoxymethane induced Colon Carcinogenesis in male f344 rats
    International Journal of Cancer, 2002
    Co-Authors: Hiroyuki Kohno, Kunihiro Kawabata, Shigeyuki Sugie, Takuji Tanaka, Yoshinobu Hirose, Hiroyuki Tsuda
    Abstract:

    The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced Colon Carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced Colonic ACF, being putative precursor lesions for Colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on Colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and Colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced Colon Carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of Colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced Colon Carcinogenesis reduced the incidence and multiplicity of Colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. β-Glucuronidase activity, PGE2 level and polyamine content were decreased in Colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced Colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human Colon cancer. © 2002 Wiley-Liss, Inc.

Toshihiko Kawamori - One of the best experts on this subject based on the ideXlab platform.

  • role for sphingosine kinase 1 in Colon Carcinogenesis
    The FASEB Journal, 2009
    Co-Authors: Toshihiko Kawamori, Tatsuya Kaneshiro, Masae Okumura, Samer Maalouf, Andre Uflacker, Yusuf A Hannun, Jacek Bielawski, Lina M Obeid
    Abstract:

    Sphingosine kinase 1 (SphK1) phosphorylates sphingosine to form sphingosine-1-phosphate (S1P) and is a critical regulator of sphingolipid-mediated functions. Cell-based studies suggest a tumor-promoting function for the SphK1/S1P pathway. Also, our previous studies implicated the SphK1/S1P pathway in the induction of the arachidonic acid cascade, a major inflammatory pathway involved in Colon Carcinogenesis. Therefore, we investigated whether the SphK1/S1P pathway is necessary for mediating Carcinogenesis in vivo. Here, we report that 89% (42/47) of human Colon cancer samples stained positively for SphK1, whereas normal Colon mucosa had negative or weak staining. Adenomas had higher expression of SphK1 vs. normal mucosa, and Colon cancers with metastasis had higher expression of SphK1 than those without metastasis. In the azoxymethane (AOM) murine model of Colon cancer, SphK1 and S1P were significantly elevated in Colon cancer tissues compared to normal mucosa. Moreover, blood levels of S1P were higher in mice with Colon cancers than in those without cancers. Notably, SphK1−/− mice subjected to AOM had significantly less aberrant crypt foci (ACF) formation and significantly reduced Colon cancer development. These results are the first in vivo evidence that the SphK1/S1P pathway contributes to Colon Carcinogenesis and that inhibition of this pathway is a potential target for chemoprevention.—Kawamori, T., Kaneshiro, T., Okumura, M., Maalouf, S., Uflacker, A., Bielawski, J., Hannun, Y. A., Obeid, L. M. Role for sphingosine kinase 1 in Colon Carcinogenesis.

  • sphingosine kinase 1 is up regulated in Colon Carcinogenesis
    The FASEB Journal, 2006
    Co-Authors: Toshihiko Kawamori, Walid Osta, Korey R Johnson, Michael J Wargovich, Takuji Tanaka, Benjamin J Pettus, Yusuf A Hannun, Jacek Bielawski, Lina M Obeid
    Abstract:

    SPECIFIC AIMSThe sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) pathway has been implicated in cell growth, apoptosis, angiogenesis, and induction of cyclooxygenase-2 (COX-2). Increased expression of COX-2 and production of PGE2 have been implicated in Colon Carcinogenesis. Therefore, we examined the potential role of SK1 in COX-2 expression during Colon Carcinogenesis. The expression of SK1 and COX-2 in Colon tumors induced by azoxymethane (AOM) in male F344 rats was examined by immunohistochemical and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. The existence of a potential mechanistic link between SK1 and COX-2 expression in Colon Carcinogenesis was examined by analysis of COX-2 expression and PGE2 production in HT-29 human Colon cancer cells after SK1 down-regulation by small interfering RNA (siRNA) and in RIE-1 rat normal intestinal epithelial cells after SK1 overexpression by gene transfection.PRINCIPAL FINDINGS1. The expression of SK1 and COX-2 is up-regula...

  • sphingosine kinase 1 is up regulated in Colon Carcinogenesis
    The FASEB Journal, 2006
    Co-Authors: Toshihiko Kawamori, Walid Osta, Korey R Johnson, Michael J Wargovich, Takuji Tanaka, Benjamin J Pettus, Yusuf A Hannun, Jacek Bielawski, Lina M Obeid
    Abstract:

    Sphingosine kinase 1 (SK1) phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has the ability to promote cell proliferation and survival and stimulate angiogenesis. The SK1/S1P pathway also plays a critical role in regulation of cyclooxygenase-2 (COX-2), a well-established pathogenic factor in Colon Carcinogenesis. Therefore, we examined the expression of SK1 and COX-2 in rat Colon tumors induced by azoxymethane (AOM) and the relationship of these two proteins in normal and malignant intestinal epithelial cells. Strongly positive SK1 staining was found in 21/28 (75%) of rat Colon adenocarcinomas induced by AOM, whereas no positive SK1 staining was observed in normal mucosa. The increase in SK1 and COX-2 expression in AOM-induced rat Colon adenocarcinoma was confirmed at the level of mRNA by real-time RT-PCR. In addition, it was found that 1) down-regulation of SK1 in HT-29 human Colon cancer cells by small interfering RNA (siRNA) decreases COX-2 expression and PGE2 production; 2) overexpression of SK1 in RIE-1 rat intestinal epithelial cells induces COX-2 expression; and 3) S1P stimulates COX-2 expression and PGE2 production in HT-29 cells. These results suggest that the SK1/S1P pathway may play an important role in Colon Carcinogenesis, in part, by regulating COX-2 expression and PGE2 production.

  • enhancement of Colon Carcinogenesis by prostaglandin e2 administration
    Carcinogenesis, 2003
    Co-Authors: Toshihiko Kawamori, Takashi Sugimura, Naoaki Uchiya, Keiji Wakabayashi
    Abstract:

    : Although an accumulating body of evidence indicates that levels of prostaglandin E(2) (PGE(2)) in human and rodent Colon cancers are higher than those in surrounding normal tissues, the precise contribution of PGE(2) to the process of Colon cancer development has still been unclear. Therefore, we designed a study using a well-established azoxymethane (AOM)-induced Colon Carcinogenesis in male F344 rat model to investigate whether administration of exogenous PGE(2) has a real impact on Colon Carcinogenesis. Intraperitoneal PGE(2) injections (7.7 micro g) once a week for 25 weeks significantly increased the AOM-induced Colon tumor incidence (percent rats with tumors, 92 versus 53%, P < 0.05), especially adenocarcinomas (92 versus 47%, P < 0.05), and multiplicity (number of tumors per rat, 2.8 versus 1.0, P < 0.05). PGE(2) treatment significantly increased 5-bromo-2'-deoxyuridine (BrdUrd) labeling index (11.8 versus 9.7%, P < 0.05) and reduced apoptotic index (0.34 versus 0.53%, P < 0.05) in Colon cancers induced by AOM. PGE(2) exhibits its physiological functions through binding to E-prostanoid (EP) membrane receptors EP(1-4). All four types of EP receptors were detected in AOM-induced Colon cancers using reverse transcription-polymerase chain reaction (RT-PCR). Our results provide evidence that PGE(2) enhances Colon Carcinogenesis through induction of cell proliferation and reduction of apoptosis.

  • peroxisome proliferator activated receptor γ ligands suppress Colon Carcinogenesis induced by azoxymethane in mice
    Gastroenterology, 2003
    Co-Authors: Emi Osawa, Toshihiko Kawamori, Atsushi Nakajima, Koichiro Wada, Satoko Ishimine, Nobutaka Fujisawa, Nobuyuki Matsuhashi, Takashi Kadowaki, Masako Ochiai, Hisahiko Sekihara
    Abstract:

    Abstract Background & Aims: Peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate growth arrest and terminal differentiation of adipocytes and is used clinically as a new class of antidiabetic drugs. Recently, several studies have reported that treatment of cancer cells with PPARγ ligands induces cell differentiation and apoptosis, suggesting a potential application as chemopreventive agents against Carcinogenesis. However, contradictory results have been reported with regards to the biologic role of PPARγ in Carcinogenesis. Tanaka et al. 24 have recently reported the suppressive effect of a PPARγ ligand, troglitazone (Tro), on the formation of aberrant crypt foci (ACF) in rats. In the present study, 3 different kinds of PPARγ ligands were subjected to the experiments to confirm their suppressive effects on Colon Carcinogenesis. Methods: Three PPARγ ligands, pioglitazone (Pio) (200 ppm), rosiglitazone (Rosi) (200 ppm), and Tro (1000 ppm) were investigated on the induction of ACF, a putative precancerous lesion of the Colon, and Colon tumor formation using an azoxymethane (AOM)-induced Colon cancer model in BALB/c mice, and dose dependency of a PPARγ ligand was also examined. Results: PPARγ ligands reduced the ACF formation by AOM (10 mg/kg body weight) and induction of Colon tumors were also markedly suppressed by a continuous feeding of Pio at 200 ppm. Conclusions: Our findings indicate that PPARγ ligands are indeed potential chemopreventive agents for Colon Carcinogenesis.