Early Gene Expression Analysis in 9L Orthotopic Tumor-Bearing Rats Identifies Immune Modulation in Molecular Response to Synchrotron Microbeam Radiation Therapy

Bouchet, Audrey; Sakakini, Nathalie; Atifi, Michèle El; Clec’h, Céline Le; Brauer, Elke; Moisan, Anaïck; Deman, Pierre; Rihet, Pascal; Duc, Géraldine Le; Pelletier, Laurent

doi:10.1371/journal.pone.0081874

Cited by 54 publications

(70 citation statements)

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“…The specific response of the tumor tissues is composed by 316 significantly modulated transcripts which are mainly related to immune/inflammatory response, as described in a previous study [35]. But there are other early biological processes underlying the differential effect of MRT on tumor and normal brain [34].…”

Section: Mrt Versus Broad Beam Irradiationmentioning

confidence: 72%

“…MRT may also induce transcriptomic changes such as an overexpression of the resistance factor Areg which is critical for tumor survival and progression, as it involves tumor cell proliferation, invasiveness, motility, inhibition of apoptosis and angiogenesis [40]. Moreover, a strong involvement of immune and/or inflammatory responses after MRT has been revealed in several recent studies [34,35,39]. MRT effects on vasculature, tumor cell proliferation arrest and death, involvement of resistance mechanisms and immune response can all be studied separately but an integrated consideration of these mechanisms is now needed to understand the efficiency of MRT and to further increase the therapeutic potential of this promising method.…”

Section: Discussion and Perspectivesmentioning

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: Mrt Versus Broad Beam Irradiationmentioning

confidence: 72%

Section: Discussion and Perspectivesmentioning

confidence: 99%

Effects of microbeam radiation therapy on normal and tumoral blood vessels

et al. 2015

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“…CCL2 or monocyte chemotactic protein-1 (MCP-1), is the protein encoded by Ccl2, which has been shown to be upregulated by MRT in 9L brain tumors at 6 h postirradiation (15). CCL2 belongs to the CC chemokine family, and recruits monocytes to inflammatory sites in diseases such as psoriasis, rheumatoid arthritis and atherosclerosis (26,27).…”

Section: Discussionmentioning

confidence: 99%

“…A number of recent studies have shown that normal tissues including the central nervous system (CNS) in animal models are extremely tolerant to MRT compared to CRT (9)(10)(11)(12)(13)(14)(15)(16). MRT at 150-625 Gy in-beam doses ablates tumors while apparently causing little or no damage to the surrounding normal tissues (17)(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

In Vitro Study of Genes and Molecular Pathways Differentially Regulated by Synchrotron Microbeam Radiotherapy

et al. 2014

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The aim of this study was to identify genes and molecular pathways differentially regulated by synchrotron-generated microbeam radiotherapy (MRT) versus conventional broadbeam radiotherapy (CRT) in vitro using cultured EMT6.5 cells. We hypothesized (based on previous findings) that gene expression and molecular pathway changes after MRT are different from those seen after CRT. We found that at 24 h postirradiation, MRT exerts a broader regulatory effect on multiple pathways than CRT. MRT regulated those pathways involved in gene transcription, translation initiation, macromolecule metabolism, oxidoreductase activity and signaling transduction in a different manner compared to CRT. We also found that MRT/CRT alone, or when combined with inflammatory factor lipopolysaccharide, upregulated expression of Ccl2, Ccl5 or Csf2, which are involved in host immune cell recruitment. Our findings demonstrated differences in the molecular pathway for MRT versus CRT in the cultured tumor cells, and were consistent with the idea that radiation plays a role in recruiting tumor-associated immune cells to the tumor. Our results also suggest that a combination of MRT/CRT with a treatment targeting CCL2 or CSF2 could repress the tumor-associated immune cell recruitment, delay tumor growth and/or metastasis and yield better tumor control than radiation alone.

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“…Furthermore, potentially antioncogenic apoptotic proteomic changes indicate that the collective interaction of such MB irradiation-induced bystander effect proteins might confer a protective effect on normal tissues [20]. (6) Transcriptional gene expression analysis of intracerebral gliosarcomas in rats [12,29] and EM6.5 breast tumours in mice [30] have identified MRT induced immunity-related modulations, clearly different from transcriptional changes induced by unsegmented broad beams.…”

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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Early Gene Expression Analysis in 9L Orthotopic Tumor-Bearing Rats Identifies Immune Modulation in Molecular Response to Synchrotron Microbeam Radiation Therapy

Cited by 54 publications

References 50 publications

Effects of microbeam radiation therapy on normal and tumoral blood vessels

Effects of microbeam radiation therapy on normal and tumoral blood vessels

In Vitro Study of Genes and Molecular Pathways Differentially Regulated by Synchrotron Microbeam Radiotherapy

Microbeam radiation therapy: Clinical perspectives

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