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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.
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11 MeSH Terms
Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA in New-Onset Type 1 Diabetes.
Haller MJ, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Miller JL, Atkinson MA, Becker DJ, Baidal D, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell W, Wilson DM, Greenbaum CJ, Type 1 Diabetes TrialNet ATG-GCSF Study Group
(2018) Diabetes Care 41: 1917-1925
MeSH Terms: Adolescent, Adult, Antilymphocyte Serum, C-Peptide, Child, Cytoprotection, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glycated Hemoglobin A, Granulocyte Colony-Stimulating Factor, Humans, Insulin-Secreting Cells, Male, Pilot Projects, Polyethylene Glycols, Recombinant Proteins, Young Adult
Show Abstract · Added May 2, 2019
OBJECTIVE - A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that ) low-dose ATG/GCSF or ) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days).
RESEARCH DESIGN AND METHODS - A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided value < 0.025.
RESULTS - The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) ( = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo ( = 0.031). HbA was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, = 0.002 and 0.011, respectively.
CONCLUSIONS - Low-dose ATG slowed decline of C-peptide and reduced HbA in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.
© 2018 by the American Diabetes Association.
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MeSH Terms
BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.
Choksi YA, Reddy VK, Singh K, Barrett CW, Short SP, Parang B, Keating CE, Thompson JJ, Verriere TG, Brown RE, Piazuelo MB, Bader DM, Washington MK, Mittal MK, Brand T, Gobert AP, Coburn LA, Wilson KT, Williams CS
(2018) Mucosal Immunol 11: 1363-1374
MeSH Terms: Adult, Animals, Caco-2 Cells, Cell Line, Cell Line, Tumor, Citrobacter rodentium, Coculture Techniques, Colitis, Ulcerative, Colon, Dextran Sulfate, Epithelial Cells, Escherichia coli, Female, HEK293 Cells, Humans, Intestinal Absorption, Intestinal Mucosa, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Middle Aged, Permeability, RNA, Messenger, Signal Transduction, Tight Junctions
Show Abstract · Added June 23, 2018
Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves mice inoculated with Citrobacter rodentium had greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. coli showed increased attaching/effacing lesions in the absence of BVES. Finally, BVES mRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.
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26 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.
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16 MeSH Terms
Mistargeting of a truncated Na-K-2Cl cotransporter in epithelial cells.
Koumangoye R, Omer S, Delpire E
(2018) Am J Physiol Cell Physiol 315: C258-C276
MeSH Terms: Animals, Cell Membrane, Cells, Cultured, Colon, Cytoplasm, Dogs, Epithelial Cells, Female, Madin Darby Canine Kidney Cells, Male, Mice, Oocytes, Salivary Glands, Sodium-Potassium-Chloride Symporters, Sodium-Potassium-Exchanging ATPase, Solute Carrier Family 12, Member 2, Xenopus laevis
Show Abstract · Added May 4, 2018
We recently reported the case of a young patient with multisystem failure carrying a de novo mutation in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1 (NKCC1). Heterologous expression studies in nonepithelial cells failed to demonstrate dominant-negative effects. In this study, we examined expression of the mutant cotransporter in epithelial cells. Using Madin-Darby canine kidney (MDCK) cells grown on glass coverslips, permeabilized support, and Matrigel, we show that the fluorescently tagged mutant cotransporter is expressed in cytoplasm and at the apical membrane and affects epithelium integrity. Expression of the mutant transporter at the apical membrane also results in the mislocalization of some of the wild-type transporter to the apical membrane. This mistargeting is specific to NKCC1 as the Na-K-ATPase remains localized on the basolateral membrane. To assess transporter localization in vivo, we created a mouse model using CRISPR/cas9 that reproduces the 11 bp deletion in exon 22 of Slc12a2. Although the mice do not display an overt phenotype, we show that the colon and salivary gland expresses wild-type NKCC1 abundantly at the apical pole, confirming the data obtained in cultured epithelial cells. Enough cotransporter must remain, however, on the basolateral membrane to participate in saliva secretion, as no significant decrease in saliva production was observed in the mutant mice.
1 Communities
1 Members
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17 MeSH Terms
Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria.
Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, Wu X, DeStefano Shields CE, Hechenbleikner EM, Huso DL, Anders RA, Giardiello FM, Wick EC, Wang H, Wu S, Pardoll DM, Housseau F, Sears CL
(2018) Science 359: 592-597
MeSH Terms: Adenomatous Polyposis Coli, Animals, Bacterial Toxins, Bacteroides fragilis, Biofilms, Carcinogenesis, Colon, Colonic Neoplasms, DNA Damage, Escherichia coli, Gastrointestinal Microbiome, Humans, Interleukin-17, Intestinal Mucosa, Metalloendopeptidases, Mice, Peptides, Polyketides, Precancerous Conditions
Show Abstract · Added March 20, 2018
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of and Genes for colibactin () and toxin (), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with (expressing colibactin), and enterotoxigenic showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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19 MeSH Terms
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F
(2018) Cell Host Microbe 23: 203-214.e5
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Bacterial Toxins, Bacteroides fragilis, Carcinogenesis, Cell Line, Tumor, Colon, Colorectal Neoplasms, Enzyme Activation, Epithelial Cells, Female, Gene Deletion, HT29 Cells, Humans, Inflammation, Interleukin-17, Male, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Receptors, Interleukin-17, Receptors, Interleukin-8B, STAT3 Transcription Factor, Transcription Factor RelA
Show Abstract · Added March 20, 2018
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
Copyright © 2018 Elsevier Inc. All rights reserved.
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26 MeSH Terms
Gastric Carcinomas With Lymphoid Stroma: Categorization and Comparison With Solid-Type Colonic Carcinomas.
Gonzalez RS, Cates JMM, Revetta F, McMahon LA, Washington K
(2017) Am J Clin Pathol 148: 477-484
MeSH Terms: Aged, Aged, 80 and over, Colonic Neoplasms, Epstein-Barr Virus Infections, Female, Humans, Lymphocytes, Male, Microsatellite Instability, Middle Aged, Stomach Neoplasms, Stromal Cells
Show Abstract · Added November 1, 2018
Objectives - To determine whether histologic features could help identify gastric carcinomas with lymphoid stroma associated with microsatellite instability (MSI) (ie, "medullary carcinomas"), Epstein-Barr virus (EBV) infection (termed lymphoepithelioma-like carcinomas in other organ systems), or neither.
Methods - We identified 17 solid-type gastric carcinomas with lymphoid stroma, assessed EBV and MSI status, and compared features across groups. We also compared them with 51 solid-type colorectal adenocarcinomas.
Results - In the stomach, EBV-associated carcinomas (n = 8) contained intratumoral germinal centers (P = .024) and eosinophils (P = .030) and lacked necrosis (P = .019) compared with MSI-associated carcinomas (n = 5) and non-EBV, non-MSI carcinomas (n = 4). In the colon, MSI-driven carcinomas (n = 40) more frequently contained intratumoral lymphocytes (P = .017) and neutrophils (P = .0050) and less often metastasized to distant sites (P = .0040) than poorly differentiated carcinomas lacking MSI (n = 11).
Conclusions - Morphology may help classify gastric carcinomas with lymphoid stroma, although ancillary testing appears more reliable. Lymphoepithelioma-like carcinoma and medullary carcinoma should not be used interchangeably.
© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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MeSH Terms
Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma.
Idrees K, Padmanabhan C, Liu E, Guo Y, Gonzalez RS, Berlin J, Dahlman KB, Beauchamp RD, Shi C
(2018) J Surg Oncol 117: 284-289
MeSH Terms: Adult, Aged, Biomarkers, Tumor, Carcinogenesis, Case-Control Studies, Colonic Neoplasms, DNA Mutational Analysis, DNA, Neoplasm, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mutation, Neuroendocrine Tumors, Prognosis, Proto-Oncogene Proteins B-raf
Show Abstract · Added March 14, 2018
BACKGROUND AND OBJECTIVES - The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease.
METHODS - We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15.
RESULTS - We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs.
CONCLUSION - Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.
© 2017 Wiley Periodicals, Inc.
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2 Members
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17 MeSH Terms
Management of colonoscopic perforations: A systematic review.
Hawkins AT, Sharp KW, Ford MM, Muldoon RL, Hopkins MB, Geiger TM
(2018) Am J Surg 215: 712-718
MeSH Terms: Algorithms, Colonoscopy, Comorbidity, Humans, Intestinal Perforation
Show Abstract · Added December 14, 2017
BACKGROUND - Perforation during colonoscopy is a rare but well recognized complication with significant morbidity and mortality. We aim to systematically review the currently available literature concerning care and outcomes of colonic perforation. An algorithm is created to guide the practitioner in management of this challenging clinical scenario.
DATA SOURCES - A systematic review of the literature based on PRISMA-P guidelines was performed. We evaluate 31 articles focusing on findings over the past 10 years.
CONCLUSION - Colonoscopic perforation is a rare event and published management techniques are marked by their heterogeneity. Reliable conclusions are limited by the nature of the data available - mainly single institution, retrospective studies. Consensus conclusions include a higher rate of perforation from therapeutic colonoscopy when compared to diagnostic colonoscopy and the sigmoid as the most common site of perforation. Mortality appears driven by pre-existing conditions. Treatment must be tailored according to the patient's comorbidities and clinical status as well as the specific conditions during the colonoscopy that led to the perforation.
Copyright © 2017 Elsevier Inc. All rights reserved.
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5 MeSH Terms