Imperial College London
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DrRobertKypta

Faculty of Medicine, Department of Surgery & Cancer

Senior Lecturer in Cancer Biology
 
 
 
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Contact

 

r.kypta Website

 
 
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Location

 

4007Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Lewis:2022:10.1042/cs20210889,
author = {Lewis, A and Sánchez, S and Berti, G and Pan-Castillo, B and Nijhuis, A and Mehta, S and Eleid, L and Gordon, H and Gadhok, R and Kimberley, C and Minicozzi, A and Chin-Aleong, J and Feakins, R and Kypta, R and Lindsay, JO and Silver, A},
doi = {10.1042/cs20210889},
journal = {Clinical Science},
pages = {1405--1423},
title = {Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease},
url = {http://dx.doi.org/10.1042/cs20210889},
volume = {136},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. The present study investigates the contribution of Wingless-Int-1 (Wnt) signalling to intestinal fibrogenesis, considers potential cross-talk between Wnt and transforming growth factor β1 (TGFβ) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors.β-catenin expression was explored by immunohistochemistry (IHC) in formalin-fixed paraffin embedded (FFPE) tissue from patient-matched nonstrictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFβ signalling, and type I collagen (Collagen-I) expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small-molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence (IF), Wnt gene expression arrays, and western blotting. Fibrotic SCD tissue was marked by an increase in β-catenin-positive cells. In vitro, activation of Wnt-β-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of β-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFβ increased β-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFβ up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a β-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix (ECM) expression. Our data highlight small-molecule Wnt inhibitors of both canonical and noncanonical Wnt signalling, as potential antifibrotic drugs to treat SCD intestinal fibrosis. They
AU  - Lewis,A
AU  - Sánchez,S
AU  - Berti,G
AU  - Pan-Castillo,B
AU  - Nijhuis,A
AU  - Mehta,S
AU  - Eleid,L
AU  - Gordon,H
AU  - Gadhok,R
AU  - Kimberley,C
AU  - Minicozzi,A
AU  - Chin-Aleong,J
AU  - Feakins,R
AU  - Kypta,R
AU  - Lindsay,JO
AU  - Silver,A
DO  - 10.1042/cs20210889
EP  - 1423
PY  - 2022///
SN  - 0143-5221
SP  - 1405
TI  - Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease
T2  - Clinical Science
UR  - http://dx.doi.org/10.1042/cs20210889
UR  - https://portlandpress.com/clinsci/article/136/19/1405/231861/Small-molecule-Wnt-inhibitors-are-a-potential
UR  - http://hdl.handle.net/10044/1/100280
VL  - 136
ER  -
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