TY - JOUR
T1 - Mechanisms of Glioma Formation
T2 - Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy
AU - Baker, Gregory J.
AU - Yadav, Viveka Nand
AU - Motsch, Sebastien
AU - Koschmann, Carl
AU - Calinescu, Anda Alexandra
AU - Mineharu, Yohei
AU - Camelo-Piragua, Sandra Ines
AU - Orringer, Daniel
AU - Bannykh, Serguei
AU - Nichols, Wesley S.
AU - deCarvalho, Ana C.
AU - Mikkelsen, Tom
AU - Castro, Maria G.
AU - Lowenstein, Pedro R.
N1 - Funding Information:
This work was supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke grants 1RO1-NS 054193, 1RO1-NS 061107, and 1RO1-NS082311 to P.R.L. and grants 1UO1-NS052465, 1RO1-NS 057711, and 1RO1-NS074387 to M.G.C.
Funding Information:
We thank Roger Tsien (Department of Pharmacology, University of California San Diego) for kindly donating the pCI-neo-mCitrine expression vector. Plasmids encoding the Sleeping Beauty transposase/luciferase (pT2C-LucPGK-SB100X), shp53 (pT2-shp53-GFP4), and NRAS (pT2CAG-NRASV12) were generously provided by the laboratory of John Ohlfest (University of Minnesota). We gratefully acknowledge support for our work received from Philip Jenkins and the Department of Neurosurgery, University of Michigan School of Medicine. We are also grateful to Karin Muraszko for her academic leadership, M. Dahlgren, D. Tomford, and S. Napolitan for their superb administrative support, and Weidong Xiong for the generation of the GL26-Cit cell line. Author contributions: G.J.B, M.G.C., and P.R.L designed the research; G.J.B., V.N.Y, C.K., and Y.M. performed the research; S.M. designed and performed mathematical computations for the agent-based simulation; A.-A.C., S.B., W.S.N., A.C.D, T.M., S.I.C.-P, and D.O. contributed reagents and provided analytical tools; G.J.B., M.G.C., and P.R.L. analyzed the data; G.J.B., M.G.C., and P.R.L. wrote the paper. The authors declare no conflicts of interest.
Publisher Copyright:
© 2014 Neoplasia Press, Inc.
PY - 2014
Y1 - 2014
N2 - As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.
AB - As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.
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UR - http://www.scopus.com/inward/citedby.url?scp=84907556027&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2014.06.003
DO - 10.1016/j.neo.2014.06.003
M3 - Article
C2 - 25117977
AN - SCOPUS:84907556027
SN - 1522-8002
VL - 16
SP - 543
EP - 561
JO - Neoplasia
JF - Neoplasia
IS - 7
ER -