Mesenchymal migration as a therapeutic target in glioblastoma

Abstract

Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma.

Figure 1

Glioblastoma cells follow the tracks created by other cells in 3D collagen gels. U87-MG glioblastoma cells were seeded into collagen type I gels for 24 hours, and then 24-hour time-lapse imaging was performed to track cell migration. Arrows (↑) indicate a “leading” cell and a “follower” cell, and arrows heads (∧) indicate the single path that they both follow in the collagen gel.

Figure 2

Schematic representation of a glioblastoma cell migrating through a 3D ECM. During migration, the cell becomes polarized with respect to the direction of movement into a leading and a trailing edge. The leading edge is characterized by dynamic membrane rearrangements and proteolytic breakdown of ECM, enabling the cell to protrude at its front. The trailing edge displays constant disassembly of mature focal adhesions, therefore promoting dislodgement of the rear. Tight regulation of actin assembly and disassembly is crucial for migration, controlling cellular protrusion, as well as myosin II-mediated contraction in interplay with myosin II.

Figure 3

The FAK/Src/Cas signaling network downstream from integrin receptor engagement. Downstream from this network, RhoA, Rac1, and Cdc42 induce cytoskeletal changes that regulate cell migration.