1. Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells.
- Author
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Huels DJ, Bruens L, Hodder MC, Cammareri P, Campbell AD, Ridgway RA, Gay DM, Solar-Abboud M, Faller WJ, Nixon C, Zeiger LB, McLaughlin ME, Morrissey E, Winton DJ, Snippert HJ, van Rheenen J, and Sansom OJ
- Subjects
- Acyltransferases antagonists & inhibitors, Adenoma etiology, Adenoma metabolism, Adenoma pathology, Adenomatous Polyposis Coli Protein deficiency, Adenomatous Polyposis Coli Protein genetics, Adenomatous Polyposis Coli Protein metabolism, Animals, Carcinogenesis drug effects, Cell Transformation, Neoplastic drug effects, Colorectal Neoplasms etiology, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Enzyme Inhibitors pharmacology, Intestinal Mucosa drug effects, Ligands, Membrane Proteins antagonists & inhibitors, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pyrazines pharmacology, Pyridines pharmacology, Stem Cells drug effects, Carcinogenesis metabolism, Cell Transformation, Neoplastic metabolism, Intestinal Mucosa cytology, Intestinal Mucosa metabolism, Stem Cells cytology, Stem Cells metabolism, Wnt Signaling Pathway drug effects
- Abstract
Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.
- Published
- 2018
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