6533b823fe1ef96bd127e258

RESEARCH PRODUCT

Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.

Jurriaan B. TuynmanMartin R. SprickMatilde TodaroJoan H. De JongChristian MerzTijana BorovskiHans M. RodermondKate CameronFelipe De Sousa E MeloLouis VermeulenDick J. RichelJan Paul MedemaMaartje Van Der HeijdenGiorgio StassiKristel Kemper

subject

Beta-cateninColorectal cancerTransplantation HeterologousMice NudeBiologyMiceCancer stem cellParacrine CommunicationmedicineAnimalsHumansAPC microenvironmentbeta CateninHepatocyte Growth FactorWnt signaling pathwayLRP6LRP5Cell BiologyNeoplasms ExperimentalFibroblastsmedicine.diseaseCoculture TechniquesCell biologyNeoplasm ProteinsWnt ProteinsColonic Neoplasmsbiology.proteinNeoplastic Stem CellsHepatocyte growth factorStem cellmedicine.drugSignal Transduction

description

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.

yearjournalcountryeditionlanguage
2010-01-01
10.1038/ncb2048http://hdl.handle.net/10447/51288