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.
Highlights
Glioblastoma brain tumors are the most common adult brain cancer and have a very poor prognosis
We focus on the adhesion signaling networks and actin cytoskeleton dynamics that are implicated in mesenchymal migration and discuss how these molecules represent exciting potential targets for therapeutic arrest of glioblastoma cell invasion
Based on the known interaction of Focal Adhesion Kinase (FAK) with the Cas family of proteins and their role in promoting cell migration it was proposed, and subsequently confirmed, that the Cas protein Neural precursor cell-expressed, developmentally downregulated 9 (NEDD9), known as Human enhancer of filamentation 1 (HEF1) and Crk-associated substrate-lymphocyte type (Cas-L), is a specific regulator of glioblastoma cell invasion through brain homogenates [70], and it is apparent that NEDD9/HEF1/Cas-L is a critical regulator of Rac-mediated mesenchymal cell migration [209]
Summary
Glioblastoma brain tumors are the most common adult brain cancer and have a very poor prognosis. The potential role, if any, of the other characteristic mutations in invasion is presently unknown Another group of glioblastomas is known to arise from previously identified gliomas, usually developing as a result of malignant transformation several years after initial diagnosis of a low grade astrocytoma [25]. This type of glioblastoma is relatively rare by contrast and occurs in younger patients with a mean age of 45 years [13].
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