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Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation

The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tu...

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Autores principales: Bassett, Erin A, Tokarew, Nicholas, Allemano, Ema A, Mazerolle, Chantal, Morin, Katy, Mears, Alan J, McNeill, Brian, Ringuette, Randy, Campbell, Charles, Smiley, Sheila, Pokrajac, Neno T, Dubuc, Adrian M, Ramaswamy, Vijay, Northcott, Paul A, Remke, Marc, Monnier, Philippe P, Potter, David, Paes, Kim, Kirkpatrick, Laura L, Coker, Kenneth J, Rice, Dennis S, Perez-Iratxeta, Carol, Taylor, Michael D, Wallace, Valerie A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100999/
https://www.ncbi.nlm.nih.gov/pubmed/27823583
http://dx.doi.org/10.7554/eLife.16764
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author Bassett, Erin A
Tokarew, Nicholas
Allemano, Ema A
Mazerolle, Chantal
Morin, Katy
Mears, Alan J
McNeill, Brian
Ringuette, Randy
Campbell, Charles
Smiley, Sheila
Pokrajac, Neno T
Dubuc, Adrian M
Ramaswamy, Vijay
Northcott, Paul A
Remke, Marc
Monnier, Philippe P
Potter, David
Paes, Kim
Kirkpatrick, Laura L
Coker, Kenneth J
Rice, Dennis S
Perez-Iratxeta, Carol
Taylor, Michael D
Wallace, Valerie A
author_facet Bassett, Erin A
Tokarew, Nicholas
Allemano, Ema A
Mazerolle, Chantal
Morin, Katy
Mears, Alan J
McNeill, Brian
Ringuette, Randy
Campbell, Charles
Smiley, Sheila
Pokrajac, Neno T
Dubuc, Adrian M
Ramaswamy, Vijay
Northcott, Paul A
Remke, Marc
Monnier, Philippe P
Potter, David
Paes, Kim
Kirkpatrick, Laura L
Coker, Kenneth J
Rice, Dennis S
Perez-Iratxeta, Carol
Taylor, Michael D
Wallace, Valerie A
author_sort Bassett, Erin A
collection PubMed
description The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tumor medulloblastoma (MB). We show that activation of the vascular regulatory signalling axis mediated by Norrin (an atypical Wnt)/Frizzled4 (Fzd4) inhibits MB initiation in the Ptch(+/−) mouse model. Loss of Norrin/Fzd4-mediated signalling in endothelial cells, either genetically or by short-term blockade, increases the frequency of pre-tumor lesions and creates a tumor-permissive microenvironment at the earliest, preneoplastic stages of MB. This pro-tumor stroma, characterized by angiogenic remodelling, is associated with an accelerated transition from preneoplasia to malignancy. These data expose a stromal component that regulates the earliest stages of tumorigenesis in the cerebellum, and a novel role for the Norrin/Fzd4 axis as an endogenous anti-tumor signal in the preneoplastic niche. DOI: http://dx.doi.org/10.7554/eLife.16764.001
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spelling pubmed-51009992016-11-10 Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation Bassett, Erin A Tokarew, Nicholas Allemano, Ema A Mazerolle, Chantal Morin, Katy Mears, Alan J McNeill, Brian Ringuette, Randy Campbell, Charles Smiley, Sheila Pokrajac, Neno T Dubuc, Adrian M Ramaswamy, Vijay Northcott, Paul A Remke, Marc Monnier, Philippe P Potter, David Paes, Kim Kirkpatrick, Laura L Coker, Kenneth J Rice, Dennis S Perez-Iratxeta, Carol Taylor, Michael D Wallace, Valerie A eLife Cancer Biology The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tumor medulloblastoma (MB). We show that activation of the vascular regulatory signalling axis mediated by Norrin (an atypical Wnt)/Frizzled4 (Fzd4) inhibits MB initiation in the Ptch(+/−) mouse model. Loss of Norrin/Fzd4-mediated signalling in endothelial cells, either genetically or by short-term blockade, increases the frequency of pre-tumor lesions and creates a tumor-permissive microenvironment at the earliest, preneoplastic stages of MB. This pro-tumor stroma, characterized by angiogenic remodelling, is associated with an accelerated transition from preneoplasia to malignancy. These data expose a stromal component that regulates the earliest stages of tumorigenesis in the cerebellum, and a novel role for the Norrin/Fzd4 axis as an endogenous anti-tumor signal in the preneoplastic niche. DOI: http://dx.doi.org/10.7554/eLife.16764.001 eLife Sciences Publications, Ltd 2016-11-08 /pmc/articles/PMC5100999/ /pubmed/27823583 http://dx.doi.org/10.7554/eLife.16764 Text en © 2016, Bassett et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Bassett, Erin A
Tokarew, Nicholas
Allemano, Ema A
Mazerolle, Chantal
Morin, Katy
Mears, Alan J
McNeill, Brian
Ringuette, Randy
Campbell, Charles
Smiley, Sheila
Pokrajac, Neno T
Dubuc, Adrian M
Ramaswamy, Vijay
Northcott, Paul A
Remke, Marc
Monnier, Philippe P
Potter, David
Paes, Kim
Kirkpatrick, Laura L
Coker, Kenneth J
Rice, Dennis S
Perez-Iratxeta, Carol
Taylor, Michael D
Wallace, Valerie A
Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
title Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
title_full Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
title_fullStr Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
title_full_unstemmed Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
title_short Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
title_sort norrin/frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100999/
https://www.ncbi.nlm.nih.gov/pubmed/27823583
http://dx.doi.org/10.7554/eLife.16764
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