Synchrotron microbeam radiation therapy induces hypoxia in intracerebral gliosarcoma but not in the normal brain

Bouchet, Audrey; Lemasson, Benjamin; Christen, Thomas; Potez, Marine; Rome, Claire; Coquery, Nicolas; Clec’h, Céline Le; Moisan, Anaïck; Bräuer-Krisch, Elke; Leduc, Géraldine; Rémy, Chantal; Laissue, Jean A.; Barbier, Emmanuel; Brun, Emmanuel; Serduc, Raphaël

doi:10.1016/j.radonc.2013.05.013

Cited by 79 publications

(69 citation statements)

References 31 publications

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“…Over the past decades, different techniques and approaches have tested and now lend support to this hypothesis. While no major modification was observed in normal vasculature [17,18,26], tumors showed a denudation of the tumor vascular endothelium, a decrease in number of vessels [26,27,30] leading to a decrease in perfusion [26] and to tumor hypoxia [30]. On the contrary, in another model study [27] the tumor vasculature presented signs of normalization of the vasculature (i.e.…”

Section: Discussion and Perspectivesmentioning

confidence: 87%

“…In addition, an in vivo MR imaging follow-up has demonstrated a significant decrease in the fractional blood volume in the tumor, and in diameter of tumor vessels, with cross-fired arrays beginning at 8 days after MRT [26]. Simultaneously, a striking remodeling of the tumor vasculature was detected histologically, as evidenced by a decreased density of tumor vessels with increased inter-vessel distances and endothelial denudation [26,30] (Fig. 5AeC).…”

Section: Brain Tumorsmentioning

confidence: 88%

“…5AeC). These changes were associated with a significant decrease of the local tissue saturation with oxygen, monitored by magnetic resonance based measurement (MR_SO 2 ) and with an histologic over-expression of an indirect marker of hypoxia (GLUT1) in tumor tissue [30] (Fig. 5DeF).…”

Section: Brain Tumorsmentioning

confidence: 99%

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Effects of microbeam radiation therapy on normal and tumoral blood vessels

et al. 2015

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Microbeam radiation therapy (MRT) is a new form of preclinical radiotherapy using quasi-parallel arrays of synchrotron X-ray microbeams. While the deposition of several hundred Grays in the microbeam paths, the normal brain tissues presents a high tolerance which is accompanied by the permanence of apparently normal vessels. Conversely, the efficiency of MRT on tumor growth control is thought to be related to a preferential damaging of tumor blood vessels. The high resistance of the healthy vascular network was demonstrated in different animal models by in vivo biphoton microscopy, magnetic resonance imaging, and histological studies. While a transient increase in permeability was shown, the structure of the vessels remained intact. The use of a chick chorioallantoic membrane at different stages of development showed that the damages induced by microbeams depend on vessel maturation. In vivo and ultrastructural observations showed negligible effects of microbeams on the mature vasculature at late stages of development; nevertheless a complete destruction of the immature capillary plexus was found in the microbeam paths. The use of MRT in rodent models revealed a preferential effect on tumor vessels. Although no major modification was observed in the vasculature of normal brain tissue, tumors showed a denudation of capillaries accompanied by transient increased permeability followed by reduced tumor perfusion and finally, a decrease in number of tumor vessels. Thus, MRT is a very promising treatment strategy with pronounced tumor control effects most likely based on the anti-vascular effects of MRT.

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Section: Discussion and Perspectivesmentioning

confidence: 87%

Section: Brain Tumorsmentioning

confidence: 88%

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Effects of microbeam radiation therapy on normal and tumoral blood vessels

et al. 2015

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“…These characteristics of MRT have been extensively demonstrated by results of preclinical experiments [12,17]. Furthermore, MRT-associated bystander effects have been identified [18e21].…”

Section: Mrt In Small Animalsmentioning

confidence: 99%

“…(3) In contrast to the high tolerance of the normal microvasculature [9] and arteries [7] to irradiation by MB, the tumour vasculature of 9L gliosarcomas in rats is selectively damaged by MRT [28] with ensuing tumour hypoxia and shrinkage. Conversely, normal brain tissues exposed to MB during MRT remain sufficiently perfused to maintain normoxia [17]. (5) MB irradiation of normal rat brains provokes proteomic responses that are indicative of oncogenesis and proteomic changes associated with bystander effects, indicative of apoptosis mediated by reactive oxygen species.…”

Section: Mrt In Small Animalsmentioning

confidence: 99%

Microbeam radiation therapy: Clinical perspectives

et al. 2015

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Microbeam radiation therapy (MRT), a novel form of spatially fractionated radiotherapy (RT), uses arrays of synchrotron-generated X-ray microbeams (MB). MRT has been identified as a promising treatment concept that might be applied to patients with malignant central nervous system (CNS) tumours for whom, at the current stage of development, no satisfactory therapy is available yet. Preclinical experimental studies have shown that the CNS of healthy rodents and piglets can tolerate much higher radiation doses delivered by spatially separated MBs than those delivered by a single, uninterrupted, macroscopically wide beam. High-dose, high-precision radiotherapies such as MRT with reduced probabilities of normal tissue complications offer prospects of improved therapeutic ratios, as extensively demonstrated by results of experiments published by many international groups in the last two decades. The significance of developing MRT as a new RT approach cannot be understated. Up to 50% of cancer patients receive conventional RT, and any new treatment that provides better tumour control whilst preserving healthy tissue is likely to significantly improve patient outcomes.

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Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy

Bouchet

Sakakini

Atifi

et al. 2014

Intl Journal of Cancer

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Synchrotron microbeam radiation therapy (MRT) relies on the spatial fractionation of a synchrotron beam into parallel micronwide beams allowing deposition of hectogray doses. MRT controls the intracranial tumor growth in rodent models while sparing normal brain tissues. Our aim was to identify the early biological processes underlying the differential effect of MRT on tumor and normal brain tissues. The expression of 28,000 transcripts was tested by microarray 6 hr after unidirectional MRT (400 Gy, 50 mm-wide microbeams, 200 mm spacing). The specific response of tumor tissues to MRT consisted in the significant transcriptomic modulation of 431 probesets (316 genes). Among them, 30 were not detected in normal brain tissues, neither before nor after MRT. Areg, Trib3 and Nppb were down-regulated, whereas all others were up-regulated. Twenty-two had similar expression profiles during the 2 weeks observed after MRT, including Ccnb1, Cdc20, Pttg1 and Plk1 related to the mitotic role of the Pololike kinase (Plk) pathway. The up-regulation of Areg expression may indicate the emergence of survival processes in tumor cells triggered by the irradiation; while the modulation of the "mitotic role of Plk1" pathway, which relates to cytokinetic features of the tumor observed histologically after MRT, may partially explain the control of tumor growth by MRT. The identification of these tumor-specific responses permit to consider new strategies that might potentiate the antitumoral effect of MRT.Microbeam radiation therapy (MRT) is a novel form of preclinical radiotherapy based on the spatial fractionation of an incident synchrotron beam into arrays of parallel microbeams, which are typically few tens microns wide and separated on centre by few hundred microns (for review 1 ). This unique irradiation geometry allows the deposition of hectogray doses in tumors. Remarkably, brain tumors can be palliated by MRT in small animals with limited damage to normal cerebral tissues.2,3 This differential effect relates to the radioresistance of normal brain vessels to MRT for doses up to 1,000 Gy 4,5 , whereas MRT induces a denudation of tumor vessel endothelium, a decrease in tumor blood volume, 6,7 and tumor hypoxia.7 However, other mechanisms may contribute to the differential effects of MRT on tumor vs. normal tissues, e.g., direct impact of ionising radiation on tumor cells occurring before the vascular effect 6 and communication between lethally irradiated cells in the microbeam's path and less damaged cells sited in-between.8 All biological mechanisms underlying these differential effects remain to identify.Increasing the knowledge about the differential response between normal and tumor tissue to MRT is crucial because the identification of processes highly specific for the tumor tissue could be exploited to increase tumor control without disturbing the repair and maintenance of surrounding normal brain tissues. Specific cellular and molecular responses could be used to design efficient and safe adjuvant therapies.We have recently d...

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Synchrotron microbeam radiation therapy induces hypoxia in intracerebral gliosarcoma but not in the normal brain

Abstract: We provide new evidence for the differential effect of MRT on tumor vasculature, an effect that leads to tumor hypoxia. As hypothesized formerly, the vasculature of the normal brain exposed to MRT remains sufficiently perfused to prevent any hypoxia.

Cited by 79 publications

References 31 publications

Effects of microbeam radiation therapy on normal and tumoral blood vessels

Effects of microbeam radiation therapy on normal and tumoral blood vessels

Microbeam radiation therapy: Clinical perspectives

Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy

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