A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts
- Simon J Leedham1,2,
- Pedro Rodenas-Cuadrado1,
- Kimberley Howarth1,
- Annabelle Lewis1,
- Sreelakshmi Mallappa3,
- Stefania Segditsas1,
- Hayley Davis1,
- Rosemary Jeffery4,
- Manuel Rodriguez-Justo5,
- Satish Keshav2,
- Simon P L Travis2,
- Trevor A Graham4,
- James East2,
- Susan Clark3,
- Ian P M Tomlinson1
- 1Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, UK
- 2Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
- 3Polyposis Registry, St Mark's Hospital, Harrow, UK
- 4Histopathology Laboratory, London Research Institute, London, UK
- 5Histopathology department, University College London Hospital, London, UK
- Correspondence to Dr Simon Leedham, Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN, UK; simon.leedham{at}cancer.org.uk
-
Contributors Data acquisition by SJL, PRC, KH, AL, SS, HD, RJ and TAG. Pathology and material support by SM, MRJ, SK, SPLT, JE and SC. Study design and paper authorship by SJL and IPMT.
- Accepted 15 December 2011
- Published Online First 27 January 2012
Abstract
Objective Wnt signalling is critical for normal intestinal development and homeostasis. Wnt dysregulation occurs in almost all human and murine intestinal tumours and an optimal but not excessive level of Wnt activation is considered favourable for tumourigenesis. The authors assessed effects of pan-intestinal Wnt activation on tissue homeostasis, taking into account underlying physiological Wnt activity and stem-cell number in each region of the bowel.
Design The authors generated mice that expressed temporally controlled, stabilised β-catenin along the crypt–villus axis throughout the intestines. Physiological Wnt target gene activity was assessed in different regions of normal mouse and human tissue. Human intestinal tumour mutation spectra were analysed.
Results In the mouse, β-catenin stabilisation resulted in a graduated neoplastic response, ranging from dysplastic transformation of the entire epithelium in the proximal small bowel to slightly enlarged crypts of non-dysplastic morphology in the colorectum. In contrast, stem and proliferating cell numbers were increased in all intestinal regions. In the normal mouse and human intestines, stem-cell and Wnt gradients were non-identical, but higher in the small bowel than large bowel in both species. There was also variation in the expression of some Wnt modulators. Human tumour analysis confirmed that different APC mutation spectra are selected in different regions of the bowel.
Conclusions There are variable gradients in stem-cell number, physiological Wnt activity and response to pathologically increased Wnt signalling along the crypt-villus axis and throughout the length of the intestinal tract. The authors propose that this variation influences regional mutation spectra, tumour susceptibility and lesion distribution in mice and humans.
- Wnt signalling
- stem cells
- just-right hypothesis
- carcinogenesis
- colon carcinogenesis
- Barrett's oesophagus
- cancer syndromes
- cancer
- colorectal cancer genes
- colorectal function
- colorectal diseases
- adenoma
- cancer genetics
- colonic adenomas
- colorectal neogenesis
- colonic polyps
- colorectal adenomas
- colorectal cancer
- colorectal carcinoma
- colonic neoplasms
- histopathology
- mucosal immunity
- paneth cells
- Crohn's disease
- gastrointestinal immune response
- IBD
- mucosal defense
- celiac disease
- epithelial barrier
- necrotising enterocolitis
- epithelial cells
- gastrointestinal cancer
- IBD basic research
- inflammation
- infliximab
- 5-aminosalicylic acid (5-ASA)
- clinical trials
- mathematical modelling
- Barretts carcinoma
- microsatellite instability
Footnotes
-
Final note During the preparation of this manuscript Albuquerque et al published a paper screening human colorectal tumours for mutations in Wnt related genes and have independently proposed a similar mechanism to that suggested by us for the apparent non-random distribution of human colorectal tumours.27
-
Funding This work was supported by Cancer Research UK (Clinician Scientist Fellowship to SJL) and the Wellcome Trust (CORE GRANT 090532/Z/09/Z).
-
Competing interests None.
-
Ethics approval All mouse work was approved by the UK Home Office and local ethics committee. Human archival tissue was obtained from St Marks Hospital, Harrow with multicentre ethics approval (MREC05/Q1606/66). Endoscopic biopsy tissue was obtained from the John Radcliffe Hospital, Oxford with local REC approval (REC 10/H0604/72).
-
Provenance and peer review Not commissioned; internally peer reviewed.
-
Data sharing statement Unpublished data on lithium chloride stimulation of RIE cells and Dickkopf and R-Spondin Wnt modulator expression are available on request to the corresponding author.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode
