RESUMEN
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.
Asunto(s)
Carcinogénesis/metabolismo , Transformación Celular Neoplásica/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Células Madre/citología , Células Madre/metabolismo , Vía de Señalización Wnt , Aciltransferasas/antagonistas & inhibidores , Adenoma/etiología , Adenoma/metabolismo , Adenoma/patología , Proteína de la Poliposis Adenomatosa del Colon/deficiencia , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Animales , Carcinogénesis/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Inhibidores Enzimáticos/farmacología , Mucosa Intestinal/efectos de los fármacos , Ligandos , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pirazinas/farmacología , Piridinas/farmacología , Células Madre/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Colorectal cancer (CRC) is one of the most common cancers in the western world and is characterised by deregulation of the Wnt signalling pathway. Mutation of the adenomatous polyposis coli (APC) tumour suppressor gene, which encodes a protein that negatively regulates this pathway, occurs in almost 80% of CRC cases. The progression of this cancer from an early adenoma to carcinoma is accompanied by a well-characterised set of mutations including KRAS, SMAD4 and TP53. Using elegant genetic models the current paradigm is that the intestinal stem cell is the origin of CRC. However, human histology and recent studies, showing marked plasticity within the intestinal epithelium, may point to other cells of origin. Here we will review these latest studies and place these in context to provide an up-to-date view of the cell of origin of CRC.