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  • 1
    Keywords: CELLS ; METABOLISM ; SEQUENCES ; INTERFACE ; inflammation ; INNATE ; PROBE LEVEL ; MICROBIAL ECOLOGY ; GUT MICROBIOME
    Abstract: Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-rasG12Dint, mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-rasG12Dint mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-rasG12Dint mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.
    Type of Publication: Journal article published
    PubMed ID: 25174708
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  62. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS); 20170917-20170921; Oldenburg; DOCAbstr. 072 /20170829/
    Publication Date: 2017-09-21
    Keywords: Medizinische Informatik ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
    Keywords: EXPRESSION ; proliferation ; TUMOR PROGRESSION ; STEM-CELLS ; PROGNOSTIC-SIGNIFICANCE ; beta-catenin ; microenvironment ; E-cadherin ; TUMORIGENESIS ; WNT ACTIVITY
    Abstract: Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments. Colorectal cancers derive from colonic crypt epithelia but, in contrast, form morphologically disarrayed glands. In this study, we investigated to which extent colorectal cancers phenocopy colonic crypt architecture and thus preserve structural organization of the normal intestinal epithelium. A subset of colon cancers showed crypt-like compartments with high WNT activity and nuclear beta-Catenin at the leading tumor edge, adjacent proliferation, and enhanced Cytokeratin 20 expression in most differentiated tumor epithelia of the tumor center. This architecture strongly depended on growth conditions, and was fully reproducible in mouse xenografts of cultured and primary colon cancer cells. Full crypt-like organization was associated with low tumor grade and was an independent prognostic marker of better survival in a collection of 221 colorectal cancers. Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments. Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes.
    Type of Publication: Journal article published
    PubMed ID: 25111606
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  • 4
    Keywords: CANCER ; EXPRESSION ; MODEL ; NEOPLASIA ; PROGRESSION ; MUTATIONS ; APC GENE ; LYMPHOCYTE DEVELOPMENT ; TRANSCRIPTION FACTOR E2-2 ; COLORECTAL TUMORIGENESIS
    Abstract: Deregulation of Wnt/beta-catenin signaling following inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene is frequently found in colorectal cancer. We have previously shown that levels of ITF-2B, encoded by the beta-catenin target gene ITF2 that is located on the tumor suppressor gene locus 18q21, are increased in colonic adenomas with deregulated beta-catenin activity. However, during tumor progression ITF-2B levels are reduced, suggesting that ITF-2B interferes with tumor development. To investigate the role of ITF2 in intestinal tumorigenesis, we specifically inactivated Itf2 in the intestinal epithelium of Apc(Min/+) mice. We found that genetic disruption of Itf2 on the Apc(Min/+) background results in earlier death and a significant increase in tumor number and size in the small intestine. Based on these data Itf2 acts as a tumor suppressor gene of the intestinal tract that inhibits tumor initiation and growth.
    Type of Publication: Journal article published
    PubMed ID: 25869068
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  • 5
    Keywords: EXPRESSION ; PROGRESSION ; COLON-CANCER ; METAANALYSIS ; TARGET GENES ; APC ; MICROSATELLITE-INSTABILITY
    Abstract: The majority of sporadic forms of colorectal carcinomas is characterized by deregulation of Wnt/beta-catenin signaling early in colorectal carcinogenesis. As a consequence, ITF-2B protein levels are increased in adenomas of these patients. However, ITF-2B protein levels are strongly reduced with increasing carcinoma stages, suggesting that reduction of ITF-2B protein is required for progression of adenomas to colorectal carcinomas. To find out if ITF-2B protein levels are correlated with the survival of patients with colorectal carcinomas, a tissue microarray containing samples from 213 colorectal carcinomas (T-categories T2 and T3) with corresponding survival information was stained with an ITF-2B antibody. In addition, we analyzed if detection of ITF-2B in microsatellite instable and microsatellite stable carcinomas as well as in colorectal carcinomas with KRAS mutations is correlated with survival. Detection of cytoplasmic ITF-2B protein was associated with better overall and progression free survival of patients with colorectal carcinomas (P=0.033 and 0.024, respectively). Multivariate Cox regression analysis revealed an increased risk to suffer from poor overall survival and recurrent disease if no cytoplasmic ITF-2B was detectable (HR=1.91; P=0.033 and HR=1.75; P=0.033, respectively). Similarly, patients with MSS carcinomas had a better overall survival, if they showed cytoplasmic positivity for ITF-2B (P=0.013). Remarkably, patients with colorectal carcinomas carrying KRAS mutations had a better overall and progression free survival rate if the carcinomas were positive for cytoplasmic ITF-2B (HR=4.71; P=0.002 and HR=2.57; P=0.024, respectively). These data suggest that cytoplasmic protein levels of ITF-2B could be used as a prognostic marker for patients with colorectal carcinomas.
    Type of Publication: Journal article published
    PubMed ID: 26328254
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  • 6
    Publication Date: 2014-09-02
    Description: Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras(G12Dint), mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras(G12Dint) mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras(G12Dint) mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233209/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233209/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schulz, Manon D -- Atay, Cigdem -- Heringer, Jessica -- Romrig, Franziska K -- Schwitalla, Sarah -- Aydin, Begum -- Ziegler, Paul K -- Varga, Julia -- Reindl, Wolfgang -- Pommerenke, Claudia -- Salinas-Riester, Gabriela -- Bock, Andreas -- Alpert, Carl -- Blaut, Michael -- Polson, Sara C -- Brandl, Lydia -- Kirchner, Thomas -- Greten, Florian R -- Polson, Shawn W -- Arkan, Melek C -- 8 P20 GM103446-12/GM/NIGMS NIH HHS/ -- P20 GM103446/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):508-12. doi: 10.1038/nature13398. Epub 2014 Aug 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany [2]. ; Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany. ; Department of Molecular Biology and Genetics, Bogazici University, 34342 Bebek, Istanbul, Turkey. ; 1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany [3] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Internal Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany. ; Microarray and Deep-Sequencing Core Facility, University Medical Center Gottingen, 37077 Gottingen, Germany. ; Institute for Mathematical Statistics, Technical University Munich, 81675 Munich, Germany. ; 1] Department of Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany [2]. ; Department of Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany. ; Center for Bioinformatics and Computational Biology, Delaware Biotechnology Institute, University of Delaware, Newark, Delaware 19711, USA. ; Institute of Pathology, Ludwig Maximilians University, 80337 Munich, Germany. ; 1] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany [2] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3] Institute of Pathology, Ludwig Maximilians University, 80337 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25174708" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Butyrates/pharmacology ; Carcinogenesis/*drug effects ; Diet, High-Fat/*adverse effects ; Dietary Fats/*adverse effects ; Disease Progression ; Dysbiosis/*chemically induced/*microbiology ; Intestinal Mucosa/immunology ; Intestinal Neoplasms/chemically induced/*microbiology ; Intestines/drug effects/microbiology ; Mice ; *Obesity/chemically induced/microbiology ; Prebiotics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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