title: Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.
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.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Vermeulen
authors.forename: Felipe
authors.initials: F
authors.lastname: De Sousa E Melo
authors.forename: Maartje
authors.initials: M
authors.lastname: van der Heijden
authors.forename: Kate
authors.initials: K
authors.lastname: Cameron
authors.forename: Joan H
authors.initials: JH
authors.lastname: de Jong
authors.forename: Tijana
authors.initials: T
authors.lastname: Borovski
authors.forename: Jurriaan B
authors.initials: JB
authors.lastname: Tuynman
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.forename: Christian
authors.initials: C
authors.lastname: Merz
authors.forename: Hans
authors.initials: H
authors.lastname: Rodermond
authors.forename: Martin R
authors.initials: MR
authors.lastname: Sprick
authors.forename: Kristel
authors.initials: K
authors.lastname: Kemper
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Richel
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin
chemical_list: D009363:Neoplasm Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D017228:Hepatocyte Growth Factor