Research ReportGlioma-induced remodeling of the neurovascular unit
Introduction
Gliomas are associated with aggressive invasion of the surrounding brain parenchyma. While resection reduces the primary tumor burden, extensive migration of glioma cells away from the primary tumor mass prevents the complete removal of tumor cells and represents a significant challenge in the treatment of glioma. In vivo experimental models of glioma have been used to demonstrate that tagging tumor cells can be used to monitor the infiltration of tumor cells in the parenchyma and/or perivascular spaces even at a single cell level (Lampson et al., 1993, Lund et al., 2006, Winkler et al., 2009, Zhang et al., 2002). However, the relationship between glioma-induced BBB dysregulation and glioma invasion remains poorly understood.
Gliomas disrupt the integrity of the blood–brain barrier (BBB), and this compromise is associated with increased glioma tumor growth and infiltration in human and rodents (Lund et al., 2006, Neuwelt and Rapoport, 1984). Whereas normally, the BBB consists of endothelial cells held together by tight junctions, it also contains a basal lamina surrounding the capillary walls and adjacent astrocyte endfeet that form a structure collectively known as the neurovascular unit, NVU (Iadecola, 2004, Simard and Nedergaard, 2004). The interactions between the different cell types of NVU are disrupted in the microenvironment of the glioma (Abbott et al., 2006, Abramsson et al., 2007, Virgintino et al., 2007).
While many studies with malignant glioma focus on the dysregulated signaling pathways in tumor cells as a potential target for therapeutics (Furnari et al., 2007), our previous studies have shown the importance of the host microenvironment to influence the migration of the tumor cells (Criscuoli et al., 2005, Lund et al., 2006). For example, the presence of specific host factors such as src in the brain endothelium is essential for tumor-mediated BBB breakdown and glioma invasion (Eliceiri et al., 1999, Lund et al., 2006). In this study, we compared tumor-induced changes in the NVU of primary vs secondary tumors (as defined by their distance from the primary tumor), and suggest that changes in basal lamina composition may mediate the capacity of gliomas to regulate BBB integrity.
Section snippets
Immunostaining of the astrocyte–endothelial interface of the BBB
In the normal brain, a subset of astrocytes extends projections to the basal lamina that surrounds the microvascular endothelium. Immunohistochemical staining with anti-glial fibrillary acidic protein (GFAP) demonstrates the difference between arterioles/venules and the capillary bed and highlights the specific association of GFAP-positive astrocytes with larger vessels that have a minimal role in regulating vascular permeability (Fig. 1A). Immunostaining of 60 μm thick tissue sections with an
Discussion
In this study, we show that tumor induces specific changes in endothelial cells, remodeling of the ECM and changes in endothelial-associated astrocytes. We observed a decrease in laminin and agrin, and an increase in tenascin in the primary tumor (Fig. 3). In secondary tumors, both astrocytes and blood vessels remain separated by a basal lamina that contains laminin and agrin (Fig. 3, Fig. 4). The changes in staining observed in the primary tumor are in general agreement with observations from
Mice
Rag2 knockout mice were used for xenograft studies based on previous studies using rag2−/−, src+/+ or rag2−/−, src+/− hosts (Eliceiri et al., 1999, Lund et al., 2006). All animal handling procedures were approved by the University of California San Diego Institutional Animal Care and Use Committee.
Glioma tumor cells
Early passages of patient-derived human glioma cells, DBTRG (a kind gift from Dr. C. Kruse) were used for xenograft studies. Cells were maintained in Dulbecco's modified Eagle's minimum essential
Acknowledgments
We acknowledge the expert technical assistance of Montha Pao. These studies were supported by grants from the NHLBI and NINDS (B.E.).
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2017, Neuroimaging Clinics of North AmericaCitation Excerpt :Such NVU also may adversely affect other applications of task and rsfMR imaging in the setting of focal brain lesions that may alter regional hemodynamics or otherwise disrupt local networks. The mechanisms underlying brain tumor–induced neurovascular uncoupling are not yet completely understood, but preclinical studies have suggested that tumors induce a variety of physiologic changes in the microenvironment that may contribute to this phenomenon.30 Previous studies31–39 have demonstrated prevalence of NVU in high-grade gliomas as well as with low-grade gliomas.