Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.
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.
Vermeulen
Louis
L
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.
De Sousa E Melo
Felipe
F
van der Heijden
Maartje
M
Cameron
Kate
K
de Jong
Joan H
JH
Borovski
Tijana
T
Tuynman
Jurriaan B
JB
Todaro
Matilde
M
Merz
Christian
C
Rodermond
Hans
H
Sprick
Martin R
MR
Kemper
Kristel
K
Richel
Dick J
DJ
Stassi
Giorgio
G
Medema
Jan Paul
JP
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
D009363:Neoplasm Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D017228:Hepatocyte Growth Factor