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.
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CAFs secrete MMPs including MMP-2, MMP-3, and MMP-9, or activate Yes-associated protein to promote ECM degradation and remodeling, EMT, and CSC stemness.
“CAFs reportedly secrete matrix metalloproteinases (MMPs), including MMP-2, MMP-3, and MMP-9, or activate Yes-associated protein to promote ECM degradation and remodeling, EMT, and CSC stemness.283–287”
From Drug repurposing for cancer therapy (2024) · cites this paper as [285]
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- Authors
- 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.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Palermo (IT)
- Apogenix (Germany) (DE)
- Corresponding author
- Medema, Jan Paul
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2010-04-25
- Volume
- 12
- Issue
- 5
- Pages
- 468-476
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2147650118
- Cited by
- 1,804
- References
- 1
- Citations by year
- 2026: 26 · 2025: 51 · 2024: 68 · 2023: 92 · 2022: 87 · 2021: 143 · 2020: 116 · 2019: 120 · 2018: 151 · 2017: 129 · 2016: 131 · 2015: 153 · 2014: 154 · 2013: 132 · 2012: 128
- FWCI
- 60.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- China Scholarship Council
- Università degli Studi di Palermo
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- Wnt signaling, colorectal cancer, cancer stem cells, tumor microenvironment, myofibroblasts, hepatocyte growth factor, β-catenin, clonogenicity, tumor stroma
- MeSH terms
- Animals, Colonic Neoplasms, Fibroblasts, Humans, Mice, Nude, Neoplasm Proteins, Neoplasms, Experimental, Transplantation, Heterologous, Neoplastic Stem Cells, Signal Transduction, Hepatocyte Growth Factor, Coculture Techniques, Paracrine Communication, Wnt Proteins, beta Catenin, Mice
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