Autocrine regulation of glioblastoma cell-cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay

Knizetova, Petra; Ehrmann, Jiří; Hlobílková, Alice; Vancova, I.; Kalita, Ondřej; Kolář, Zdeněk; Bártek, Jiří

doi:10.4161/cc.7.16.6442

Cited by 134 publications

(142 citation statements)

References 36 publications

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“…5C). Like VEGFR-1, VEGFR-2 is primarily located on the vascular endothelium, but its expression has also been verified on neuronal, hematopoietic and cancer cells including glioma cells (Knizetova et al, 2008;Ivy et al, 2009). Notably, expression of both, VEGF and VEGFR-2, becomes induced as a consequence of ionizing radiation and is markedly counteracted in response to treatment with CCI-779 (Fig.…”

Section: Discussionmentioning

confidence: 92%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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Section: Discussionmentioning

confidence: 92%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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“…Confocal images were acquired with equal settings and processed with Zen 2008 software (Carl Zeiss MicroImaging, Inc., Jena, Germany). (c) U373MG, U251MG cells and (d) A172, T98G cells were treated with ionizing radiation of 5 Gy (dose rate 2.18 Gy/min by an X-ray generator, Pantak, Berkshire, UK; HF160; 150 kV; 15 mA) or left untreated and analyzed 1 hour (c) or 30 min (d) after irradiation, as described (Knizetova et al, 2008). Further increase of p-p53 Ser15 and p-Chk2 Thr68 after ionizing radiation (5 Gy) over the already enhanced basal activation was observed in both GBM cell lines.…”

Section: Resultsmentioning

confidence: 99%

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

et al. 2010

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Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low-and highgrade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n ¼ 41) and grade IV GBM (n ¼ 60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (cH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high-or lowoxygen culture conditions and in clinical specimens of both low-and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.

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“…Regarding the toxicity profile the currently only available information from this trial is that 16 125 mg were better tolerated. A previous report of a phase II study in thyroid cancer reported a considerable toxicity profile including diarrhea, fatigue, palmar plantar erythrodysesthesia, nausea, thromboembolism, mucositis and elevation of liver enzymes [76].…”

Section: Clinical Datamentioning

confidence: 99%

“…Of note, hypoxia which represents a major stimulatory factor of proangiogenic signaling, downregulates the expression of sVEGFR-1 in endothelial cells [15]. Some authors suggest that VEGF-VEGFR-2 signaling may represent an autocrine regulation pathway of glioma cells in addition to the paracrine interplay of tumor and endothelial cells [16,17]. Further members of the VEGF family represent VEGF-B and placental growth factor (PlGF) which also bind VEGFR-1 and may act as competitive antagonists of VEGF-A.…”

Section: Identification Of Key Molecules In the Process Of Angiogenesismentioning

confidence: 99%

Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma?

Seystahl

Weller²

2012

Expert Opinion on Investigational Drugs

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INTRODUCTION: Antiangiogenic approaches are currently the dominating experimental therapeutic strategy in glioblastoma. First enthusiasm was provoked by promising radiological response rates and an apparent clinical benefit with some of these agents. Major limitations include the modest number of durable responses, the lack of cytotoxic antitumor activity, of synergy when combined with chemotherapy and of an overall survival benefit. AREAS COVERED: We review the rationale as well as preclinical and clinical evidence for the future development of antiangiogenic agents in glioblastoma. The most prominent approach targets VEGF and includes agents such as the VEGF antibody bevacizumab, the VEGF receptor fusion protein aflibercept or the tyrosine kinase inhibitors cediranib and XL-184. Inhibition of angiogenic pathways by small molecules, for example, enzastaurin, or anti-integrin-based approaches, for example, cilengitide, represent alternative strategies. EXPERT OPINION: Enzastaurin and cediranib failed in randomized Phase III trials in recurrent glioblastoma, aflibercept in Phase II. By contrast, bevacizumab was conditionally approved in many countries. Recently completed Phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma. Expert opinion: Enzastaurin and cediranib failed in randomized phase III trials in recurrent glioblastoma, aflibercept in phase II. In contrast, bevacizumab was conditionally approved in many countries. Recently completed phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma.

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Autocrine regulation of glioblastoma cell-cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay

Cited by 134 publications

References 36 publications

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma?

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