Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.

Autor:	Bassett EA; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada., Tokarew N; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada., Allemano EA; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada., Mazerolle C; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada., Morin K; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada., Mears AJ; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada., McNeill B; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada., Ringuette R; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada., Campbell C; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada., Smiley S; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada., Pokrajac NT; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada., Dubuc AM; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada., Ramaswamy V; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada.; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada.; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada., Northcott PA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada., Remke M; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada., Monnier PP; Genetics and Development Division, Krembil Research Institute, University Health Network, Toronto, Canada.; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada., Potter D; Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States., Paes K; Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States., Kirkpatrick LL; Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States., Coker KJ; Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States., Rice DS; Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States., Perez-Iratxeta C; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada., Taylor MD; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada.; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada., Wallace VA; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada.; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2016 Nov 08; Vol. 5. Date of Electronic Publication: 2016 Nov 08.
DOI:	10.7554/eLife.16764
Abstrakt:	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. Competing Interests: The authors declare that no competing interests exist.
Databáze:	MEDLINE
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