Implications of Rho GTPase Signaling in Glioma Cell Invasion and Tumor Progression

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.

Differential Proteomics Analysis of Oligodendrogliomas and Astrocytomas Using iTRAQ Quantification

“…Also, pharmacologic inhibition of Ras in GBM resulted in decreased Rac1 activity, which was consistent with the findings under increased RhoA activation [26,27]. Treating glioblastoma cell with plant growth regulator Narciclasine led to increase ROCK activity and stress fiber formation, and these led to an increase in the survival rate of orthotopic transplanted tumor mice [16,28]. In the present work, we found RhoA is highly expressed in oligodendrogliomas but not astrocytomas.…”

“…As a downstream of PDGFRa, Cdc42 activation promoted the cell migration along with Rac1 activation in Glioblastoma Multiforme (GBM) cells [15]. Both Cdc42 and Rac1 displayed high activity in GBM cells in the process of penetrating brain parenchyma and would be potential bio-sensors [16,17]. Furthermore, CDC42 participated in a pathogenic crosstalk between tumor cells and pericytes in GBM [18].…”

Bergamottin, a natural furanocoumarin abundantly present in grapefruit juice, suppresses the invasiveness of human glioma cells via inactivation of Rac1 signaling

“…Rho GTPases are a family of small signaling G-proteins that perform critical roles in cancer cell migration, invasion and metastasis (5). They act as molecular switches through cycling between an inactive GDP-bound and active GTP-bound form.…”

“…They act as molecular switches through cycling between an inactive GDP-bound and active GTP-bound form. Rac1 is one of the most studied Rho GTPase family members (5). Several lines of evidence indicate that Rac1 activation contributes to glioma cell invasion (6)(7)(8).…”

RHOA (ras homolog gene family, member A)

“…Oncogenesis Decreased RhoA activity occurred in correlation with increased glioma cell migration (Fortin Ensign et al, 2013).…”