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Identification and Characterization of Unique Neutralizing Antibodies to Mouse EGF Receptor.
Jae Huh W, Niitsu H, Carney B, McKinley ET, Houghton JL, Coffey RJ
(2020) Gastroenterology 158: 1500-1502
MeSH Terms: Animals, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Azoxymethane, Carcinogens, Cells, Cultured, Colonic Neoplasms, Dextran Sulfate, Disease Models, Animal, ErbB Receptors, Gastritis, Hypertrophic, Genes, Reporter, Hepatocytes, Humans, Mice, Mice, Transgenic, Primary Cell Culture
Added January 31, 2020
1 Communities
1 Members
0 Resources
17 MeSH Terms
Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.
Coburn LA, Singh K, Asim M, Barry DP, Allaman MM, Al-Greene NT, Hardbower DM, Polosukhina D, Williams CS, Delgado AG, Piazuelo MB, Washington MK, Gobert AP, Wilson KT
(2019) Oncogene 38: 1067-1079
MeSH Terms: Amino Acid Transport Systems, Basic, Animals, Azoxymethane, Cell Line, Tumor, Cell Transformation, Neoplastic, Colonic Neoplasms, Inflammation, Inflammatory Bowel Diseases, Mice, Mice, Knockout, Neoplasm Proteins
Show Abstract · Added September 12, 2018
Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2 mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2 mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1β, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11bF4/80ARG1 cells with no alteration in CD11bF4/80NOS2 cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2 mice. In bone marrow chimeras between Slc7a2 and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.
0 Communities
3 Members
0 Resources
11 MeSH Terms
Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses.
Singh K, Coburn LA, Asim M, Barry DP, Allaman MM, Shi C, Washington MK, Luis PB, Schneider C, Delgado AG, Piazuelo MB, Cleveland JL, Gobert AP, Wilson KT
(2018) Cancer Res 78: 4303-4315
MeSH Terms: Animals, Azoxymethane, Carcinogenesis, Colitis, Ulcerative, Colon, Colonic Neoplasms, Cytokines, Dextran Sulfate, Inflammation, Macrophage Activation, Macrophages, Male, Mice, Ornithine Decarboxylase, Transcription, Genetic, Up-Regulation
Show Abstract · Added June 15, 2018
Ornithine decarboxylase (ODC) is the rate-limiting enzyme for polyamine biosynthesis and restricts M1 macrophage activation in gastrointestinal (GI) infections. However, the role of macrophage ODC in colonic epithelial-driven inflammation is unknown. Here, we investigate cell-specific effects of ODC in colitis and colitis-associated carcinogenesis (CAC). Human colonic macrophages expressed increased ODC levels in active ulcerative colitis and Crohn's disease, colitis-associated dysplasia, and CAC. Mice lacking in myeloid cells ( mice) that were treated with dextran sulfate sodium (DSS) exhibited improved survival, body weight, and colon length and reduced histologic injury versus control mice. In contrast, GI epithelial-specific knockout had no effect on clinical parameters. Despite reduced histologic damage, colitis tissues of mice had increased levels of multiple proinflammatory cytokines and chemokines and enhanced expression of M1, but not M2 markers. In the azoxymethane-DSS model of CAC, mice had reduced tumor number, burden, and high-grade dysplasia. Tumors from mice had increased M1, but not M2 macrophages. Increased levels of histone 3, lysine 9 acetylation, a marker of open chromatin, were manifest in tumor macrophages of mice, consistent with our findings that macrophage ODC affects histone modifications that upregulate M1 gene transcription during GI infections. These findings support the concept that macrophage ODC augments epithelial injury-associated colitis and CAC by impairing the M1 responses that stimulate epithelial repair, antimicrobial defense, and antitumoral immunity. They also suggest that macrophage ODC is an important target for colon cancer chemoprevention. Ornithine decarboxylase contributes to the pathogenesis of colitis and associated carcinogenesis by impairing M1 macrophage responses needed for antitumoral immunity; targeting ODC in macrophages may represent a new strategy for chemoprevention. .
©2018 American Association for Cancer Research.
0 Communities
2 Members
0 Resources
16 MeSH Terms
Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma.
Al-Greene NT, Means AL, Lu P, Jiang A, Schmidt CR, Chakravarthy AB, Merchant NB, Washington MK, Zhang B, Shyr Y, Deane NG, Beauchamp RD
(2013) PLoS One 8: e69660
MeSH Terms: Animals, Azoxymethane, Cell Line, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Dextran Sulfate, Female, Humans, In Vitro Techniques, Mice, Mice, Nude, Neovascularization, Pathologic, Nerve Tissue Proteins
Show Abstract · Added August 22, 2013
Angiogenesis, the recruitment and re-configuration of pre-existing vasculature, is essential for tumor growth and metastasis. Increased tumor vascularization often correlates with poor patient outcomes in a broad spectrum of carcinomas. We identified four jointed box 1 (FJX1) as a candidate regulator of tumor angiogenesis in colorectal cancer. FJX1 mRNA and protein are upregulated in human colorectal tumor epithelium as compared with normal epithelium and colorectal adenomas, and high expression of FJX1 is associated with poor patient prognosis. FJX1 mRNA expression in colorectal cancer tissues is significantly correlated with changes in known angiogenesis genes. Augmented expression of FJX1 in colon cancer cells promotes growth of xenografts in athymic mice and is associated with increased tumor cell proliferation and vascularization. Furthermore, FJX1 null mice develop significantly fewer colonic polyps than wild-type littermates after combined dextran sodium sulfate (DSS) and azoxymethane (AOM) treatment. In vitro, conditioned media from FJX1 expressing cells promoted endothelial cell capillary tube formation in a HIF1-α dependent manner. Taken together our results support the conclusion that FJX1 is a novel regulator of tumor progression, due in part, to its effect on tumor vascularization.
1 Communities
8 Members
0 Resources
14 MeSH Terms
Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis.
Barrett CW, Singh K, Motley AK, Lintel MK, Matafonova E, Bradley AM, Ning W, Poindexter SV, Parang B, Reddy VK, Chaturvedi R, Fingleton BM, Washington MK, Wilson KT, Davies SS, Hill KE, Burk RF, Williams CS
(2013) PLoS One 8: e67845
MeSH Terms: 8-Hydroxy-2'-Deoxyguanosine, Animals, Azoxymethane, Carcinogenesis, Colitis, Colonic Neoplasms, DNA Damage, Deoxyguanosine, Dextran Sulfate, Diet, Epidermal Growth Factor, Gene Expression Regulation, Inflammation, Mice, Mice, Inbred C57BL, Selenium, Signal Transduction, Transforming Growth Factor beta, Weight Loss
Show Abstract · Added March 5, 2014
Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.
3 Communities
8 Members
0 Resources
19 MeSH Terms
Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer.
Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, Lozano G, Pikarsky E, Forshew T, Rosenfeld N, Rozenfeld N, Harpaz N, Itzkowitz S, Harris CC, Rotter V, Gorgoulis VG, Oren M
(2013) Cancer Cell 23: 634-46
MeSH Terms: Animals, Azoxymethane, Colitis, Colon, Colorectal Neoplasms, DNA Damage, Dextran Sulfate, Genetic Predisposition to Disease, Histones, Humans, Mice, Mice, Inbred C57BL, NF-kappa B, Nitric Oxide Synthase Type II, Protein Isoforms, Tumor Necrosis Factor-alpha, Tumor Suppressor Protein p53
Show Abstract · Added July 31, 2013
The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-α-induced NF-κB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-κB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC.
Copyright © 2013 Elsevier Inc. All rights reserved.
0 Communities
0 Members
0 Resources
17 MeSH Terms
MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model.
Barrett CW, Fingleton B, Williams A, Ning W, Fischer MA, Washington MK, Chaturvedi R, Wilson KT, Hiebert SW, Williams CS
(2011) Cancer Res 71: 1302-12
MeSH Terms: Animals, Azoxymethane, Carcinoma, Cell Transformation, Neoplastic, Colitis, Colonic Neoplasms, Dextran Sulfate, Disease Models, Animal, Disease Progression, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Repressor Proteins
Show Abstract · Added July 28, 2012
Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1(-/-) mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1(-/-) mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1(-/-) tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1(-/-) tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3(+) and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1(-/-) mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis.
©2011 AACR.
3 Communities
6 Members
0 Resources
16 MeSH Terms
Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model.
Borinstein SC, Conerly M, Dzieciatkowski S, Biswas S, Washington MK, Trobridge P, Henikoff S, Grady WM
(2010) Mol Carcinog 49: 94-103
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, Azoxymethane, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion Molecule-1, Cell Adhesion Molecules, Colonic Neoplasms, Connexins, Cyclin-Dependent Kinase Inhibitor p16, DNA Methylation, DNA Modification Methylases, DNA Repair Enzymes, DNA-Binding Proteins, Death-Associated Protein Kinases, Disease Models, Animal, Humans, Immunoglobulins, Inhibitor of Differentiation Proteins, Insulin-Like Growth Factor Binding Protein 3, Intestinal Mucosa, Membrane Proteins, Mice, MutL Protein Homolog 1, Nuclear Proteins, Receptors, CXCR4, Repressor Proteins, Transcription Factors, Tumor Suppressor Proteins
Show Abstract · Added April 12, 2016
Mouse models of intestinal tumors have advanced our understanding of the role of gene mutations in colorectal malignancy. However, the utility of these systems for studying the role of epigenetic alterations in intestinal neoplasms remains to be defined. Consequently, we assessed the role of aberrant DNA methylation in the azoxymethane (AOM) rodent model of colon cancer. AOM induced tumors display global DNA hypomethylation, which is similar to human colorectal cancer. We next assessed the methylation status of a panel of candidate genes previously shown to be aberrantly methylated in human cancer or in mouse models of malignant neoplasms. This analysis revealed different patterns of DNA methylation that were gene specific. Zik1 and Gja9 demonstrated cancer-specific aberrant DNA methylation, whereas, Cdkn2a/p16, Igfbp3, Mgmt, Id4, and Cxcr4 were methylated in both the AOM tumors and normal colon mucosa. No aberrant methylation of Dapk1 or Mlt1 was detected in the neoplasms, but normal colon mucosa samples displayed methylation of these genes. Finally, p19(Arf), Tslc1, Hltf, and Mlh1 were unmethylated in both the AOM tumors and normal colon mucosa. Thus, aberrant DNA methylation does occur in AOM tumors, although the frequency of aberrantly methylated genes appears to be less common than in human colorectal cancer. Additional studies are necessary to further characterize the patterns of aberrantly methylated genes in AOM tumors.
2009 Wiley-Liss, Inc.
0 Communities
1 Members
0 Resources
29 MeSH Terms
Dietary iron promotes azoxymethane-induced colon tumors in mice.
Ilsley JN, Belinsky GS, Guda K, Zhang Q, Huang X, Blumberg JB, Milbury PE, Roberts LJ, Stevens RG, Rosenberg DW
(2004) Nutr Cancer 49: 162-9
MeSH Terms: Animals, Apoptosis, Azoxymethane, Carcinogens, Cell Division, Colonic Neoplasms, DNA Damage, Disease Models, Animal, Dose-Response Relationship, Drug, In Situ Nick-End Labeling, Iron, Dietary, Mice, Oxidative Stress, Precancerous Conditions, Random Allocation, Time Factors
Show Abstract · Added December 10, 2013
There is accumulating evidence that high levels of dietary iron may play a role in colon carcinogenesis. We used a mouse model to investigate the impact of elevated dietary iron on incidence of aberrant crypt foci (ACF; a preneoplastic lesion) on tumor formation and on induction of oxidative stress. A/J mice were injected intraperitoneally, once a week for 6 weeks, with the colonotropic carcinogen, azoxymethane (AOM) or saline (vehicle controls). Following AOM or saline treatments, mice were placed on diets of high (3,000 ppm) and low (30 ppm) iron. Mice in each treatment group were sacrificed at 6 and 10 weeks following the final injection with AOM or saline. Colons were removed for subsequent histopathological analysis, which revealed average increases of 4.6 +- 1.3 vs. 10.4 +- 2.5 total tumors at 6 weeks and 30.75 +- 2.7 vs. 41.5 +- 4.4 total tumors at 10 weeks per AOM-treated mouse on low- and high-iron diets, respectively. There were no significant differences in incidence of ACF attributable to iron, although there was a trend toward greater crypt multiplicity per focus in mice on high-iron diets. Notably, no tumors were observed in mice receiving vehicle control injections in place of carcinogen, regardless of the level of dietary iron. These data suggest that iron exerts its effect at the stage of tumor promotion, but is not sufficient to initiate tumor formation. To learn more about mechanisms by which iron promotes tumor growth, colons were assayed for several biomarkers of oxidative stress [BOS; total F2-isoprostanes (F2-IsoPs), 15-F2t-isoprostanes (8-IsoPGF2s), Isofurans (IsoFs), and 8-hydroxyguanosines (8-OH[d]Gs)], as well as iron absorption, programmed cell death, and cellular proliferation. Elevated PCNA and TUNEL staining of the colon epithelium revealed hyperproliferative and apoptotic responses to iron, while no significant differences between iron groups were observed in each of the BOS that were assayed. Our results suggest that, following carcinogen exposure, elevated dietary iron promotes the growth of tumors with altered cellular homeostasis through a mechanism that is independent of oxidative stress.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer.
Biswas S, Chytil A, Washington K, Romero-Gallo J, Gorska AE, Wirth PS, Gautam S, Moses HL, Grady WM
(2004) Cancer Res 64: 4687-92
MeSH Terms: Animals, Apoptosis, Azoxymethane, Carcinogens, Carrier Proteins, Cell Differentiation, Cell Division, Cell Transformation, Neoplastic, Colon, Colonic Neoplasms, Cyclooxygenase 2, Disease Models, Animal, Disease Progression, Fatty Acid-Binding Proteins, Female, Gene Silencing, Genetic Predisposition to Disease, Isoenzymes, Male, Mice, Mutation, Prostaglandin-Endoperoxide Synthases, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta
Show Abstract · Added February 17, 2014
Deregulation of members of the transforming growth factor (TGF)-beta signaling pathway occurs often in colon cancers and is believed to affect the formation of primary colon cancer. Mutational inactivation of TGFBR2 is the most common genetic event affecting the TGF-beta signaling pathway and occurs in approximately 20-30% of all colon cancers. By mating Fabpl(4xat-132) Cre mice with Tgfbr2(flx/flx) mice, we have generated a mouse model that is null for Tgfbr2 in the colonic epithelium, and in this model system, we have assessed the effect of loss of TGF-beta signaling in vivo on colon cancer formation induced by azoxymethane (AOM). We have observed a significant increase in the number of AOM-induced adenomas and adenocarcinomas in the Fabpl(4xat-132) Cre Tgfbr2(flx/flx) mice compared with Tgfbr2(flx/flx) mice, which have intact TGF-beta receptor type II (TGFBR2) in the colon epithelium, and we have found increased proliferation in the neoplasms occurring in the Fabpl(4xat-132) Cre Tgfbr2(flx/flx) mice. These results implicate the loss of TGF-beta-mediated growth inhibition as one of the in vivo mechanisms through which TGFBR2 inactivation contributes to colon cancer formation. Thus, we have demonstrated that loss of TGFBR2 in colon epithelial cells promotes the establishment and progression of AOM-induced colon neoplasms, providing evidence from an in vivo model system that TGFBR2 is a tumor suppressor gene in the colon.
0 Communities
2 Members
0 Resources
25 MeSH Terms