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Regulation of stem cell self-renewal and differentiation by Wnt and Notch are conserved throughout the adenoma-carcinoma sequence in the colon

Pramudita Ramadhina Prasetyanti1, Cheryl Doreen Zimberlin1, Michael Bots1, Louis Vermeulen12, Felipe De Sousa E Melo1 and Jan Paul Medema1*

Author Affiliations

1 Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Room G2-131, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands

2 Current affiliation: Cancer Research UK, Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK

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Molecular Cancer 2013, 12:126  doi:10.1186/1476-4598-12-126

Published: 21 October 2013

Abstract

Background

Colon cancer stem cells are shown to be the self-renewing cells within a tumor that give rise to all lineages of more differentiated tumor cells. In this respect they are remarkably similar to their non-malignant counterparts that orchestrate the intestinal lining. This suggests that, despite the numerous genetic aberrations and morphological changes that have occurred during cancer initiation and progression, a remnant homeostatic regulation persists.

Findings

Using a number of human and mouse intestinal-derived organoid cultures from normal, adenoma and cancerous tissues, we show here that Notch signals coordinate self-renewal and lineage determination not only in normal, but also at the adenoma and carcinoma stage in both mice and humans. Moreover, the Wnt pathway, which carries activating mutations in virtually all colon cancers, is not as previously predicted constitutively active in adenomas and carcinomas, but still displays a heterogeneous activity pattern that determined stemness in all stages of disease.

Conclusion

These data for the first time provide a comprehensive overview of Wnt and Notch-mediated signaling in the different stages of the adenoma-carcinoma sequence and demonstrates that these morphogenic pathways, despite mutations, remain crucial determinants of both architecture and hierarchy in normal and malignant intestinal tissue.

Keywords:
Colorectal cancer; Wnt; Notch; Stem cells; Adenoma; Morphogenic pathways; Organoid cultures