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EMBO Mol Med. 2017 Dec;9(12):1629-1645. doi: 10.15252/emmm.201607445.

Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth.

Author information

1
Vascular Patterning Lab, Center for Cancer Biology, VIB, Leuven, Belgium thomas.mathivet@inserm.fr holger.gerhardt@kuleuven.vib.be.
2
Vascular Patterning Lab, Department of Oncology, KU Leuven, Leuven, Belgium.
3
Vascular Patterning Lab, Center for Cancer Biology, VIB, Leuven, Belgium.
4
Department of Neurosciences, Laboratory of Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven, Belgium.
5
Laboratory for Vascular Morphogenesis, RIKEN Center for Developmental Biology, Kobe, Japan.
6
Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
7
UMR 970, Paris Cardiovascular Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
8
Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium.
9
Lab of Molecular Oncology and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
10
Department of Neurosciences, KU Leuven, Leuven, Belgium.
11
Integrative Vascular Biology Laboratory, Max-Delbrück-Center for Molecular Medicine, Helmholtz Association (MDC), Berlin, Germany.
12
Berlin Institute of Health (BIH), Berlin, Germany.

Abstract

Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro-inflammatory M1-like macrophages in the early stages, followed by in situ repolarization to M2-like macrophages, which produced VEGF-A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti-CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences.

KEYWORDS:

VEGF ; glioma; live imaging; myeloid cells; vessel dysmorphia

PMID:
29038312
PMCID:
PMC5709745
DOI:
10.15252/emmm.201607445
[Indexed for MEDLINE]
Free PMC Article

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