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Wnt activity defines colon cancer stem cells and is regulated by the microenvironment
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Journal Article
Wnt activity defines colon cancer stem cells and is regulated by the microenvironment
2010
Overview
Cancer stem cell activity may not merely be an intrinsic characteristic of a subset of cancer cells and could be regulated by environmental cues. High Wnt activity in human colorectal cancer designates a tumour-initiating population and is orchestrated by the microenvironment.
Despite the presence of mutations in APC or β-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when β-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate β-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both
in vitro
and
in vivo
. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Biomedical and Life Sciences
/ Cellular signal transduction
/ Cloning
/ Colonic Neoplasms - metabolism
/ Colonic Neoplasms - pathology
/ Hepatocyte Growth Factor - physiology
/ Hepatocyte Growth Factor - secretion
/ Humans
/ Mice
/ Mutation
/ Neoplastic Stem Cells - metabolism
/ Neoplastic Stem Cells - pathology
/ Oncology
/ Transplantation, Heterologous
/ Tumors
