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Sci Rep. 2017 Mar 21;7:44899. doi: 10.1038/srep44899.

A non-cell autonomous mouse model of CNS haemangioblastoma mediated by mutant KRAS.

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Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, University of Oxford, Oxford, OX3 9DS, UK.
MRC Laboratory of Molecular Biology, Francis Crick Ave, Cambridge CB2 OQH, UK.
Centre for Comparative Pathology &Division of Pathology, University of Edinburgh, Institute of Genetics &Molecular Medicine, Crewe Road, Edinburgh, EH4 2XR, UK.
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.


Haemangioblastoma is a rare malignancy of the CNS where vascular proliferation causes lesions due to endothelial propagation. We found that conditionally expressing mutant Kras, using Rag1-Cre, gave rise to CNS haemangioblastoma in the cortex and cerebellum in mice that present with highly vascular tumours with stromal cells similar to human haemangioblastomas. The aberrant haemangioblastoma endothelial cells do not express mutant Kras but rather the mutant oncogene is expressed in CNS interstitial cells, including neuronal cells and progeny. This demonstrates a non-cell autonomous origin of this disease that is unexpectedly induced via Rag1-Cre expression in CNS interstitial cells. This is the first time that mutant RAS has been shown to stimulate non-cell autonomous proliferation in malignancy and suggests that mutant RAS can control endothelial cell proliferation in neo-vascularisation when expressed in certain cells.

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