The Neural Extracellular Matrix, Cell Adhesion Molecules and Proteolysis in Glioma Invasion and Tumorigenicity

High-grade gliomas are the most prevalent and lethal form of primary intracranial tumors. Despite significant progress in surgical and adjuvant therapeutic treatments for gliomas, patient prognosis still remains dismal. The ability of gliomas to invade the normal surrounding brain tissue contributes to their capacity to evade therapeutic interventions, ultimately leading to tumor recurrence and subsequent disease progression (Rich & Bigner, 2004). Another major therapeutic obstacle comes from the high degree of intratumoral cellular heterogeneity. The tumor mass is comprised of both terminally differentiated cells, cells that exhibit finite capabilities of self-renewal and multipotency, and a smaller subpopulation of cells that exhibit stem cell-like qualities. These stem-like cells, termed Glioma Initiating Cells (GICs), exihibit pluripotency, self-renewal and, importantly, are capable of repopulating the original parental tumor. Therefore, more effective therapies may be derived from targeting both the infiltrative nature of gliomas and GICs (Louis, 2006; Park & Rich, 2009). The ability of glioma tumor cells to infiltrate the normal surrounding brain tissue is a property that is restricted to intracranial tumors that are phenotypically glial within the central nervous system (CNS). As metastatic tumor cells that are highly invasive in the periphery fail to invade surrounding brain tissue once within the confines of the CNS, and invasive glioma tumors that originate in the brain rarely metastasize outside of the CNS. These findings suggest that the unique interaction between glioma tumor cells and the neural extracellular environment mediate glioma invasion (Bellail et al., 2004; Nutt et al., 2001a). A defining attribute of the neural extracellular environment is the unique composition of the neural extracellular matrix (ECM), which unlike other peripheral matrices has low levels of fibrilliar proteins like collagens, fibronectin, and laminin (Ruoslahti, 1996). In both neural development and pathogenesis, the neural ECM regulates key biological processes including cellular migration, maturation, synapse formation, and plasticity. In the adult brain the composition of the neural ECM is largely inhibitory to cellular reorganization (Galtrey & Fawcett, 2007; Zimmermann & Dours-Zimmermann, 2008). Therefore, glioma tumor cell invasion into the normal surrounding brain tissue is derived from their ability to overcome this normally inhibitory extracellular environment. Decades of research has