Publications (139) View all
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Article: Intestinal renin-angiotensin system is stimulated after deletion of Lkb1.
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ABSTRACT: LKB1 is a serine-threonine kinase, mutation of which can lead to the development of multiple benign intestinal hamartomas (Peutz-Jeghers syndrome). In this study, the authors investigate the mechanisms underlying this phenotype by exploring the transcriptional changes associated with Lkb1 deletion in intestinal epithelium. The authors used mice with Lkb1 deleted in the intestinal epithelium using a Cyp1a1-specific inducible Cre recombinase and used Affymetrix (Santa Clara, California, USA) microarray analysis to examine the transcriptional changes occurring immediately after Lkb1 loss. The authors also generated crypt-villus organoid culture to analyse Lkb1 role in intestinal responses to exogenous stimuli. Affymetrix analysis identified the most significant change to be in Ren1 expression, a gene encoding a protease involved in angiotensinogen processing. Lkb1 deletion also enhanced ACE expression and subsequently angiotensin II (AngII) production in the mouse intestine. Intestinal apoptosis induced by Lkb1 deficiency was suppressed by ACE inhibitor captopril. Lkb1-deficient intestinal epithelium showed dynamic changes in AngII receptor type 1, suggesting a possible compensatory response to elevated AngII levels. A similar reduction in epithelial AngII receptor type 1 was also observed in human Peutz-Jeghers syndrome tumours contrasting with high expression of the receptor in the tumour stroma. Mechanistically, the authors showed two pieces of data that position Lkb1 in renin expression regulation, and they implied the importance of Lkb1 in linking cell responses with nutrient levels. First, the authors showed that Lkb1 deletion in isolated epithelial organoid culture resulted in renin upregulation only when the organoids were challenged with external cues such as AngII; second, that renin upregulation was dependent upon the MEK/ERK pathway in a circadian fashion and corresponded to active feeding time when nutrient levels were high. Taken together, these data reveal a novel role for Lkb1 in regulation of the gastrointestinal renin-angiotensin system.Gut 08/2011; 61(2):202-13. · 10.11 Impact Factor -
Article: Diversity counts. Visualizing pretumor progression in the gastrointestinal tract.
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ABSTRACT: Tumor progression is critically dependent on the selection of genetic alterations. This clonal evolution can be traced to the stage preceding visible tumor formation called pretumor progression, in which genetic change occurs without visible change. Recently, the identification of intestinal stem cell markers in animal models has made visualization of stem cells possible in vivo. Translating this work to the clinical setting by visualizing stem cells in patient material may allow us to understand differences in patients' vulnerability to cancer development and target preventive measures to high-risk groups. In this review article, we examine some of the analytic methods currently used in research settings tracing stem cell dynamics.American Journal of Clinical Pathology 06/2011; 135(6):878-88. · 2.60 Impact Factor -
Article: Loss of Indian Hedgehog activates multiple aspects of a wound healing response in the mouse intestine.
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ABSTRACT: Indian Hedgehog (Ihh) is expressed by the differentiated epithelial cells of the small intestine and signals to the mesenchyme where it induces unidentified factors that negatively regulate intestinal epithelial precursor cell fate. Recently, genetic variants in the Hh pathway have been linked to the development of inflammatory bowel disease. We deleted Ihh from the small intestinal epithelium in adult mice using Cyp1a1-CreIhh(fl/fl) conditional Ihh mutant mice. Intestines were examined by immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction. Deletion of Ihh from the intestinal epithelium initially resulted in a proliferative response of the intestinal epithelium with lengthening and fissioning of crypts and increased Wnt signaling. The epithelial proliferative response was associated with loss of bone morphogenetic protein and Activin signaling from the epithelium of the villus and crypts, respectively. At the same stage we observed a substantial influx of fibroblasts and macrophages into the villus core with increased mesenchymal transforming growth factor-β signaling and deposition of extracellular matrix proteins. Prolonged loss of Ihh resulted in progressive leukocyte infiltration of the crypt area, blunting and loss of villi, and the development of intestinal fibrosis. Loss of Ihh initiates several events that are characteristic of an intestinal wound repair response. Prolonged loss resulted in progressive inflammation, mucosal damage, and the development of intestinal fibrosis. Ihh is a signal derived from the superficial epithelial cells that may act as a critical indicator of epithelial integrity.Gastroenterology 11/2010; 139(5):1665-76, 1676.e1-10. · 11.68 Impact Factor -
Article: Adenocarcinoma in the anal canal after heal pouch-anal anastomosis for familial adenomatous polyposis using a double-stapled technique: Report of two cases
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ABSTRACT: Restorative proctocolectomy with an ileal pouch-anal anastomosis is thought to abolish the risk of colorectal adenoma development in patients suffering from familial adenomatous polyposis. Both after mucosectomy with a handsewn anastomosis and after a double-stapled anastomosis, rectal mucosa is left behind at the anastomotic site. This carries the potential for the development of polyps and a subsequent malignancy. In our clinic, two patients recently developed an adenocarcinoma at the anastomotic site, despite a yearly follow-up endoscopy. A 40-year-old female under-went an ileal pouch-anal anastomosis with a double-stapled anastomosis in 1991. She refrained from follow-up for several years, but returned eight years postoperatively with a fistula at the anastomotic site. Biopsies revealed an adenocarcinoma infiltrating in the fistula tract T2N0M0. The patient was treated with preoperative radiotherapy (60 Gy), abdominoperineal resection, and a permanent ileostomy. A 27-year-old male underwent an ileal pouch-anal anastomosis with a double-stapled anastomosis in 1990. Because of his profession, endoscopy was performed only once every two years. Endoscopic biopsies ten years postoperatively revealed adenocarcinoma T4N0M0. The patient underwent an abdominoperineal resection with partial resection of the prostate, and a permanent ileostomy was constructed.Diseases of the Colon & Rectum 04/2012; 47(4):530-534. · 3.13 Impact Factor -
Article: Pancreatic ductal adenocarcinoma in hereditary diffuse gastric cancer. A case report.
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ABSTRACT: Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome characterized by highly penetrant diffuse gastric cancer. It is caused by germ line mutations in CDH1, encoding the cell-cell adhesion protein E-cadherin. Pancreatic ductal adenocarcinoma is one of the most dismal malignancies in humans. Although absent E-cadherin expression in pancreatic ductal adenocarcinoma is related to a higher tumor grade and a worse prognosis, there have been no reports of pancreatic ductal adenocarcinoma associated with hereditary diffuse gastric cancer. Here, we describe a patient with hereditary diffuse gastric cancer who was subsequently diagnosed with pancreatic ductal adenocarcinoma. To investigate if the previously identified CDH1 germ line mutation initiated pancreatic ductal adenocarcinoma development, we performed mutational and proteomic analyses. We conclude that the pancreatic ductal adenocarcinoma did not occur in the context of the germ line CDH1 mutation but rather appeared as a sporadic event. Immunohistochemistry ultimately proved to be the most valuable tool of investigation as persistent CDH1 staining in the pancreatic ductal adenocarcinoma unequivocally revealed E-cadherin expression.Human pathology 03/2012; 43(3):457-61. · 3.03 Impact Factor
