Publications by authors named "Christoph Gasche"

90 Publications

Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia.

Sci Rep 2021 Jul 1;11(1):13699. Epub 2021 Jul 1.

Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK.

Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.
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http://dx.doi.org/10.1038/s41598-021-93155-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249613PMC
July 2021

Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis.

Gastroenterology 2021 Oct 17;161(4):1245-1256.e20. Epub 2021 Jun 17.

Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria; Loha for Life, Center for Gastroenterlogy and Iron Deficiency, Vienna, Austria. Electronic address:

Background & Aims: Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism.

Methods: The presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning-based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays.

Results: Biofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea.

Conclusions: The presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease.
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http://dx.doi.org/10.1053/j.gastro.2021.06.024DOI Listing
October 2021

The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models.

Sci Rep 2021 Mar 4;11(1):5188. Epub 2021 Mar 4.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Inflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10 model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.
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http://dx.doi.org/10.1038/s41598-021-84571-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933154PMC
March 2021

Endoscopic retrograde appendicitis therapy: new approach in the treatment of stump appendicitis.

Endoscopy 2021 Feb 16. Epub 2021 Feb 16.

Division of Gastroenterology and Hepatology, Internal Medicine III, Medical University of Vienna, Austria.

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http://dx.doi.org/10.1055/a-1346-8677DOI Listing
February 2021

Iron deficiency, depression, and fatigue in inflammatory bowel diseases.

Z Gastroenterol 2020 Dec 8;58(12):1191-1200. Epub 2020 Dec 8.

Div. of Gastroenterology and Hepatology, Dept Medicine 3.

Background:  Iron deficiency and anemia are common findings in IBD. Treatment of anemia improves quality of life. Neurological symptoms like depression or anxiety are also common in IBD; however, their relationship with ID has not been studied in detail.

Methods:  Prospective, single center, non-interventional trial in an IBD cohort (n = 98), which is generally at risk for ID. Quality of sleep (using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Insomnia Severity Index) and the presence of fatigue (Piper fatigue scale), depression (Self-rating Depression Scale [SDS]) or anxiety (Self-rating Anxiety Scale [SAS]) were related to ID (ferritin, transferrin saturation), anemia (hemoglobin), and inflammatory disease activity (CRP).

Results:  ID was present in 35 %, anemia in 16 %, and inflammation in 30 %. The overall quality of sleep in this cohort was similar to that reported for the general population. ID, anemia, or inflammation had no influence on the PSQI (median 4.0 [CI 3.0-5.0]), the ESS 5.5 (5.0-7.0), and the ISI 4.00 (2.5-5.5). Fatigue (PFS; present in 30 %), anxiety (SAS; present in 24 %), and depression (SDS; present in 33 %) were more common than in the general population. Iron deficient and anemic patients were more likely to be depressed (p = 0.02 and p < 0.01) and showed a trend towards presence of fatigue (p = 0.06 and 0.07). Systemic inflammation as measured by CRP had no effect on any of these conditions.

Conclusion:  In this IBD cohort, ID and anemia affect depression and possibly fatigue independent of the presence of inflammation.
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http://dx.doi.org/10.1055/a-1283-6832DOI Listing
December 2020

A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.

Cell Mol Gastroenterol Hepatol 2021 12;11(3):892-907.e1. Epub 2020 Nov 12.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address:

Background & Aims: p21-activated kinase-1 (PAK1) belongs to a family of serine-threonine kinases and contributes to cellular pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Wingless-related integration site(Wnt)/β-catenin, all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to inflammatory bowel disease as well as colitis-associated cancer (CAC), and similarly was observed in interleukin (IL)10 knockout (KO) mice, a model of colitis and CAC. Here, we tested the effects of PAK1 deletion on intestinal inflammation and carcinogenesis in IL10 KO mice.

Methods: IL10/PAK1 double-knockout (DKO) mice were generated and development of colitis and CAC was analyzed. Large intestines were measured and prepared for histology or RNA isolation. Swiss rolls were stained with H&E and periodic acid-Schiff. Co-immunoprecipitation and immunofluorescence were performed using intestinal organoids, SW480, and normal human colon epithelial cells 1CT.

Results: When compared with IL10 KO mice, DKOs showed longer colons and prolonged crypts, despite having higher inflammation and numbers of dysplasia. Crypt hyperproliferation was associated with Notch1 activation and diminished crypt differentiation, indicated by a reduction of goblet cells. Gene expression analysis indicated up-regulation of the Notch1 target hairy and enhancer of split-1 and the stem cell receptor leucin-rich repeat-containing G-protein-coupled receptor 5 in DKO mice. Interestingly, the stem cell marker olfactomedin-4 was present in colonic tissue. Increased β-catenin messenger RNA and cytoplasmic accumulation indicated aberrant Wnt signaling. Co-localization and direct interaction of Notch1 and PAK1 was found in colon epithelial cells. Notch1 activation abrogated this effect whereas silencing of PAK1 led to Notch1 activation.

Conclusions: PAK1 contributes to the regulation of crypt homeostasis under inflammatory conditions by controlling Notch1. This identifies a novel PAK1-Notch1 axis in intestinal pathophysiology of inflammatory bowel disease and CAC.
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http://dx.doi.org/10.1016/j.jcmgh.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900837PMC
November 2020

Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome.

Int J Cancer 2020 10 18;147(8):2316-2326. Epub 2020 May 18.

Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria.

Colorectal cancer is a multifactorial disease involving inherited DNA mutations, environmental factors, gut inflammation and intestinal microbiota. Certain germline mutations within the DNA mismatch repair system are associated with Lynch syndrome tumors including right-sided colorectal cancer with mucinous phenotype and presence of an inflammatory infiltrate. Such tumors are more often associated with bacterial biofilms, which may contribute to disease onset and progression. Inflammatory bowel diseases are also associated with colorectal cancer and intestinal dysbiosis. Herein we addressed the question, whether inflammation can aggravate colorectal cancer development under mismatch repair deficiency. MSH2 mice were crossed into the IL-10 background to study the importance of inflammation and mucosal bacteria as a driver of tumorigenesis in a Lynch syndrome mouse model. An increase in large bowel tumorigenesis was found in double knockout mice both under conventional housing and under specific pathogen-free conditions. This increase was mostly due to the development of proximal tumors, a hotspot for tumorigenesis in Lynch syndrome, and was associated with a higher degree of inflammation. Additionally, bacterial invasion into the mucus of tumor crypts was observed in the proximal tumors. Inflammation shifted fecal and mucosal microbiota composition and was associated with enrichment in Escherichia-Shigella as well as Akkermansia, Bacteroides and Parabacteroides genera in fecal samples. Tumor-bearing double knockout mice showed a similar enrichment for Escherichia-Shigella and Parabacteroides. Lactobacilli, Lachnospiraceae and Muribaculaceae family members were depleted upon inflammation. In summary, chronic inflammation aggravates colonic tumorigenesis under mismatch repair deficiency and is associated with a shift in microbiota composition.
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http://dx.doi.org/10.1002/ijc.33028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496850PMC
October 2020

Iron deficiency-induced thrombocytosis increases thrombotic tendency in rats.

Haematologica 2021 03 1;106(3):782-794. Epub 2021 Mar 1.

Div. of Gastroenterology and Hepatology,Dept. of Internal Medicine III, Medical University of Vienna.

Iron deficiency (ID) is globally prevalent, and apart from anemia is associated with thrombocytosis. While considered benign, studies linking thrombotic events with prior ID anemia suggest otherwise. Herein we used animal models to assess the influence of ID on thrombotic tendency. Sprague-Dawley rats were fed control or iron deficient diets and ferric carboxymaltose was used to reverse ID. Thrombosis was induced via stenosis of the inferior vena cava or damage to the right carotid artery using ferric chloride. Thrombi were evaluated histologically and via high frequency ultrasound in the venous model. ID consistently induced thrombocytosis alongside anemia. Venous thrombus growth and final dimensions in both arterial and venous thrombi were largest in ID. In both models, platelet numbers correlated with the final thrombus size, with ID thrombi having the largest platelet areas. Platelet function was also evaluated in surgically naive rats. Coagulability on thromboelastography and hemostasis on tail transection were augmented in ID. Platelet and plasma P-selectin expression were both higher in ID. Platelet adhesion and aggregation in ID was impaired under shear flow but was intact on static assays. Iron replacement therapy reversed all ID-related changes in hematological parameters, thrombus dimensions, and platelet assays. In summary, ID alone increases thrombotic tendency. Iron replacement therapy reverses these changes, making it a viable strategy for prevention of ID-related thrombotic disease. This may be of importance in patients with chronic illnesses which may already be at increased risk for thrombosis such as inflammatory bowel disease, chronic kidney disease, or cancer.
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http://dx.doi.org/10.3324/haematol.2019.245092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928018PMC
March 2021

Dietary Guidance From the International Organization for the Study of Inflammatory Bowel Diseases.

Clin Gastroenterol Hepatol 2020 05 15;18(6):1381-1392. Epub 2020 Feb 15.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Recent evidence points to a plausible role of diet and the microbiome in the pathogenesis of both Crohn's disease (CD) and Ulcerative Colitis (UC). Dietary therapies based on exclusion of table foods and replacement with nutritional formulas and/or a combination of nutritional formulas and specific table foods may induce remission in CD. In UC, specific dietary components have also been associated with flare of disease. While evidence of varying quality has identified potential harmful or beneficial dietary components, physicians and patients at the present time do not have guidance as to which foods are safe, may be protective or deleterious for these diseases. The current document has been compiled by the nutrition cluster of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) based on the best current evidence to provide expert opinion regarding specific dietary components, food groups and food additives that may be prudent to increase or decrease in the diet of patients with inflammatory bowel diseases to control and prevent relapse of inflammatory bowel diseases.
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http://dx.doi.org/10.1016/j.cgh.2020.01.046DOI Listing
May 2020

Switching to a Healthy Diet Prevents the Detrimental Effects of Western Diet in a Colitis-Associated Colorectal Cancer Model.

Nutrients 2019 Dec 23;12(1). Epub 2019 Dec 23.

Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria.

Inflammatory bowel disease increases the odds of developing colitis-associated cancer. We hypothesized that Western-style diet (WD) aggravates azoxymethane (AOM)/dextran sulfate sodium salt (DSS)-induced colitis-associated tumorigenesis and that switching to the standard AIN93G diet will ameliorate disease symptoms even after cancer initiation. Female BALB/c mice received either WD (WD group) or standard AIN93G diet (AIN group) for the whole experimental period. After five weeks, the mice received 12.5 mg/kg AOM intraperitoneally, followed by three DSS cycles. In one group of mice, the WD was switched to AIN93G the day before starting the first DSS cycle (WD/AIN group). Feeding the WD during the whole experimental period aggravated colitis symptoms, shortened the colon ( < 0.05), changed microbiota composition and increased tumor promotion. On molecular level, the WD reduced proliferation ( < 0.05) and increased expression of the vitamin D catabolizing enzyme ( < 0.001). The switch to the AIN93G diet ameliorated this effect, reflected by longer colons, fewer ( < 0.05) and smaller ( < 0.01) aberrant colonic crypt foci, comparable with the AIN group. Our results show that switching to a healthy diet, even after cancer initiation is able to revert the deleterious effect of the WD and could be an effective preventive strategy to reduce colitis symptoms and prevent tumorigenesis.
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http://dx.doi.org/10.3390/nu12010045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019913PMC
December 2019

p-21 Activated Kinase as a Molecular Target for Chemoprevention in Diabetes.

Geriatrics (Basel) 2018 Oct 19;3(4). Epub 2018 Oct 19.

Department of Internal Medicine III, Medical University of Vienna, Vienna 1090, Austria.

Hypothesis: Anti-diabetic drugs modulate p-21 activated kinase (PAK) signaling. : Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease associated with increased cancer risk. PAK signaling is implicated in cellular homeostasis when regulated, and cancer when unrestrained. Recent reports provided a role for PAK signaling in glucose homeostasis, but the role of PAKs in the pathogenesis of T2DM is unknown. Here, we performed a mini-meta-analysis to explore if anti-diabetic drugs modify PAK signaling pathways, and provide insight regarding modulation of these pathways, to potentially reduce diabetes-associated cancer risk. : PAK interacting partners in T2DM were identified using the online STRING database. Correlation studies were performed via systematic literature review to understand the effect of anti-diabetic drugs on PAK signaling. A mini-meta-analysis correlated multiple clinical studies and revealed the overall clinical response rate and percentage of adverse events in piogliazone (n = 53) and metformin (n = 91) treated patients with PAK-associated diseases. : A total of 30 PAK interacting partners were identified (10: reduced beta-cell mass; 10: beta-cell dysfunction; 10: obesity-insulin resistance), which were highly associated with Wnt, and G-protein signaling. The anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall, clinical response upon pioglitazone treatment was 53%. Seventy-nine percent of pioglitazone and 75% of metformin treated patients had adverse events. Pioglitazone reduced molecular-PAK biomarkers of proliferation (Ki67 and CyclinD1), and metformin had the opposite effect. : PAK signaling in T2DM likely involves Wnt and G-protein signaling, which may be altered by the anti-diabetic drugs metformin and pioglitazone. Apart from the therapeutic limitations of adverse events, pioglitazone may be promising in chemoprevention. However long-term multi-centered studies, which initiate pioglitazone treatment early will be required to fully assess the full potential of these drugs.
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http://dx.doi.org/10.3390/geriatrics3040073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371191PMC
October 2018

Management of Iron Deficiency Anaemia in Inflammatory Bowel Disease.

Acta Haematol 2019 10;142(1):30-36. Epub 2019 Apr 10.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,

Inflammatory bowel disease (IBD) is a group of chronic relapsing inflammatory disorders affecting the large and small intestine, with a rising worldwide incidence and prevalence. Anaemia is the most common extraintestinal manifestation of IBD, correlating with disease activity, and tending to relapse even after successful therapy. Iron deficiency is the most common cause; however, it often manifests in combination with anaemia of inflammation. As such, multiple parameters are used for the diagnosis of iron deficiency anaemia in IBD. Timely recognition and selection of appropriate therapy leads to an improvement in the quality of life and prevention of potential sequelae. Oral iron can be effective under specific circumstances; however, as luminal iron changes microbiota and bacterial metabolism, oral administration should be avoided. Intravenous iron is preferred as it bypasses the sites of inflammation. Nevertheless, the optimization of IBD treatment should occur simultaneously, as this improves both patient condition and response to iron therapy. Herein, we discuss the screening, diagnosis, selection of therapy, and follow-up for iron deficiency anaemia in IBD.
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http://dx.doi.org/10.1159/000496728DOI Listing
December 2019

Mesalamine and azathioprine modulate junctional complexes and restore epithelial barrier function in intestinal inflammation.

Sci Rep 2019 02 26;9(1):2842. Epub 2019 Feb 26.

Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.

Disruption of mucosal structure and barrier function contribute to the pathogenesis of inflammatory bowel disease (IBD). Efficacy of therapy in IBD is based on endoscopic mucosal healing, which occurs by a dynamic interplay of epithelial cell regeneration, migration and differentiation. Both mesalamine (5-ASA) and azathioprine (AZTP) promote this process through mechanisms not clearly understood. We examined molecular pathways implicated in epithelial barrier function that were altered by 5-ASA and AZTP. Paracellular permeability induced by inflammatory mediators was mitigated by both compounds through restoration of cellular anchoring complexes. 5-ASA and AZTP induced rearrangement and membranous localization of junctional proteins and modulated genes involved in tight junctions. Intestinal organoids from wildtype-mice treated with TNF-α and IL-10- deficient-mice displayed impaired epithelial barrier with loss of membranous E-cadherin and reduced Desmoglein-2 expression. These effects were counteracted by 5-ASA and AZTP. Unlike AZTP that exhibited antiproliferative effects, 5-ASA promoted wound healing in colon epithelial cells. Both affected cellular senescence, cell cycle distribution and restricted cells in G1 or S phase without inducing apoptosis. This study provides mechanistic evidence that molecular actions of 5-ASA and AZTP on intestinal epithelia are fundamental in the resolution of barrier dysfunction.
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http://dx.doi.org/10.1038/s41598-019-39401-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391397PMC
February 2019

Iron deficiency workup reveals high incidence of autoimmune gastritis with parietal cell antibody as reliable screening test.

Semin Hematol 2018 10 7;55(4):256-261. Epub 2018 Aug 7.

Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria; Loha for life, Center of Excellence for Iron Deficiency, Vienna, Austria. Electronic address:

Iron deficiency (ID) workup is a common challenge for gastrointestinal endoscopy. In premenopausal women current guidelines recommend serologic evaluation of coeliac disease only. Here we systematically tested serologic screening for autoimmune gastritis (AIG) in a large cohort of patients with ID. This is a retrospective analysis of patients who attended an out-patient clinic specialized for ID. Patients with ferritin <50 µg/L or transferrin saturation <15% were included. Laboratory workup included endomysial antibodies and parietal-cell antibodies (PCA). Upper gastrointestinal endoscopy with pH-measurement of gastric juice and histology was performed to confirm positive serologic results. Three hundred seventy-three patients with ID were included, about half of whom were anemic. Patients were predominately female with a median age of 40 (confidence interval 11). Positive endomysial antibodies were found in 4 (1%) patients, elevated levels of PCA (>20 U/mL) were found in 69 (18.5%) patients, PCA >100 U/mL in 23 (6.2%). Twenty-six were followed up by gastroscopy; in 12 of 26 patients the diagnosis of AIG was confirmed by histology with 2 additional patients diagnosed as early and/or questionable AIG. A sensitivity of 93% and a specificity of 98% were estimated for a PCA cut-off of 100 U/mL. In 20 patients gastric pH was measured. Achlorhydria was found in 7 patients all diagnosed with AIG. In this ID cohort AIG is by far more common than coeliac disease. PCA above 100 U/mL are a sensitive and specific cut-off for workup of patients with ID prior to endoscopy. Serologic suspicion of AIG helps preselection of patients for endoscopic workup for ID.
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http://dx.doi.org/10.1053/j.seminhematol.2018.07.003DOI Listing
October 2018

A siphon-like retrogastric transverse colon: A case report.

Int J Surg Case Rep 2018 31;44:110-113. Epub 2018 Jan 31.

Department of Surgery, Division of Transplantation, Medical University of Vienna, Waehringer Gürtel 18-20, 1090 Vienna, Austria. Electronic address:

Introduction: Intestinal interposition is a term that describes rare anatomic variations where parts of the colon deviate from their normal intraabdominal position, attaching between two organs. Most patients with colonic interpositions are asymptomatic and diagnosed incidentally by computed tomography or ultrasound. Here we present a case of a symptomatic restrogastric colon, interposing kinked between stomach and pancreas.

Presentation Of Case: A 66-year old female patient presented with an eight-year history of intermittent spastic bowel movements, epigastralgia and nausea. Consecutively, the patient lost 12 kg. Physical examination was unremarkable and routine blood tests were within normal limits. Subsequently performed colonoscopy and cross-sectional imaging diagnosed a retrogastric colon. Finally, the patient underwent surgical treatment. The intraoperative findings were consistent with the computed tomography images and showed a kinked retrogastric protrusion of the transverse colon into the lesser sac, adhering to both, the posterior wall of the stomach, and the anterior surface of the pancreas. After adhesiolysis and mobilization, the transverse colon slipped back to the normal position within the abdominal cavity. The patient recovered well after surgery and was discharged on the sixth postoperative day. Six-month follow-up revealed cured bowel function, weight regain and no signs of recurrence.

Discussion & Conclusion: These rare cases of intestinal interpositions are very often difficult to diagnose, as symptoms are misleading. In case of diagnosis adequate surgical treatment strategies should be considered.
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http://dx.doi.org/10.1016/j.ijscr.2018.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910513PMC
January 2018

Overt Increase of Oxidative Stress and DNA Damage in Murine and Human Colitis and Colitis-Associated Neoplasia.

Mol Cancer Res 2018 04 29;16(4):634-642. Epub 2018 Jan 29.

Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.

Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated-cancer (CAC); however, the underlying processes of disease progression are not completely understood. Here, the molecular processes of inflammation-driven colon carcinogenesis were investigated using IL10-deficient mice (IL10 KO). IL10 KO mice were euthanized after development of colitis and dysplasia. IHC was performed for markers of colitis-induced DNA damage (CIDD): oxidative DNA lesions (8-oxoG), double-strand breaks (DSB; γH2AX). and DSB repair. MSI, LOH (), and global methylation (CIMP) were assessed on microdissected tissue. Comet assay for DNA damage, immunofluorescence, and immunoblotting were performed on intestinal organoids from wild-type (WT) and IL10 KO mice. Sequential biopsies and surgical specimens from IBD and CAC patients were used for IHC analysis. Severity of inflammation correlated with number of dysplasia. 8-oxoG and γH2AX-positive cells were significantly increased in inflamed and dysplastic areas along with activation of DSB repair. The amount of positively stained cells strongly correlated with degree of inflammation (8-oxoG: = 0.923; γH2AX: = 0.858). Neither CIMP, MSI nor LOH was observed. Enhanced DSBs in IL10 KO organoids were confirmed by comet assay and increased expression of γH2AX. Human clinical specimens exhibited significantly higher γH2AX and 8-oxoG in IBD, dysplasia, and CAC compared with normal mucosa. These data indicate that inflammation-driven colon carcinogenesis in IL10 KO mice and IBD patients is associated with oxidative DNA damage and overt presence of DSB. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0451DOI Listing
April 2018

Identification of PMN-released mutagenic factors in a co-culture model for colitis-associated cancer.

Carcinogenesis 2018 02;39(2):146-157

Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.

Microsatellite instability (MSI) is present in ulcerative colitis (UC) and colitis-associated colorectal cancers (CAC). Certain factors released by polymorphonuclear cells (PMNs) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116 + chr3 and human colonic epithelial cells (HCEC)-1CT MSI-reporter cell lines harboring mono-, di- or tetranucleotide DNA repeats linked to enhanced green fluorescent protein (EGFP) to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry. Activated PMNs released superoxide and hydrogen peroxide (H2O2), as measured by lucigenin-amplified chemiluminescence and fluorometry, respectively. Catalase, which scavenges H2O2, reduced such PMN-induced MSI. The NADPH-oxidase inhibitor apocynin, which blocks the oxidative burst in PMNs, similarly inhibited PMN-induced MSI. A bead-based multiplex assay revealed that PMNs release a wide range of cytokines such as interleukin (IL)-8, IL-6 and tumor necrosis factor-α (TNF-α). In vitro, these cytokines increased MSI in colon epithelial cells, and the Janus kinase (JAK) inhibitor tofacitinib abolished IL-6-induced or PMN-induced MSI. Intracellular reactive oxygen species (ROS) formation, as measured by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, was induced upon cytokine treatment. DNA oxidation upon IL-6 was present, as detected by formamidopyrimidine glycosylase (FPG)-modified comet assay. In conclusion, activated PMNs induce frameshift mutations in colon epithelial cells resulting in MSI. Both oxidative burst with release of ROS and PMN-secreted cytokines, such as IL-8, IL-6 or TNF-α, contribute to MSI. ROS scavengers and/or specific inhibitors of cytokine signaling may delay or prevent cancer development in the setting of colitis.
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http://dx.doi.org/10.1093/carcin/bgx118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826597PMC
February 2018

HuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis.

Cancer Res 2017 05 20;77(9):2424-2438. Epub 2017 Feb 20.

Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.

HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3' untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia. Intraperitoneal injection of the HuR small-molecule inhibitor MS-444 in AOM/DSS mice, a model of IBD and inflammatory colon cancer, augmented DSS-induced weight loss and increased tumor multiplicity, size, and invasiveness. MS-444 treatment also abrogated tumor cell apoptosis and depleted tumor-associated eosinophils, accompanied by a decrease in IL18 and eotaxin-1. In contrast, HuR inhibition in APC mice, a model of FAP and colon cancer, diminished the number of small intestinal tumors generated. In this setting, fecal microbiota, evaluated by 16S rRNA gene amplicon sequencing, shifted to a state of reduced bacterial diversity, with an increased representation of , and Taken together, our results indicate that HuR activation is an early event in FAP-adenoma but is not present in IBD-dysplasia. Furthermore, our results offer a preclinical proof of concept for HuR inhibition as an effective means of FAP chemoprevention, with caution advised in the setting of IBD. .
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826591PMC
May 2017

Development of an index to define overall disease severity in IBD.

Gut 2018 02 25;67(2):244-254. Epub 2016 Oct 25.

Medical University and General Hospital Vienna, Vienna, Austria.

Background And Aim: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC.

Methods: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute.

Results: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities.

Conclusions: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.
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http://dx.doi.org/10.1136/gutjnl-2016-312648DOI Listing
February 2018

Assessment of Gaps in Care and the Development of a Care Pathway for Anemia in Patients with Inflammatory Bowel Diseases.

Inflamm Bowel Dis 2017 01;23(1):35-43

*Houston VA HSR&D Center of Excellence, Michael E. DeBakey VAMC, Houston, Texas; †Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; ‡Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; §Cedars-Sinai Medical Center, Los Angeles, California; ‖Crohn's & Colitis Foundation of America (CCFA), New York, New York; ¶Survey Research Institute, Cornell University, Ithaca, New York; **Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Background: Anemia is a common complication among patients with inflammatory bowel diseases (IBD) and is associated with high rates of IBD-related complications, resource utilization, and impaired quality of life. Despite practice guidelines for anemia in patients with IBD, gaps remain in the perceptions of anemia among health care providers. The aims of this study were to identify gaps in care and to develop a care pathway for anemia in patients with IBD.

Methods: The Crohn's & Colitis Foundation of America anemia care pathway was developed by a committee using principles of cognitive task analysis. Focus groups of providers of patients with IBD were performed to identify domains of perceptions and management decisions for anemia and IBD. Knowledge elicitation from subject experts in anemia was conducted using case-based scenarios of patients with IBD and anemia to determine decision-making branch points. The care pathway was modified in an iterative fashion to encompass clinical presentations of anemia in IBD and potential barriers to the recognition, management, and follow-up of anemia.

Results: Variations were observed in how providers define iron deficiency, thresholds for treatment of anemia, and route of iron therapy. A care pathway for anemia incorporating the World Health Organization definition of anemia, universal hemoglobin and ferritin screening, evaluation of iron stores using ferritin and transferrin saturation, management of anemia based on adequacy of iron stores, and follow-up was developed.

Conclusions: The authors identified domains of how providers perceive and manage patients with IBD and anemia, and developed a care pathway to align clinical practices with guideline recommendations.
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http://dx.doi.org/10.1097/MIB.0000000000000953DOI Listing
January 2017

[WMW special issue on iron metabolism].

Authors:
Christoph Gasche

Wien Med Wochenschr 2016 Oct;166(13-14):401

Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, und Loha for Life, Medizinisches Kompetenzzentrum Eisenmangel, Wien, Österreich.

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http://dx.doi.org/10.1007/s10354-016-0507-5DOI Listing
October 2016

On both sides of the ocean.

Blood Transfus 2016 05 28;14(2):197-8. Epub 2016 Apr 28.

Georgetown University School of Medicine, Washington DC, United States of America.

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http://dx.doi.org/10.2450/2016.0304-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918549PMC
May 2016

Management of Iron Deficiency Anemia.

Gastroenterol Hepatol (N Y) 2015 Apr;11(4):241-50

Dr Jimenez is a fellow in gastroenterology, Dr Kulnigg-Dabsch is a specialist in internal medicine, and Dr Gasche is a specialist in internal medicine, gastroenterology, and hepatology and is an associate professor at the Medical University of Vienna in Vienna, Austria. Dr Gasche is also the founder and head of Loha for Life, Centre of Excellence for Iron Deficiency in Vienna, Austria.

Anemia affects one-fourth of the world's population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blood transfusions. Treatment options include oral and intravenous iron therapy; however, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis. This article provides a critical summary of the diagnosis and treatment of iron deficiency anemia. In addition, it includes a management algorithm that can help the clinician determine which patients are in need of further gastrointestinal evaluation. This facilitates the identification and treatment of the underlying condition and avoids the unnecessary use of invasive methods and their associated risks.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836595PMC
April 2015

PAK1 promotes intestinal tumor initiation.

Cancer Prev Res (Phila) 2015 Nov 24;8(11):1093-101. Epub 2015 Aug 24.

Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.

p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC(min) or APC(min)/PAK1(-/-) mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six- to 8-week-old PAK1(-/-) and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC(min) mice. IHC revealed that PAK1 deletion reduced p-AKT, β-catenin, and c-Myc expression in APC(min) adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked β-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0205-TDOI Listing
November 2015

Quality of colonoscopy in Lynch syndrome.

Endosc Int Open 2014 Dec 24;2(4):E252-5. Epub 2014 Oct 24.

Division of Surgery and of Gastroenterology and Hepatology and Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.

Lynch syndrome (LS) accounts for 2 - 4 % of all colorectal cancers. Affected family members have a germline mutation in one of the DNA mismatch repair genes MLH1, PMS2, MSH2, or MSH6, and a lifetime risk for development of colorectal cancer of 25 - 75 %. Current guidelines recommend annual to biannual surveillance colonoscopy in mutation carriers. Several factors may predict failure to prevent interval cancer in LS: more lesions in the right colon; more flat ("non polypoid") and lateral growing polyps; small adenomas may already harbor high grade dysplasia or a high percentage of villous component and become advanced adenomas; there is a short duration of the adenoma - carcinoma sequence; synchronous lesions have high prevalence; patients are younger and less tolerant to colonoscopy (need more sedation); and repeated colonoscopies are needed for lifelong surveillance (patient experience is important for compliance). In order to prevent cancer in LS patients, surveillance colonoscopy should be performed in an endoscopic unit experienced with LS, every 1 - 2 years, starting at age 20 - 25 years, or 10 years younger than the age of first diagnosis in the family (whichever is first), and yearly after the age of 40 years. Colonoscopy in LS patients should be a very meticulous and precise procedure (i. e. taking sufficient withdrawal time, documentation of such warranted), with removal of all of the polyps, special attention to the right colon and alertness to flat lesions. Following quality indicators such as successful cleansing of the colon and removal of every polyp will probably improve prevention of interval cancers. At this moment, none of the new endoscopic techniques have shown convincing superiority over conventional high resolution white light colonoscopy.
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http://dx.doi.org/10.1055/s-0034-1377920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423269PMC
December 2014

IL10R2 Overexpression Promotes IL22/STAT3 Signaling in Colorectal Carcinogenesis.

Cancer Immunol Res 2015 Nov 30;3(11):1227-35. Epub 2015 Jun 30.

Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria.

The mucosal immune response in the setting of intestinal inflammation contributes to colorectal cancer. IL10 signaling has a central role in gut homeostasis and is impaired in inflammatory bowel disease (IBD). Out of two IL10 receptor subunits, IL10R1 and IL10R2, the latter is shared among the IL10 family of cytokines and activates STAT signaling. STAT3 is oncogenic in colorectal cancer; however, knowledge about IL10 signaling upstream of STAT3 in colorectal cancer is lacking. Here, expression of IL10 signaling genes was examined in matched pairs from normal and tumor tissue from colorectal cancer patients showing overexpression (mRNA, protein) of IL10R2 and STAT3 but not IL10R1. IL10R2 overexpression was related to microsatellite stability. Transient overexpression of IL10R2 in HT29 cells increased proliferation upon ligand activation (IL10 and IL22). IL22, and not IL10, phosphorylated STAT3 along with increased phosphorylation of AKT and ERK. A significantly higher expression of IL22R1 and IL10R2 was also confirmed in a separate cohort of colorectal cancer samples. IL22 expression was elevated in gut mucosa from patients with IBD and colitis-associated cancer, which also exhibited increased expression of IL22R1 but not its coreceptor IL10R2. Overall, these data indicate that overexpression of IL10R2 and STAT3 contributes to colorectal carcinogenesis in microsatellite-stable tumors through IL22/STAT3 signaling.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0031DOI Listing
November 2015

PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation.

Biochim Biophys Acta 2015 Oct 31;1853(10 Pt A):2349-60. Epub 2015 May 31.

Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria. Electronic address:

P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNFα injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFα. NF-κB and PPARγ were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFNγ, IL-1β, and TNFα. In vivo, mice administered with TNFα showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-κB activation. p65 nuclear translocation downstream of TNFα was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-κB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARγ and mesalamine recovered PPARγ through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-κB, which was recovered using BADGE, a PPARγ antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-κB activity via suppression of PPARγ in intestinal epithelial cells.
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http://dx.doi.org/10.1016/j.bbamcr.2015.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576212PMC
October 2015

Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer.

Gut 2016 09 20;65(9):1470-81. Epub 2015 May 20.

Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.

Objective: miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC).

Design: miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches.

Results: miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in β-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-κB activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice.

Conclusions: These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.
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http://dx.doi.org/10.1136/gutjnl-2014-308455DOI Listing
September 2016

Overexpression of PAK1 promotes cell survival in inflammatory bowel diseases and colitis-associated cancer.

Inflamm Bowel Dis 2015 Feb;21(2):287-96

Christian Doppler Laboratory for Molecular Cancer Chemoprevention Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Chronic gut inflammation predisposes to the development of colorectal cancer and increased mortality. Use of mesalamine (5-ASA) in the treatment of ulcerative colitis modulates the risk of neoplastic progression. p21 activated kinase 1 (PAK1) mediates 5-ASA activity by orchestrating MAPK signaling, Wnt-β catenin pathway, and cell adhesion; all implicated in the colon carcinogenesis. We evaluated the role of PAK1 in IBD and in colitis-associated cancer (CAC).

Methods And Results: PAK1 expression was scored by immunohistochemistry in human samples from IBD, CAC, and in normal mucosa. Compared with controls, a higher PAK1 expression was detected in IBD which further increased in CAC. The consequence of PAK1 overexpression was investigated using normal diploid colon epithelial cells (HCEC-1CT), which showed higher proliferation and decreased apoptosis on overexpression of PAK1. Analysis of IBD and CAC samples showed activation of AKT (p-AKT). However, mTOR pathway was activated in IBD but not in CAC. Treatment of cells with specific inhibitors (PD98059/LY294002/rapamycin) of growth signaling pathways (MEK/PI3K/mTOR) demonstrated that in HCEC-1CT, PAK1 expression is regulated by MEK, PI3K, and mTOR. In colorectal cancer cell lines, PAK1, and beta-catenin expression correlated and inhibition of PAK1 and addition of 5-ASA elicited similar molecular affects by reducing ERK and AKT activation. Moreover, 5-ASA disrupted PAK1 interaction and colocalization with β-catenin.

Conclusions: Our data indicate that (1) PAK1 is upregulated in IBD and CAC (2) PAK1 overexpression is associated with activation of PI3K-AKT/mTOR prosurvival pathways in IBD.
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http://dx.doi.org/10.1097/MIB.0000000000000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345971PMC
February 2015
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