Possible Future Issues in the Treatment of Glioblastomas: Special Emphasis on Cell Migration and the Resistance of Migrating Glioblastoma Cells to Apoptosis

Lefranc, Florence; Brotchi, Jacques; Kiss, Róbert

doi:10.1200/jco.2005.03.089

Cited by 498 publications

(445 citation statements)

References 116 publications

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“…Tumor type-specific responses to chemotherapy are known to affect the prognosis for various neoplasms of the CNS; for example, brain tumors of astrocytic origin are remarkably more resistant to radiation and chemotherapy compared with many CNS tumors arising from other lineages (Behin et al, 2003;Lefranc et al, 2005;Prados and Levin, 2000). Strong correlations have been observed among certain cellular responses unique to astrocytes and their ability to resist treatment with DNA damaging agents (Harrison et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Altering DNA base excision repair: Use of nuclear and mitochondrial‐targeted N‐methylpurine DNA glycosylase to sensitize astroglia to chemotherapeutic agents

Harrison

Rinne

Kelley

et al. 2007

Glia

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Primary astrocyte cultures were used to investigate the modulation of DNA repair as a tool for sensitizing astrocytes to genotoxic agents. Base excision repair (BER) is the principal mechanism by which mammalian cells repair alkylation damage to DNA and involves the processing of relatively nontoxic DNA adducts through a series of cytotoxic intermediates during the course of restoring normal DNA integrity. An adenoviral expression system was employed to target high levels of the BER pathway initiator, N-methylpurine glycosylase (MPG), to either the mitochondria or nucleus of primary astrocytes to test the hypothesis that an alteration in BER results in increased alkylation sensitivity. Increasing MPG activity significantly increased BER kinetics in both the mitochondria and nuclei. Although modulating MPG activity in mitochondria appeared to have little effect on alkylation sensitivity, increased nuclear MPG activity resulted in cell death in astrocyte cultures treated with methylnitrosourea (MNU). Caspase-3 cleavage was not detected, thus indicating that these alkylation sensitive astrocytes do not undergo a typical programmed cell death in response to MNU. Astrocytes were found to express relatively high levels of antiapoptotic Bcl-2 and Bcl-XL and very low levels of proapoptotic Bad and Bid suggesting that the mitochondrial pathway of apoptosis may be blocked making astrocytes less vulnerable to proapoptotic stimuli compared with other cell types. Consequently, this unique characteristic of astrocytes may be responsible, in part, for resistance of astrocytomas to chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Altering DNA base excision repair: Use of nuclear and mitochondrial‐targeted N‐methylpurine DNA glycosylase to sensitize astroglia to chemotherapeutic agents

Harrison

Rinne

Kelley

et al. 2007

Glia

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“…The extensive dispersion of these motile tumor cells, coupled to their high resistance to apoptosis compared to the cells at the core of the tumor, are major features that make invasive gliomas virtually impossible to eliminate by surgery followed by conventional radio-and chemotherapies [2,3].…”

Section: Introductionmentioning

confidence: 99%

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

2008

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Malignant gliomas are the most common and deadly primary brain tumors, due to their infiltrative invasion of the normal neural tissue that makes them virtually impossible to completely eliminate. We have previously identified and characterized the proteoglycan BEHAB/brevican in gliomas and have demonstrated that upregulation and cleavage of this CNS-specific molecule promote glioma invasion. Here, we have further investigated if the proteolytic processing of BEHAB/ brevican by metalloproteases of the ADAMTS family is a necessary step in mediating its proinvasive effect in glioma. By generating a site-specific ( 396 SRG 398 → NVY) mutant form resistant to ADAMTS cleavage, we have shown that the predominant proteolytic processing of BEHAB/ brevican by glioma cells occurs only at this site. More importantly, "uncleavable" BEHAB/ brevican is unable to enhance glioma cell invasion in vitro and tumor progression in vivo. In addition, our results suggest that the full-length protein and its cleavage products may act independently because the mutant form does not exert a dominant negative effect on normal BEHAB/brevican expression or cleavage. These results illustrate how the regulated processing of major components of the neural extracellular matrix has important functional implications in glioma progression. In addition, our findings underscore the relevance of the ADAMTS family of metalloproteases as attractive targets for novel pharmacological approaches in glioma therapy.

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“…While previous studies have characterized glioma tumor growth, host-mediated mechanisms by which glioma cells migrate and invade the brain is still unclear [29][30][31]. Like most solid tumors, gliomas express and secrete vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) that induces proliferation and migration of neighboring endothelial cells [32][33][34][35][36].…”

Section: Introductionmentioning

confidence: 99%

Reduced Glioma Infiltration in Src-deficient Mice

et al. 2006

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SummaryMalignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant factor in tumor recurrence following surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated vascular permeability (VP) has been associated with the progression of glioma tumor growth and infiltration into surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src +/+ or src +/− ), the VP response is blocked in src −/− mice that demonstrate a 'leakage-resistant phenotype' in the brain. We used the Src-deficient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src −/− mice, the infiltrating component of glioma growth was reduced in src −/− mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect of a Src-mediated VP defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src −/− mice mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.

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Possible Future Issues in the Treatment of Glioblastomas: Special Emphasis on Cell Migration and the Resistance of Migrating Glioblastoma Cells to Apoptosis

Cited by 498 publications

References 116 publications

Altering DNA base excision repair: Use of nuclear and mitochondrial‐targeted N‐methylpurine DNA glycosylase to sensitize astroglia to chemotherapeutic agents

Altering DNA base excision repair: Use of nuclear and mitochondrial‐targeted N‐methylpurine DNA glycosylase to sensitize astroglia to chemotherapeutic agents

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

Reduced Glioma Infiltration in Src-deficient Mice

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