title: A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts.
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.
  
  
  METHODS
  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.
authors.affiliation: Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN, UK. simon.leedham@cancer.org.uk
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Leedham
authors.forename: Pedro
authors.initials: P
authors.lastname: Rodenas-Cuadrado
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lewis
authors.forename: Sreelakshmi
authors.initials: S
authors.lastname: Mallappa
authors.forename: Stefania
authors.initials: S
authors.lastname: Segditsas
authors.forename: Hayley
authors.initials: H
authors.lastname: Davis
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.forename: Satish
authors.initials: S
authors.lastname: Keshav
authors.forename: Simon P L
authors.initials: SP
authors.lastname: Travis
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
authors.forename: James
authors.initials: J
authors.lastname: East
authors.forename: Susan
authors.initials: S
authors.lastname: Clark
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D017491:Genes, APC; D005819:Genetic Markers; D006706:Homeostasis; D006801:Humans; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000166:cytology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D051153:Wnt Proteins; D051176:beta Catenin