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Nat Commun ; 9(1): 1132, 2018 03 19.
Article in English | MEDLINE | ID: mdl-29556067

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.


Subject(s)
Carcinogenesis/metabolism , Cell Transformation, Neoplastic/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Wnt Signaling Pathway , 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 , Wnt Signaling Pathway/drug effects
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