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Cancer Cell. 2018 May 14;33(5):874-889.e7. doi: 10.1016/j.ccell.2018.03.020. Epub 2018 Apr 19.

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.

Author information

1
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
2
Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
3
Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
4
Barrow Neurological Institute, Saint Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
5
Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
6
Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
7
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
8
ICM Brain and Spine Institute, 47 Boulevard de l'Hopital, 75013 Paris, France.
9
Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA; Sandler Neurosciences Center, University of California San Francisco, San Francisco, CA 94143, USA.
10
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA.
11
Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology and Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
12
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
13
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
14
Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
15
Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: jain@steele.mgh.harvard.edu.
16
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of Cambridge and Wellcome Trust-MRC Stem Cell Institute, Hills Road, Cambridge CB2 0AN, UK. Electronic address: dhr25@medschl.cam.ac.uk.

Abstract

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.

KEYWORDS:

Olig2; Wnt; angiogenesis; astrocyte; blood-brain barrier; glioma; invasiveness; oligodendrocyte precursor; p53; vessel co-option

PMID:
29681511
PMCID:
PMC6211172
DOI:
10.1016/j.ccell.2018.03.020
[Indexed for MEDLINE]
Free PMC Article

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