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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.

Prasetyanti PR, Zimberlin CD, Bots M, Vermeulen L, Melo Fde S, Medema JP - Mol. Cancer (2013)

Bottom Line: In this respect they are remarkably similar to their non-malignant counterparts that orchestrate the intestinal lining.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Room G2-131, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. j.p.medema@amc.nl.

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.

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Related in: MedlinePlus

The signaling architecture defining self-renewal and lineage specification is maintained in colon cancer progression. Although genetic hits accumulate during progression (e.g. depicted as APC mutation in adenoma), signals defining self-renewal and lineage specification are orchestrated similarly between normal and cancerous tissues. On the left part of each progression step, stemness potential is defined by a gradient of Wnt signals (green, high (dark green) in normal stem cells and cancer stem cells and low (light green) in differentiated (tumor) cells). The right part of each progression step depicts the response to a specific morphogenic cue; in this case inhibition of Notch signaling promotes differentiation towards goblet cells (pink).
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Figure 4: The signaling architecture defining self-renewal and lineage specification is maintained in colon cancer progression. Although genetic hits accumulate during progression (e.g. depicted as APC mutation in adenoma), signals defining self-renewal and lineage specification are orchestrated similarly between normal and cancerous tissues. On the left part of each progression step, stemness potential is defined by a gradient of Wnt signals (green, high (dark green) in normal stem cells and cancer stem cells and low (light green) in differentiated (tumor) cells). The right part of each progression step depicts the response to a specific morphogenic cue; in this case inhibition of Notch signaling promotes differentiation towards goblet cells (pink).

Mentions: Our data on a unique panel of cultures, representing normal, pre-malignant neoplastic lesions as well as adenocarcinoma tissue from both mouse and human origin, shows that at all stages of disease, the tissue is organized in a highly similar hierarchical fashion and present with cell types encompassing multiple differentiation lineages. Here we find that the Wnt and Notch pathways are not only crucial for the orchestration of this hierarchy but their function in regulating self-renewal and cell fate is also conserved during cancer development. Furthermore, our data provide evidence that the robust mechanism orchestrating hierarchy in normal intestinal epithelium is strongly wired in the epithelial cells and its regulation is sustained throughout carcinogenesis (FigureĀ 4). The Wnt and Notch pathways, even though subjected to mutation or aberrant regulation, maintain their central position in the regulation of this hierarchy. These parallels between normal and neoplastic tissue notably makes targeted therapies towards these pathways challenging, as it will predictably impact normal hierarchy. Understanding similarities, but above all the differences in molecular mechanisms will help in highlighting crucial differences that can be exploited for therapeutic design.


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

Prasetyanti PR, Zimberlin CD, Bots M, Vermeulen L, Melo Fde S, Medema JP - Mol. Cancer (2013)

The signaling architecture defining self-renewal and lineage specification is maintained in colon cancer progression. Although genetic hits accumulate during progression (e.g. depicted as APC mutation in adenoma), signals defining self-renewal and lineage specification are orchestrated similarly between normal and cancerous tissues. On the left part of each progression step, stemness potential is defined by a gradient of Wnt signals (green, high (dark green) in normal stem cells and cancer stem cells and low (light green) in differentiated (tumor) cells). The right part of each progression step depicts the response to a specific morphogenic cue; in this case inhibition of Notch signaling promotes differentiation towards goblet cells (pink).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016508&req=5

Figure 4: The signaling architecture defining self-renewal and lineage specification is maintained in colon cancer progression. Although genetic hits accumulate during progression (e.g. depicted as APC mutation in adenoma), signals defining self-renewal and lineage specification are orchestrated similarly between normal and cancerous tissues. On the left part of each progression step, stemness potential is defined by a gradient of Wnt signals (green, high (dark green) in normal stem cells and cancer stem cells and low (light green) in differentiated (tumor) cells). The right part of each progression step depicts the response to a specific morphogenic cue; in this case inhibition of Notch signaling promotes differentiation towards goblet cells (pink).
Mentions: Our data on a unique panel of cultures, representing normal, pre-malignant neoplastic lesions as well as adenocarcinoma tissue from both mouse and human origin, shows that at all stages of disease, the tissue is organized in a highly similar hierarchical fashion and present with cell types encompassing multiple differentiation lineages. Here we find that the Wnt and Notch pathways are not only crucial for the orchestration of this hierarchy but their function in regulating self-renewal and cell fate is also conserved during cancer development. Furthermore, our data provide evidence that the robust mechanism orchestrating hierarchy in normal intestinal epithelium is strongly wired in the epithelial cells and its regulation is sustained throughout carcinogenesis (FigureĀ 4). The Wnt and Notch pathways, even though subjected to mutation or aberrant regulation, maintain their central position in the regulation of this hierarchy. These parallels between normal and neoplastic tissue notably makes targeted therapies towards these pathways challenging, as it will predictably impact normal hierarchy. Understanding similarities, but above all the differences in molecular mechanisms will help in highlighting crucial differences that can be exploited for therapeutic design.

Bottom Line: In this respect they are remarkably similar to their non-malignant counterparts that orchestrate the intestinal lining.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Room G2-131, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. j.p.medema@amc.nl.

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.

Show MeSH
Related in: MedlinePlus