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1 Department of Medical Oncology and Therapeutics Research, 2 Department of Anatomic Pathology, and 3 Division of Information Sciences, City of Hope Comprehensive Cancer Center, Duarte, California, and 4 Department of Veteran Affairs Medical Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Glutathione peroxidases (GPX) are a family of four selenium-dependent antioxidant enzymes in mice (five in humans; Ref. 10 ) that reduce H2O2 and organic hydroperoxides by oxidizing glutathione. Taken together, the ubiquitous GPX-1 and epithelium-specific GPX-2 contribute nearly all glutathione-dependent H2O2-reducing activity in the intestinal epithelium (11) . We have previously reported that GPX-DKO mice, with targeted disruption of Gpx1 and Gpx2 genes, exhibit ileocolitis between 2 and 7 weeks of age, which is accompanied by accumulation of lipid hydroperoxides, weight loss, and proctitis (12) . Because some colitis models such as Mdr1-KO mice do not appear to develop cancer (13 , 14) , we set out to determine whether GPX-DKO mice would develop intestinal cancer. Because most mouse IBD and ileocolitis-associated cancer models are either immunodeficient or defective in membrane proteins that affect epithelial barrier integrity (15 , 16) , showing that intracellular GPX activity could prevent microflora-induced ileocolitis and cancer would strengthen the notion that peroxidative stress is one basis for the pathogenesis of inflammation-associated cancer. Although elevated reactive oxygen and nitrogen species are recognized as an integral part of the pathophysiology of IBD, there is little evidence to specify the precise role of hydroperoxides in IBD pathology (17 , 18) . Demonstrating that epithelial GPX activity could inhibit both IBD and IBD-associated cancers might set the stage for the prevention of IBD-related cancers with inhibitors of the major hydroperoxide-generating enzymes that reside in the mucosal epithelium or inflammatory cells.
Our original non-specific-pathogen-free (non-SPF) GPX-DKO mouse colony harbors several enterohepatic Helicobacter species such as H. hepaticus, which is widely spread in rodents (19) . Although H. hepaticus was originally identified as causing hepatitis and hepatocellular tumors in A/JCr mice, its primary site of colonization is in the intestine. Colonization of H. hepaticus to SPF mice causes ileocolitis and colon cancer in immune-deficient animals such as nude mice, IL-10 KO, and T-cell deficient mice (20, 21, 22) . However, H. hepaticus only induces mild or no colitis in SPF and immune competent wild-type C57BL/6 and Mdr1-KO mice (19 , 23) . In this article, we address whether specific microflora are essential for ileocolitis and its associated cancer in GPX-DKO mice by comparing the extent of ileocolitis and cancer incidences in mice harboring non-SPF, SPF, or no enteric microflora.
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MATERIALS AND METHODS |
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Tumor Analysis.
Six non-SPF mice > 5 months of age were found dead or appeared moribund and were thus euthanized for cause. Four of these mice had tumors. The remaining asymptomatic mice not warranting euthanasia were thus examined after 5 months of age to evaluate tumor prevalence. We visually examined the entire length of the small and large intestine of every animal sacrificed for any abnormal growth or tumor formation. In most cases, we excised tumors and made Swiss rolls on the remaining ileum and colon to avoid missing small lesions (24)
. All tissue samples were fixed in 10% formalin in phosphate buffer and then processed for sectioning. Most sections were stained with H&E for histological analysis. Only those lesions that had dysplastic histology (as defined below) examined by our staff pathologists were scored as tumors. Goblet cells were stained with Alcian Blue and counterstained with Nuclear Fast Red.
The tumors were analyzed for the stages of cancer progression described by Riddel et al. (2) . Because of the nature of the GPX-DKO intestinal epithelium, which always had focal inflammation or pathology in the presence of luminal microflora, we did not include hyperplastic epithelium, which only showed crypt distortion or enlarged and branched glands as seen in polyps, as tumors. We scored tumors with low-grade dysplasia and high-grade dysplasia as precancerous lesions; cancers included both invasive carcinomas and signet-ring cell malignancies. The criteria for low-grade dysplasia were hyperplasia with cytological abnormalities, primarily loss of nuclear polarity, marked stratification of nuclei, nuclear hyperchromatism, and cellular and nuclear pleomorphism. High-grade dysplasia was scored when dysplastic epithelium extended to the apical surface or involved a large area. High-grade dysplasia also included carcinoma in situ, which has neoplastic epithelium forming a complex cribriform pattern (back-to-back glands with no intervening stroma) yet without evidence of invasion into the muscularis mucosa. Invasive carcinoma was scored when the atypical glands were seen in the muscularis mucosa, serosal adipose tissue, or muscle layers.
Logistic regression was used to test the association of cancer prevalence with age at sacrifice, sex, parity, and colony conditions, each factor being adjusted for the others. Significant (P < 0.05) likelihood-ratio tests with multiple degrees of freedom were followed by specific contrasts (Wald tests).
Immunohistochemistry.
Mouse monoclonal anti-ß-catenin (1 µg/ml) antibody (BD Transduction Labs) was used to determine cellular localization of ß-catenin, which was detected with horseradish peroxidase and 3,3'-diaminobenzidine (Ultravision Detection System; Lab Vision Co., Fremont, CA). Cell proliferation was detected with a BrdUrd immunohistochemistry kit (Oncogene Research Products, San Diego, CA). Mice were injected i.p. with 5'-bromo-2'-deoxyuridine (BrdUrd, 120 mg/kg) and 5'-fluoro-2'-deoxyuridine (12 mg/kg) dissolved in sterile Ringer’s solution. Mice were euthanized 2 h after injection, and the small and large intestines were processed for routine paraffin embedding. Apoptotic cells were detected in situ by a TdT-FragEL DNA Fragmentation Detection kit (Oncogene) on the paraffin-embedded tissue sections. Rabbit polyclonal anti-myeloperoxidase antibody (7 µg/ml; DakoCytomation, Carpinteria, CA) was used to detect polymorphonuclear neutrophils and monocytes (25)
. The proliferative index (stained cells/crypt) was determined by counting the number of stained cells in at least seven crypts of the most distorted region of the intestine for each mouse.
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RESULTS |
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. When bacterial colonization occurs at birth, the ileal and colonic epithelium always exhibits focal pathology or inflammation throughout the life of the GPX-DKO mice (Fig. 2)
. The pathology and inflammation was scored in nontumorous areas based on a 17-point system, which includes inflammation as shown by lymphocyte or neutrophil infiltration (0–3 points), mucin depletion (0–2 points), reactive epithelium such as crypt distortion (0–3 points), number of intraepithelial lymphocytes (0–3 points), inflammatory foci (0–3 points), and apoptotic figures (0–3 points; Ref. 12
). The pathology/inflammation scores in GPX-DKO ileal epithelium vary in degree based on exposure to microflora, with scores greatest in non-SPF > SPF > GF = non-DKO mice. In colonic epithelium, the order of pathology scores was non-SPF = SPF > GF = non-DKO (Fig. 2)
. SPF mouse ilea have significantly lower inflammation scores than non-SPF ilea when compared by age (P < 0.04, t test), whereas the colon scores remain the same (with Ps ranging between 0.06 and 0.37, t test). We have previously reported that colonization with SPF microflora of adult GF GPX-DKO mice caused acute ileocolitis (26)
. Similarly, colonization with non-SPF microflora at weaning (4 weeks old) of the SPF GPX-DKO mice also caused acute ileocolitis, which resulted in one death in a group of 15 at the 53rd day after transfer. These transferred (SPF
non-SPF) GPX-DKO mice had similar inflammation scores as non-SPF GPX-DKO mice when analyzed 4–6 months later. On the basis of these observations, we conclude that non-SPF microflora provoked a more severe and persistent pathology than SPF microflora in the ilea of GPX-DKO mice.
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. At least seven crypts were counted in the most distorted regions. The ilea of GPX-DKO mice had 2.2-fold higher numbers of proliferating cells than non-DKO control mice. The ileal MI for GPX-DKO mice was 17 ± 5 (mean ± SD, n = 5) labeled cells/crypt and that for non-DKO (with one or one each wild-type Gpx1 and Gpx2 allele) 8 ± 4 (n = 6; P = 0.004, Wilcoxon test). Similarly, colonic crypts of GPX-DKO mice also had significantly higher numbers of proliferating cells than in non-DKO mice. The colonic MI for GPX-DKO was 11 ± 2 (n = 4) and for non-DKO 4 ± 2 (n = 4; P < 0.03, Wilcoxon test). This higher MI in GPX-DKO mice may be necessary to avoid crypt atrophy caused by high levels of apoptosis. We found a lower number of ileal crypts (68 ± 8/cross-section, n = 5) in GPX-DKO mice compared with non-DKO mice (95 ± 19/cross section, n = 5, P = 0.03) at 7–10 weeks of age. This suggests that the crypt loss due to apoptosis may not be fully compensated by a higher MI.
To determine tumor incidence, we euthanized mice primarily between 5 and 9 months of age in non-SPF, SPF, SPFnon-SPF, and GF colonies (Table 1)
. Because age variation at sacrifice could confound comparisons among the colonies, we adjusted for age variation by using a logistic regression test. We found age at sacrifice was not significantly associated with tumor prevalence (P = 0.3). However, tumor prevalence varied significantly across colony conditions after adjustments for age and sex (P < 0.0001, 3 degrees of freedom, logistic regression test; Table 1
). The effect was primarily due to the difference between "the clean conditions" (the GF and SPF) as opposed to "the dirty conditions" (non-SPF and SPFnon-SPF conditions; P = 0.0003). Comparisons within the clean and dirty conditions were not statistically significant (P = 0.15 between GF and SPF, and P = 0.7 between non-SPF and SPFnon-SPF). However, the data are consistent with the hypothesis that the risk of developing a tumor to GPX-DKO mice in SPF conditions was intermediate between that in GF and non-SPF conditions. The tumor rate among females varied significantly with parity adjusted for age and conditions, with nonbreeder females having significantly fewer tumors (P = 0.02). Male mice were not statistically distinguishable from either group of females (P > 0.07). No tumors were found under any conditions in mice that had at least one wild-type Gpx1 or Gpx2 allele. These non-DKO mice were littermates of GPX-DKO mice and shared identical housing conditions. These observations exclude genetic background, nonintestinal environmental and dietary factors as etiologies for cancer susceptibility in this model.
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. Most mice had single tumors, except for a few mice that had 2 tumors each. Ten of 36 (28%) tumors analyzed in the non-SPF colony (from birth) were adenocarcinomas with 8 invasive carcinomas and two signet-ring cell carcinoma (SRCC; Table 2
). Two of 4 tumors in the SPFnon-SPF colony were cancerous with 1 invasive and 1 SRCC. Most of the tumors were located in the distal ileum, except for 1 non-SPF mouse that had a tumor in the distal jejunum. Six mice had colonic tumors; this includes 1 SPF female, 1 SPFnon-SPF male, and 4 SPF male GPX-DKO mice.
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and Fig. 3
). Two SRCCs from the non-SPF colony and 1 from the SPFnon-SPF colony did not show nuclear accumulation of ß-catenin (Fig. 3)
. Signet-ring morphology appeared to be caused by the large amounts of mucin (stained by Alcian Blue) pressing nuclei against the plasma membrane. The only invasive adenocarcinoma that did not have nuclear accumulation of ß-catenin was from the SPFnon-SPF colony.
The higher ileal tumor rates in non-SPF mice than SPF and GF mice correlated with higher pathology scores. Among the male non-SPF GPX-DKO mice, we also found that tumor-bearing mice had significantly higher ileal pathology scores than those that were tumor free (Fig. 3)
. Also, similar ileal scores were found between male (6.0 ± 2.4, n = 29) and female (6.6 ± 2.6, n = 12) GPX-DKO mice regardless of breeding status. However, although similar scores were found in the ileum and colon in the SPF colony, colon tumors were most prevalent.
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DISCUSSION |
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-irradiation (26
, 37)
. However, elevated GPX gene expression has also been associated with tumorigenesis, presumably because of its antiapoptotic activity (38)
. Elevated Gpx2 gene expression is observed in squamous cell carcinomas, Barrett’s mucosa, and colorectal adenomas compared with normal tissues (39, 40, 41)
, and overexpression of the Gpx1 gene increases skin cancer risk (42)
. Therefore, it has been a quandary whether increased GPX activity is anti-inflammatory or procarcinogenic. Our results suggest that GPX can prevent tumorigenesis in intestinal epithelium by its antioxidant activity. The tumor incidence that we observed in the ilea of GPX-DKO mice is correlated with pathology/inflammation scores, with the highest cancer rate occurring in the non-SPF colony or SPF mice made non-SPF at weaning. However, the colon shows no correlation between the tumor incidence and pathology/inflammation scores. Both non-SPF and SPF colonies have similar pathology/inflammation scores in the colon, but SPF mice have more colonic tumors than non-SPF mice. Also, female non-SPF GPX-DKO mice had similar inflammation scores regardless of their breeding status. These results suggest that inflammatory changes are necessary but not sufficient for tumorigenesis.
Although male mice did not have a significantly higher tumor incidence than female mice, breeder females appeared to have a higher tumor incidence than nulliparous females. It has been noted that H. hepaticus causes more severe hepatic lesions in male mice, and H. pylori causes more severe intestinal-type gastritis and gastric cancer in men and male mice (19 , 43 , 44) . Apparently, those microflora harbored in the non-SPF colony, from which most tumor-bearing mice were derived, did not have as strong an effect on ileal and colonic cancer incidence as H. pylori has on gastric cancer. In humans, parity is not recognized as a risk factor for colon cancer. However, it is unclear whether the pregnancy-associated risk in women with IBD can be obscured by decreased numbers of pregnancies due either to reduced fertility or choice and by more preterm births or smaller birth weights (45, 46, 47) . Although we have found that multiparous female GPX-DKO mice had a significantly higher tumor incidence than nulliparous females because breeder females were on a diet with slightly higher fat content to promote their own and the litters’ health and high-fat diet has been implicated in higher colorectal cancer risk (48) , we cannot exclude the possibility that the different cancer rate is skewed by different diets. During normal pregnancy and preeclampsia, there is increased lipid peroxidation in multiple organs, which can increase oxidative DNA damage and gene mutations (49, 50, 51, 52) . Additional analysis will be needed to better evaluate whether parity increases cancer rate in GPX-DKO mice fed with the same 9% fat diet.
There are multiple sources for bacteria-induced oxidative stress. A few strains of commensal bacteria in Enterococcus spp. can generate reactive oxygen species in the lumen and cause inflammation-associated cancer in IL-10 KO mice (53, 54, 55)
. Epithelial cells also respond to bacterial colonization by modulating inflammatory responses (7
, 9
, 56)
. Colonization with H. hepaticus in A/JCr mice induces oxidative DNA damage in the liver and the expression of a subset of immune-related genes, including -IFN in cecal epithelium (57, 58, 59)
. H. pylori induces H2O2 production and cyclooxygenase-2 expression in gastric epithelial cells (60)
. Although our results are consistent with the notion that H. hepaticus is pathogenic in GPX-DKO mice, additional studies are needed to fulfill Koch’s postulates and to elucidate the molecular mechanism for bacteria-induced ileocolitis.
The tumor pathology in these mice is unique. Although most of tumors were adenomas, among 13 adenocarcinomas, there were 3 SRCCs. In humans, the occurrence of SRCC in the small intestine or colon is a rare but distinctive event, typically found in younger patients; it carries an adverse prognosis (61 , 62) . Few murine intestinal cancer models demonstrate signet-ring histology. Among the exceptions are the azoxymethane-induced colorectal cancer model in rats, duodenal polyps of Smad4-heterozygous mice, and intestinal tumors in Smad4/Apc-double heterozygous mice (16 , 63, 64, 65) . All 3 SRCCs in our GPX-DKO mice still had membranous ß-catenin localization, suggesting that the Wnt pathway remains intact. This is consistent with the hypothesis that a set of genes other than those in the Apc-ß-catenin pathway may be mutated in SRCC (62 , 64) . This result also suggests that mutations in multiple pathways may occur during tumorigenesis in GPX-DKO mouse intestines.
Mutations in the Apc gene are a common early event in sporadic colon cancer. Whether Apc gene mutations occur as frequently in colitis-associated cancer is less certain (18) . Opposing results have been found in mouse IBD models; IL-2/ß2-microglobulin-deficient mice have mutated Apc genes in all adenocarcinomas determined by DNA sequence analysis (32) , but IL-10 deficient mice do not have Apc mutations in all tumors analyzed by immunohistochemistry of APC protein (66) . Our results, showing most adenomas and non-SRCC adenocarcinomas have nuclear accumulation of ß-catenin, support the notion that mutations in genes in the Wnt pathway occur in our inflammation-associated mouse model.
In summary, we have described a new mouse ileocolitis-associated cancer model. This is the first mouse ileal and colonic cancer model produced by a deficiency in antioxidant enzyme levels. Inflammation and cancer occurring in our GPX-DKO mice provide direct evidence, suggesting that intracellular hydroperoxides, which are reduced by GPX-1 and GPX-2, play an important role in cancer initiation, promotion, or progression. However, whether this goes beyond suppression of inflammation is not clear. Although some commensal microflora may be harmless or even beneficial to the host by preventing inflammation in intestinal mucosa (67 , 68) , certain luminal bacteria may drastically increase cancer incidence.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Fong-Fong Chu, Department of Medical Oncology, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010-3000. Phone: (626) 256-4673, ext. 63831; Fax: (626) 301-8898; E-mail: fchu{at}coh.org
Received 7/24/03. Revised 11/12/03. Accepted 11/19/03.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B-
ubiquitination. Science (Wash. DC), 289: 1560-1563, 2000.-irradiation damage. Am. J. Physiol. Gastrointest. Liver Physiol., 279: G426-G436, 2000.This article has been cited by other articles:
|
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 |
|
  C. Di Cosmo, N. McLellan, X.-H. Liao, K. K. Khanna, R. E. Weiss, L. Papp, and S. Refetoff Clinical and Molecular Characterization of a Novel Selenocysteine Insertion Sequence-Binding Protein 2 (SBP2) Gene Mutation (R128X) J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 4003 - 4009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Westbrook, B. Wei, J. Braun, and R. H. Schiestl Intestinal Mucosal Inflammation Leads to Systemic Genotoxicity in Mice Cancer Res., June 1, 2009; 69(11): 4827 - 4834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Hahn, T. Hahn, D.-H. Lee, R. S. Esworthy, B.-w. Kim, A. D. Riggs, F.-F. Chu, and G. P. Pfeifer Methylation of Polycomb Target Genes in Intestinal Cancer Is Mediated by Inflammation Cancer Res., December 15, 2008; 68(24): 10280 - 10289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Banning, A. Kipp, S. Schmitmeier, M. Lowinger, S. Florian, S. Krehl, S. Thalmann, R. Thierbach, P. Steinberg, and R. Brigelius-Flohe Glutathione Peroxidase 2 Inhibits Cyclooxygenase-2-Mediated Migration and Invasion of HT-29 Adenocarcinoma Cells but Supports Their Growth as Tumors in Nude Mice Cancer Res., December 1, 2008; 68(23): 9746 - 9753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Peters, N. Chatterjee, R. B. Hayes, R. E. Schoen, Y. Wang, S. J. Chanock, and C. B. Foster Variation in the Selenoenzyme Genes and Risk of Advanced Distal Colorectal Adenoma Cancer Epidemiol. Biomarkers Prev., May 1, 2008; 17(5): 1144 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Naiki-Ito, M. Asamoto, N. Hokaiwado, S. Takahashi, H. Yamashita, H. Tsuda, K. Ogawa, and T. Shirai Gpx2 Is an Overexpressed Gene in Rat Breast Cancers Induced by Three Different Chemical Carcinogens Cancer Res., December 1, 2007; 67(23): 11353 - 11358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Walshe, M. M. Serewko-Auret, N. Teakle, S. Cameron, K. Minto, L. Smith, P. C. Burcham, T. Russell, G. Strutton, A. Griffin, et al. Inactivation of Glutathione Peroxidase Activity Contributes to UV-Induced Squamous Cell Carcinoma Formation Cancer Res., May 15, 2007; 67(10): 4751 - 4758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Matsui, M. Ito, H. Nishiyama, H. Uno, H. Kotani, J. Watanabe, P. Guilford, A. Reeve, M. Fukushima, and O. Ogawa Genomic characterization of multiple clinical phenotypes of cancer using multivariate linear regression models Bioinformatics, March 15, 2007; 23(6): 732 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Singh, T. Rangasamy, R. K. Thimmulappa, H. Lee, W. O. Osburn, R. Brigelius-Flohe, T. W. Kensler, M. Yamamoto, and S. Biswal Glutathione Peroxidase 2, the Major Cigarette Smoke-Inducible Isoform of GPX in Lungs, Is Regulated by Nrf2 Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 639 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-H. Lee, R. S. Esworthy, C. Chu, G. P. Pfeifer, and F.-F. Chu Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Cancer Res., October 15, 2006; 66(20): 9845 - 9851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bauer-Marinovic, S. Florian, K. Muller-Schmehl, H. Glatt, and G. Jacobasch Dietary resistant starch type 3 prevents tumor induction by 1,2-dimethylhydrazine and alters proliferation, apoptosis and dedifferentiation in rat colon Carcinogenesis, September 1, 2006; 27(9): 1849 - 1859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Halliwell Reactive Species and Antioxidants. Redox Biology Is a Fundamental Theme of Aerobic Life Plant Physiology, June 1, 2006; 141(2): 312 - 322. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Diwadkar-Navsariwala, G. S. Prins, S. M. Swanson, L. A. Birch, V. H. Ray, S. Hedayat, D. L. Lantvit, and A. M. Diamond Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model PNAS, May 23, 2006; 103(21): 8179 - 8184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Irons, B. A. Carlson, D. L. Hatfield, and C. D. Davis Both Selenoproteins and Low Molecular Weight Selenocompounds Reduce Colon Cancer Risk in Mice with Genetically Impaired Selenoprotein Expression J. Nutr., May 1, 2006; 136(5): 1311 - 1317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Lu, W. Ouyang, and C. Huang Inflammation, a Key Event in Cancer Development Mol. Cancer Res., April 1, 2006; 4(4): 221 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Yan and X. Chen GPX2, a Direct Target of p63, Inhibits Oxidative Stress-induced Apoptosis in a p53-dependent Manner J. Biol. Chem., March 24, 2006; 281(12): 7856 - 7862. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Doroshow Redox modulation of chemotherapy-induced tumor cell killing and normal tissue toxicity. J Natl Cancer Inst, February 15, 2006; 98(4): 223 - 225. [Full Text] [PDF]
|
|
|
|
|
|
U. Peters, N. Chatterjee, T. R. Church, C. Mayo, S. Sturup, C. B. Foster, A. Schatzkin, and R. B. Hayes High serum selenium and reduced risk of advanced colorectal adenoma in a colorectal cancer early detection program. Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 315 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Maggio-Price, P. Treuting, W. Zeng, M. Tsang, H. Bielefeldt-Ohmann, and B. M. Iritani Helicobacter Infection Is Required for Inflammation and Colon Cancer in Smad3-Deficient Mice Cancer Res., January 15, 2006; 66(2): 828 - 838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang and R. A. Casero Jr. Mammalian Polyamine Catabolism: A Therapeutic Target, a Pathological Problem, or Both? J. Biochem., January 1, 2006; 139(1): 17 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hu, R. V. Benya, R. E. Carroll, and A. M. Diamond Allelic Loss of the Gene for the GPX1 Selenium-Containing Protein Is a Common Event in Cancer J. Nutr., December 1, 2005; 135(12): 3021S - 3024S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ouyang, T. L. DeWeese, W. G. Nelson, and C. Abate-Shen Loss-of-Function of Nkx3.1 Promotes Increased Oxidative Damage in Prostate Carcinogenesis Cancer Res., August 1, 2005; 65(15): 6773 - 6779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Banning, S. Deubel, D. Kluth, Z. Zhou, and R. Brigelius-Flohe The GI-GPx Gene Is a Target for Nrf2 Mol. Cell. Biol., June 15, 2005; 25(12): 4914 - 4923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Esworthy, L. Yang, P. H. Frankel, and F.-F. Chu Epithelium-Specific Glutathione Peroxidase, Gpx2, Is Involved in the Prevention of Intestinal Inflammation in Selenium-Deficient Mice J. Nutr., April 1, 2005; 135(4): 740 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Carlson, X.-M. Xu, V. N. Gladyshev, and D. L. Hatfield Selective Rescue of Selenoprotein Expression in Mice Lacking a Highly Specialized Methyl Group in Selenocysteine tRNA J. Biol. Chem., February 18, 2005; 280(7): 5542 - 5548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xu, R. Chaturvedi, Y. Cheng, F. I. Bussiere, M. Asim, M. D. Yao, D. Potosky, S. J. Meltzer, J. G. Rhee, S. S. Kim, et al. Spermine Oxidation Induced by Helicobacter pylori Results in Apoptosis and DNA Damage: Implications for Gastric Carcinogenesis Cancer Res., December 1, 2004; 64(23): 8521 - 8525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Itzkowitz and X. Yio Inflammation and Cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G7 - G17. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Huycke and H. R. Gaskins Commensal Bacteria, Redox Stress, and Colorectal Cancer: Mechanisms and Models Experimental Biology and Medicine, July 1, 2004; 229(7): 586 - 597. [Abstract] [Full Text] [PDF]
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) and the SPF (
) colonies in the ileum (A) and in the colon (B) by age. Only one-sided error bars are shown for clarity. Between 5 and 15 mice were analyzed at each time point. The ilea of the mice in the non-SPF colony had significantly higher inflammation/pathology scores than those of the SPF colony at matched ages (P < 0.04 for each time point, t test). Colonic inflammation/pathology scores were similar for the non-SPF and SPF colonies.
) and with ileal tumors (