Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player

2021 ◽  
Author(s):  
Eduarda Leite-Gomes ◽  
Ana M Dias ◽  
Catarina M Azevedo ◽  
Beatriz Santos-Pereira ◽  
Mariana Magalhães ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Serum Proteins ◽  
Major Complication ◽  
Cancer Pathogenesis ◽  
Colon Inflammation ◽  
Inflammatory Bowel

Abstract Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.

scholarly journals The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses

2020 ◽  
Vol 21 (24) ◽  
pp. 9772
Author(s):  
Reyes Gamez-Belmonte ◽  
Lena Erkert ◽  
Stefan Wirtz ◽  
Christoph Becker
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Immune Responses ◽  
Immune Cells ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Clinical Care ◽  
Important Barrier ◽  
Inflammatory Bowel

The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the gastrointestinal tract such as inflammatory bowel disease, infections, or colorectal cancer, therefore, pose substantial challenges to clinical care. The intestinal epithelium plays an important role in intestinal disease development. It not only establishes an important barrier against the gut lumen but also constantly signals information about the gut lumen and its composition to immune cells in the bowel wall. Such signaling across the epithelial barrier also occurs in the other direction. Intestinal epithelial cells respond to cytokines and other mediators of immune cells in the lamina propria and shape the microbial community within the gut by producing various antimicrobial peptides. Thus, the epithelium can be considered as an interpreter between the microbiota and the mucosal immune system, safeguarding and moderating communication to the benefit of the host. Type 2 immune responses play important roles in immune-epithelial communication. They contribute to gut tissue homeostasis and protect the host against infections with helminths. However, they are also involved in pathogenic pathways in inflammatory bowel disease and colorectal cancer. The current review provides an overview of current concepts regarding type 2 immune responses in intestinal physiology and pathophysiology.

New developments in oestrogen signalling in colonic epithelium

2006 ◽  
Vol 34 (6) ◽  
pp. 1114-1116 ◽  
Author(s):  
O. Wada-Hiraike ◽  
M. Warner ◽  
J.-Å. Gustafsson
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Animal Models ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Adherens Junction ◽  
Colonic Epithelium ◽  
Proliferating Cells ◽  
Junction Protein ◽  
Inflammatory Bowel

Epidemiological studies show that oestrogen reduces the risk of colorectal cancer in postmenopausal women and ERβ (oestrogen receptor β)-selective ligands have been reported to be very effective treatment in animal models of inflammatory bowel disease. Several studies have shown that ERβ is the predominant ER in the colonic epithelium, but it is not clear whether the benefit of ERβ agonists in inflammatory bowel disease are due to their action on the colon epithelium itself, or on the immune system. In order to address this issue, we have compared colons of ERβ−/− and wild-type mice with regard to morphology, histology, proliferation and differentiation. We found that the number of proliferating cells was higher in ERβ−/− mice, and the migration of labelled cells from base to lumen of the crypts was faster. Additionally, immunohistochemical staining revealed fewer apoptotic cells (cleaved caspase 3-positive), a significant decrease in expression of the epithelial differentiation marker, cytokeratin CK20, the adherens junction protein, α-catenin, and the hemidesmosomal protein, plectin, in ERβ−/− mice. These findings suggest a role for ERβ in growth, organization and maintenance of the normal colonic crypt–villus architecture. The next step is to elucidate the molecular mechanisms that underlie the signalling of ERβ in normal cell growth and assess whether or not ERβ agonists will be useful drugs in the prevention or treatment of colorectal cancer. Dietary phyto-oestrogens are believed to play a role in protection against colorectal cancer. Lignans, such as enterolactone, an ER agonist, prevent cancer development in animal models. Since ERβ is the only ER in the colon, there is enough reason to speculate that phyto-oestrogens are acting through ERβ.

scholarly journals Colorectal Cancer in Inflammatory Bowel Disease

2018 ◽  
Vol 31 (03) ◽  
pp. 168-178 ◽  
Author(s):  
Peter Higgins ◽  
Ryan Stidham
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Detection Techniques ◽  
Clinical Scenarios ◽  
Increased Risk ◽  
Consensus Statements ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

AbstractPatients with inflammatory bowel disease (IBD) are at significantly increased risk of colorectal cancer (CRC), principally resulting from the pro-neoplastic effects of chronic intestinal inflammation. Epidemiologic studies continue to highlight the increased risk of CRC in IBD. However, the incidence has declined over the past 30 years, attributed to both successful CRC-surveillance programs and improved control of mucosal inflammation. Risk factors that further increase the risk of IBD-related CRC include disease duration, extent and severity, the presence of inflammatory pseudopolyps, coexistent primary sclerosing cholangitis, and a family history of CRC. All major professional societies agree that IBD-CRC surveillance should occur more frequently than in the general population. Yet, guidelines and consensus statements differ on the surveillance schedule and preferred method of surveillance. Improved sensitivity to previously “invisible” flat dysplastic lesions using high definition and chromoendoscopy methods has resulted in many guidelines abandoning requirements for random untargeted biopsies of the colon. While colonic dysplasia remains a worrisome finding, and several clinical scenarios remain best addressed by total proctocolectomy due to concerns of synchronous undetected lesions and the unpredictable tempo of progression to malignancy, better detection techniques have also increased opportunities for endoscopic resection of dysplastic lesions that can be clearly delineated. Finally, the expanding armamentarium of medical options in IBD, including anti-tumor necrosis factor and anti-adhesion biologic therapies, have substantially improved our ability to control severe inflammation and likely reduce the risk of CRC over time.

scholarly journals Salivary and Serum Inflammatory Profiles Reflect Different Aspects of Inflammatory Bowel Disease Activity

2020 ◽  
Vol 26 (10) ◽  
pp. 1588-1596 ◽  
Author(s):  
Mirjam Majster ◽  
Ronaldo Lira-Junior ◽  
Charlotte M Höög ◽  
Sven Almer ◽  
Elisabeth A Boström
Keyword(s):  
Inflammatory Bowel Disease ◽  
Oral Cavity ◽  
Disease Activity ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Serum Proteins ◽  
Biochemical Status ◽  
Whole Saliva ◽  
Inflammatory Bowel ◽  
Inflammatory Proteins

Abstract Background Inflammatory bowel disease (IBD) can manifest both macroscopically and microscopically in the oral cavity; however, little is known about salivary changes in IBD. Therefore, this study aimed to assess salivary and circulatory inflammatory profiles in IBD and to compare their potential to reflect the presence and activity of IBD. Methods We measured 92 known inflammatory proteins in serum and in unstimulated and stimulated whole saliva samples from patients with IBD with active intestinal inflammation (n = 21) and matched control patients (n = 22) by proximity extension assay. Fifteen of the patients with IBD returned 10 to 12 weeks after treatment escalation for resampling. Results Sixty-seven of the proteins were detected in all 3 sample fluids but formed distinct clusters in serum and saliva. Twenty-one inflammatory proteins were significantly increased and 4 were significantly decreased in the serum of patients with IBD compared with that of the control patients. Two of the increased serum proteins, IL-6 and MMP-10, were also significantly increased in stimulated saliva of patients with IBD and correlated positively to their expressions in serum. None of the investigated proteins in serum or saliva were significantly altered by IBD treatment at follow-up. Overall, inflammatory proteins in serum correlated to biochemical status, and salivary proteins correlated positively to clinical parameters reflecting disease activity. Conclusions Saliva and serum inflammatory profiles in IBD share a similar composition but reflect different aspects of disease activity. The oral cavity reflects IBD through elevated IL-6 and MMP-10 in stimulated saliva.

scholarly journals Elevated Expression of AXL May Contribute to the Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Éva Boros ◽  
Zoltán Kellermayer ◽  
Péter Balogh ◽  
Gerda Strifler ◽  
Andrea Vörös ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Mesenchymal Transition ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

Understanding the molecular mechanisms inducing and regulating epithelial-to-mesenchymal transition (EMT) upon chronic intestinal inflammation is critical for understanding the exact pathomechanism of inflammatory bowel disease (IBD). The aim of this study was to determine the expression profile of TAM family receptors in an inflamed colon. For this, we used a rat model of experimental colitis and also collected samples from colons of IBD patients. Samples were taken from both inflamed and uninflamed regions of the same colon; the total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that AXL is highly induced in active-inflamed colon, which is accompanied with reduced expression of AXL-regulating microRNAs. In addition, the expression of genes responsible for inducing or maintaining mesenchymal phenotype, such as SNAI1, ZEB2, VIM, MMP9, and HIF1α, were all significantly induced in the active-inflamed colon of IBD patients while the epithelial marker E-cadherin (CDH1) was downregulated. We also show that, in vitro, monocytic and colonic epithelial cells increase the expression of AXL in response to LPS or TNFα stimuli, respectively. In summary, we identified several interacting genes and microRNAs with mutually exclusive expression pattern in active-inflamed colon of IBD patients. Our results shed light onto a possible AXL- and microRNA-mediated regulation influencing epithelial-to-mesenchymal transition in IBD.

scholarly journals RNF20 and RNF40 regulate vitamin D receptor-dependent signaling in inflammatory bowel disease

2021 ◽  
Author(s):  
Robyn Laura Kosinsky ◽  
Maria Zerche ◽  
Ana Patricia Kutschat ◽  
Asha Nair ◽  
Zhenqing Ye ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Mouse Intestine ◽  
Inflammatory Bowel

AbstractDespite the identification of several genetic factors linked to increased susceptibility to inflammatory bowel disease (IBD), underlying molecular mechanisms remain to be elucidated in detail. The ubiquitin ligases RNF20 and RNF40 mediate the monoubiquitination of histone H2B at lysine 120 (H2Bub1) and were shown to play context-dependent roles in the development of inflammation. Here, we aimed to examine the function of the RNF20/RNF40/H2Bub1 axis in intestinal inflammation in IBD patients and mouse models. For this purpose, intestinal sections from IBD patients were immunohistochemically stained for H2Bub1. Rnf20 or Rnf40 were conditionally deleted in the mouse intestine and mice were monitored for inflammation-associated symptoms. Using mRNA-seq and chromatin immunoprecipitation (ChIP)-seq, we analyzed underlying molecular pathways in primary intestinal epithelial cells (IECs) isolated from these animals and confirmed these findings in IBD resection specimens using ChIP-seq.The majority (80%) of IBD patients displayed a loss of H2Bub1 levels in inflamed areas and the intestine-specific deletion of Rnf20 or Rnf40 resulted in spontaneous colorectal inflammation in mice. Consistently, deletion of Rnf20 or Rnf40 promoted IBD-associated gene expression programs, including deregulation of various IBD risk genes in these animals. Further analysis of murine IECs revealed that H3K4me3 occupancy and transcription of the Vitamin D Receptor (Vdr) gene and VDR target genes is RNF20/40-dependent. Finally, these effects were confirmed in a subgroup of Crohn’s disease patients which displayed epigenetic and expression changes in RNF20/40-dependent gene signatures. Our findings reveal that loss of H2B monoubiquitination promotes intestinal inflammation via decreased VDR activity thereby identifying RNF20 and RNF40 as critical regulators of IBD.

Sign in / Sign up

Export Citation Format

Share Document