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

Louis Vermeulen; Felipe de Sousa E Melo; Maartje van der Heijden; Kate Cameron; Joan H. de Jong; Tijana Borovski; Jurriaan B. Tuynman; Matilde Todaro; Christian Merz; Hans Rodermond; Martin R. Sprick; Kristel Kemper; Dick J. Richel; Giorgio Stassi; Jan Paul Medema

doi:https://doi.org/10.1038/ncb2048

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

Louis Vermeulen, Felipe de Sousa E Melo, Maartje van der Heijden, Kate Cameron, Joan H. de Jong, Tijana Borovski, Jurriaan B. Tuynman, Matilde Todaro, Christian Merz, Hans Rodermond, Martin R. Sprick, Kristel Kemper, Dick J. Richel, Giorgio Stassi, Jan Paul Medema

Research output: Contribution to journal › Article › Academic › peer-review

1496 Citations (Scopus)

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

Original language	English
Pages (from-to)	468-U121
Journal	Nature cell biology
Volume	12
Issue number	5
DOIs	https://doi.org/10.1038/ncb2048
Publication status	Published - 2010

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https://doi.org/10.1038/ncb2048

Cite this

Vermeulen, L., de Sousa E Melo, F., van der Heijden, M., Cameron, K., de Jong, J. H., Borovski, T., Tuynman, J. B., Todaro, M., Merz, C., Rodermond, H., Sprick, M. R., Kemper, K., Richel, D. J., Stassi, G., & Medema, J. P. (2010). Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature cell biology, 12(5), 468-U121. https://doi.org/10.1038/ncb2048

@article{be0f35564bad42fd8a5e7db026bd679b,

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",

author = "Louis Vermeulen and {de Sousa E Melo}, Felipe and {van der Heijden}, Maartje and Kate Cameron and {de Jong}, {Joan H.} and Tijana Borovski and Tuynman, {Jurriaan B.} and Matilde Todaro and Christian Merz and Hans Rodermond and Sprick, {Martin R.} and Kristel Kemper and Richel, {Dick J.} and Giorgio Stassi and Medema, {Jan Paul}",

year = "2010",

doi = "https://doi.org/10.1038/ncb2048",

language = "English",

volume = "12",

pages = "468--U121",

journal = "Nature cell biology",

issn = "1465-7392",

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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, JP 2010, 'Wnt activity defines colon cancer stem cells and is regulated by the microenvironment', Nature cell biology, vol. 12, no. 5, pp. 468-U121. https://doi.org/10.1038/ncb2048

TY - JOUR

T1 - Wnt activity defines colon cancer stem cells and is regulated by the microenvironment

AU - Vermeulen, Louis

AU - de Sousa E Melo, Felipe

AU - van der Heijden, Maartje

AU - Cameron, Kate

AU - de Jong, Joan H.

AU - Borovski, Tijana

AU - Tuynman, Jurriaan B.

AU - Todaro, Matilde

AU - Merz, Christian

AU - Rodermond, Hans

AU - Sprick, Martin R.

AU - Kemper, Kristel

AU - Richel, Dick J.

AU - Stassi, Giorgio

AU - Medema, Jan Paul

PY - 2010

Y1 - 2010

N2 - 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

AB - 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

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DO - https://doi.org/10.1038/ncb2048

M3 - Article

C2 - 20418870

SN - 1465-7392

VL - 12

SP - 468-U121

JO - Nature cell biology

JF - Nature cell biology

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ER -