Differential regulation of VEGF, HIF1α and angiopoietin‐1, ‐2 and ‐4 by hypoxia and ionizing radiation in human glioblastoma

Lund, Eva Løbner; Høg, Anja; Olsen, Minna W.B.; Hansen, Lasse Tengbjerg; Engelholm, Svend A.; Kristjansen, Paul E.G.

doi:10.1002/ijc.11662

Cited by 62 publications

(42 citation statements)

References 18 publications

(16 reference statements)

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“…VEGF expression and vessel density decreased after low-dose XRT, while HIF-1a expression showed no obvious change, Lund et al also reported that VEGF upregulation occurred from 18 to 24 hr after 5Gy ionizing radiation, whereas 2Gy ionizing radiation had no effect on the expression of VEGF from 18 to 24 hr after radiotherapy. 26 HIF-1a expression was markedly suppressed by rhK5 treatment and its level was highly correlated with vessel density. It was noted that failure of tumor control in radiotherapy was due to increased radioresistance of endothelial cells.…”

Section: Discussionmentioning

confidence: 90%

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect

Jin

et al. 2007

Intl Journal of Cancer

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Antiangiogenic therapy could destroy tumor vasculature and inhibit tumor growth. It might inhibit tumor growth significantly when used as a single treatment modality and its therapeutic benefit may even be greater when used in combination with established treatment modalities such as radiation therapy (RT). In the present report, we investigated the effect of recombinant human plasminogen kringle 5 domain (rhK5) in combination with ionizing radiation on angiogenesis, tumor growth and survival in a murine Lewis lung carcinoma (LLC) tumor model. Combined treatment using rhK5 and radiotherapy displayed obvious suppressive effect on LLC tumor growth as compared with single treatment with either modality (p < 0.05), and resulted in a more additive effect on tumor growth delay in this model. In addition, combined treatment significantly enhanced the survival of mice and no toxic effect, such as weight loss, was observed. The significant antitumor effect of rhK5 plus radiation was associated with a direct suppression effect on early neoangiogenesis and tumor cell apoptosis. Furthermore, the expression of VEGF and HIF-1a in tumor tissue correlated well with decreased vessel density. The results suggest that rhK5 significantly enhances the antitumor activity of RT and could be a potent adjuvant therapeutic approach to improve the efficacy of radiotherapy for lung cancer. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 90%

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect

Jin

et al. 2007

Intl Journal of Cancer

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“…Hence, we tested whether CCI-779 reverses the release of hypoxia-inducible factor (HIF)-1-driven VEGF that becomes increased in response to ionizing radiation and hypoxia (Lund et al, 2004;Tabatabai et al, 2006). Inhibition of mTOR markedly suppressed HIF-1 production induced by irradiation or sublethal hypoxia and reduced VEGF levels (Fig.…”

Section: Irradiation-enhanced Mtor Inhibition Exerts Combined Antiangmentioning

confidence: 99%

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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“…The hypoxic region in tumors required higher radiation doses to obtain similar biologic effects compared with normoxic regions (Lund et al, 2004). In hypoxic conditions, tumor cells would undergo gene mutation to adequate the circumstances they lived, which resulted in the radioresistance.…”

Section: Introductionmentioning

confidence: 99%

Influence of Ionizing Radiation on Ovarian Carcinoma SKOV-3 Xenografts in Nude Mice under Hypoxic Conditions

Zhang

Gang²,

Gao³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Purpose: We aimed to detect the expression of HIF-1α, VEGF, HPSE-1 and CD31 in SKOV3 xenografts in nude mice treated with different doses of ionizing radiation, trying to explore the possible mechanism of hypoxia and radioresistance. Methods: Nude mice bearing SKOV3 xenografts were randomly divided into 4 groups: Group A (control group, no ionizing radiation), Group B (treated with low dose of ionizing radiation: 50cGy), Group C (treated with high dose of ionizing radiation: 300cGy), Group D ( combined ionizing radiation, treated with ionizing radiation from low dose to high dose : 50cGy first and 300cGy after 6h interval). The mRNA levels of HIF-1 and VEGF in each group were detected by real time polymerase chain reaction, while HPSE-1 expression was measured by ELISA. The microvessel density (MVD) and hypoxic cells were determined through immunohistochemical (IHC) staining of CD31 and HIF-1a. Results: Significant differences of HIF-1α mRNA level could be found among the 4 groups (F=74.164, P<0.001): Group C>Group A>Group D> Group B. The mRNA level of VEGF in Group C was significantly higher than in the other three groups (t=-5.267, P=0.000), while no significant difference was observed among Group A, B and D (t=1.528, 1.588; P=0.205, 0.222). In addition, the MVD was shown to be the highest in Group C (t=6.253, P=0.000), whereas the HPSE-1 level in Group A was lower than in Group B (t=14.066, P=0.000) and higher than in Group C (t=-21.919, P=0.000), and similar with Group D (t=-2.066, P=0.058). Through IHC staining of HIF-1a, the expression of hypoxic cells in Group A was (++), Group B was (+), Group C was (+++) and Group D was (+). Conclusion: Ionizing radiation with lowerdoses might improve tumor hypoxia through inhibiting the expression of HIF-1 and HPSE-1, whereas higherdoses worsen tumor hypoxic conditions by up-regulating HIF-1α, HPSE-1, VEGF and CD31 levels. A protocol of low-dose ionizing radiation followed by a high-dose irradiation might at least partly improve tumor hypoxia and enhance radiosensitivity.

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Differential regulation of VEGF, HIF1α and angiopoietin‐1, ‐2 and ‐4 by hypoxia and ionizing radiation in human glioblastoma

Cited by 62 publications

References 18 publications

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Influence of Ionizing Radiation on Ovarian Carcinoma SKOV-3 Xenografts in Nude Mice under Hypoxic Conditions

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