Abstract:
:Despite the presence of mutations in APC or beta-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when beta-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 beta-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.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Vermeulen L,De Sousa E Melo F,van der Heijden M,Cameron K,de Jong JH,Borovski T,Tuynman JB,Todaro M,Merz C,Rodermond H,Sprick MR,Kemper K,Richel DJ,Stassi G,Medema JPdoi
10.1038/ncb2048subject
Has Abstractpub_date
2010-05-01 00:00:00pages
468-76issue
5eissn
1465-7392issn
1476-4679pii
ncb2048journal_volume
12pub_type
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