Abstract
Glioblastoma (GB) is the most malignant of primary adult brain tumors, characterized by a highly locally invasive cell population, as well as abundant proliferative cells, neoangiogenesis, and necrosis. Clinical intervention with chemotherapy or radiation may either promote or establish an environment for manifestation of invasive behavior. Understanding the molecular drivers of invasion in the context of glioma progression may be insightful in directing new treatments for patients with GB. Here, we review current knowledge on Rho family GTPases, their aberrant regulation in GB, and their effect on GB cell invasion and tumor progression. Rho GTPases are modulators of cell migration through effects on actin cytoskeleton rearrangement; in non-neoplastic tissue, expression and activation of Rho GTPases are normally under tight regulation. In GB, Rho GTPases are deregulated, often via hyperactivity or overexpression of their activators, Rho GEFs. Downstream effectors of Rho GTPases have been shown to promote invasiveness and, importantly, glioma cell survival. The study of aberrant Rho GTPase signaling in GB is thus an important investigation of cell invasion as well as treatment resistance and disease progression.
Highlights
GLIOMA CHARACTERIZATION Gliomas comprise the most common group of primary brain tumors and are of neuroepithelial designation, named for a glial cell origin [1]
The RhoA and Rac1 pathways are increasingly associated with the promotion of divergent modes of cell migration in other systems; amoeboid type motility, characterized by cell rounding has been demonstrated to be regulated by the Rho/ROCK pathway, whereas prominent Rac signaling regulates mesenchymal type invasion with long morphological process extension [99]
Functional evidence for the role of RhoA has been demonstrated under the inhibition of the RhoA effector ROCK, which led to activation of Rac1 in glioma cells and promoted invasion
Summary
GLIOMA CHARACTERIZATION Gliomas comprise the most common group of primary brain tumors and are of neuroepithelial designation, named for a glial cell origin [1]. Glioma cell invasion is promoted via the overexpression of receptors such as MET or EGFR, as well as downstream signaling through PI3K and MAPK pathways, and the Rho family of GTPases, among others [8, 9]. RhoA, Rac, and Cdc42 are well-characterized members of the Rho family of GTPases and have been described as key regulators of cell migration [17].
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