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

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.

Author(s):  
Eduarda Leite-Gomes ◽  
Ana M Dias ◽  
Catarina M Azevedo ◽  
Beatriz Santos-Pereira ◽  
Mariana Magalhães ◽  
...  

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.


Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 605
Author(s):  
Mara Gagliardi ◽  
Romina Monzani ◽  
Nausicaa Clemente ◽  
Luca Fusaro ◽  
Valentina Saverio ◽  
...  

Inflammatory bowel disease (IBD) is a complex, chronic, and dysregulated inflammatory condition which etiology is still largely unknown. Its prognosis and disease progression are highly variable and unpredictable. IBD comprises several heterogeneous inflammatory conditions ranging from Ulcerative Colitis (UC) to Crohn’s Disease (CD). Importantly, a definite, well-established, and effective clinical treatment for these pathologies is still lacking. The urgent need for treatment is further supported by the notion that patients affected by UC or CD are also at risk of developing cancer. Therefore, a deeper understanding of the molecular mechanisms at the basis of IBD development and progression is strictly required to design new and efficient therapeutic regimens. Although the development of animal models has undoubtedly facilitated the study of IBD, such in vivo approaches are often expensive and time-consuming. Here we propose an organ ex vivo culture (Gut-Ex-Vivo system, GEVS) based on colon from Balb/c mice cultivated in a dynamic condition, able to model the biochemical and morphological features of the mouse models exposed to DNBS (5–12 days), in 5 h. Indeed, upon DNBS exposure, we observed a dose-dependent: (i) up-regulation of the stress-related protein transglutaminase 2 (TG2); (ii) increased intestinal permeability associated with deregulated tight junction protein expression; (iii) increased expression of pro-inflammatory cytokines, such as TNFα, IFNγ, IL1β, IL6, IL17A, and IL15; (iv) down-regulation of the anti-inflammatory IL10; and (v) induction of Endoplasmic Reticulum stress (ER stress), all markers of IBD. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of IBD, in a time- and cost-effective manner.


2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A38-A38
Author(s):  
Shilpa Ravindran ◽  
Heba Sidahmed ◽  
Harshitha Manjunath ◽  
Rebecca Mathew ◽  
Tanwir Habib ◽  
...  

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.


2015 ◽  
Vol 36 (9) ◽  
pp. 999-1007 ◽  
Author(s):  
Hamed Khalili ◽  
Jian Gong ◽  
Hermann Brenner ◽  
Thomas R. Austin ◽  
Carolyn M. Hutter ◽  
...  

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