Angiogenesis in Gliomas
Malignant brain tumors, including glioblastoma (GBM), display growth, survival, and invasive properties that are coupled to blood vessels and vascular-derived factors. For example, GBM stem cells (GSCs) home to perivascular niches and invasive tumor cells
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Angiogenesis in Gliomas Mujeeburahim Cheerathodi and Joseph H. McCarty
Abstract
Malignant brain tumors, including glioblastoma (GBM), display growth, survival, and invasive properties that are coupled to blood vessels and vascularderived factors. For example, GBM stem cells (GSCs) home to perivascular niches and invasive tumor cells commonly disperse through the brain microenvironment via extracellular matrix (ECM)-rich vascular basement membranes. Anti-vascular agents that target angiogenesis, and particularly those involving vascular endothelial cell growth factor-A (VEGF-A) and its receptors, improve progression-free survival in GBM patients. However, these benefits are often transient due to compensation by alternative angiogenic pathways. The detailed molecular mechanisms that couple GBM cells to blood vessels during tumor growth and progression as well as following anti-angiogenesis therapies are just beginning to be elucidated, with various cytokines, growth factors, and ECM proteins playing important roles. In this review we will highlight molecular pathways that link cerebral blood vessels and GBM cells during tumor growth, progression, and invasion. We will also discuss mechanisms underlying GBM-induced angiogenesis, with a particular focus placed on roles for integrin adhesion receptors and their ECM protein ligands. Therapies that target angiogenesis in GBM and other brain cancers will also be summarized. Keywords
Brain cancer • Glioblastoma • Growth factors • Integrins • Extracellular matrix • Invasion • Neurovascular unit • Vascular niches
M. Cheerathodi • J.H. McCarty (*) Department of Neurosurgery, Unit 1004 S5.8136c, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA e-mail: [email protected] A. Sedo and R. Mentlein (eds.), Glioma Cell Biology, DOI 10.1007/978-3-7091-1431-5_7, # Springer-Verlag Wien 2014
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M. Cheerathodi and J.H. McCarty
Abbreviations BBB CNS EC ECM EGF FGF HGF GBM GSC IL MAPK MMP MRP PDGF RTK TGFβ TIMP VEGF
7.1
Blood–brain barrier Central nervous system Endothelial cell Extracellular matrix Epidermal growth factor Fibroblast growth factor Hepatocyte growth factor Glioblastoma GBM stem cell Interleukin Mitogen-activated protein kinase Matrix metalloproteinase Multidrug resistance protein Platelet-derived growth factor Receptor tyrosine kinase Transforming growth factor β Tissue inhibitors of matrix metalloproteinase Vascular endothelial cell growth factor
Introduction
The formation of new blood vessels via endothelial cell (EC) proliferation and sprouting, or angiogenesis, is essential for proper development and physiology of all mammalian organs (Adams and Alitalo 2007; Potente et al. 2011). This is particularly relevant in the central nervous system (CNS)—comprised of the brain, spinal cord, and retina—where neurons and glia regulate EC behaviors via direct cell–cell contacts as well as secreted growth factors and extracellular matrix (ECM) proteins (McCarty 2009a; Zacchigna et al. 2008). Aberrant regulation of a
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