**1. Introduction**

Malignant gliomas are the most common primary tumors of the central nervous system (CNS) accounting for over 22,000 new cases in the USA each year [1]. Glioblastoma multiforme (GBM) is the most aggressive (WHO grade IV) glioma and is characterized histologically by high mitotic activity leading to hypoxia and necrosis, nuclear atypia and cellular pleomorphism, and microvascular proliferation due to secretion of pro-angiogenic factors. These tumors are uniformly fatal with standard treatment consisting of maximal surgical resection followed by radiation and chemotherapy which targets cell proliferation (Temozolomide or other DNA modifying agents) [2] or angiogenesis (Bevacizumab) [3], as well as other newly developed methods of attacking dividing tumor cells (Optune-TTF) [4].

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Gliomas differ from metastatic tumors in their ability to migrate into the surrounding brain parenchyma. While most recurrence occurs within 1–2 cm of the original tumor bed [5], seemingly multifocal disease or so-called "butterfly glioma" can develop at distant sites as a consequence of migration of cells along blood vessels and white matter tracts [6] (**Figure 1**). Although they are highly infiltrative, less than 2% of gliomas spread outside the CNS, suggesting that tumor cells are either not able to cross the basement membrane and enter the vasculature or that they require a specific neural environment containing specific molecules through which they can proliferate and migrate. Tumor cells switch from a proliferative to a migratory or mesenchymal phenotype, resorting to this more primitive state, which mimics the behavior of their migratory progenitors such as the radial glia that traversed white matter pathways and other structures during embryonic development [7]. The molecular mechanisms of this transition are currently poorly understood.

**Figure 1.** Butterfly glioma in a patient with bihemispheric spread due to involvement of the corpus callosum.

In this chapter, we discuss the composition of the brain's extracellular matrix, as well as the mechanisms by which tumor cells transition to a migratory phenotype and remodel the ECM through degradation by novel proteases and their inhibitors. We discuss the search for ECM molecules expressed by the tumor cells, which then respond to chemoattractants in the environment in order to direct growth. Finally, we discuss potential targets of anti-infiltrative therapy and the obstacles that must yet be overcome to address this important neuro-oncologic problem.
