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Glycolysis-related gene induction and ATP reduction during fractionated irradiation

Markers for radiation responsiveness of human tumor xenografts

Glykolyse-assoziierte Geninduktion und ATP-Absenkung während fraktionierter Bestrahlung

Marker für das Therapieansprechen humaner Tumorxenografts

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Abstract

Background and purpose

Lactate was previously shown to be a prognostic but not a predictive pre-therapeutic marker for radiation response of tumor xenografts. We hypothesize that metabolic changes during fractionated irradiation may restrict the predictiveness of lactate regarding tumor radiosensitivity.

Materials and methods

Tumor xenografts were generated in nude mice by implanting 4 head and neck squamous cell carcinoma lines with different sensitivities to fractionated irradiation. Tumors were irradiated with up to 15 fractions of 2 Gy over a period of 3 weeks, and ATP and lactate levels were measured in vital tumor areas with induced metabolic bioluminescence imaging. Corresponding changes in mRNA expression of glycolysis-related genes were determined by quantitative RT-PCR.

Results

Lactate content decreased significantly in 3 out of 4 cell lines in the course of irradiation showing no correlation with cell line-specific radiosensitivity. Radiation-induced changes in ATP levels and glycolysis-related mRNA expression, however, only occurred in radiosensitive or intermediately radioresistant xenografts, whereas these parameters remained unchanged in radioresistant tumors.

Conclusion

Sensitivity-related differences in the transcriptional response of tumors to radiotherapy may be exploited in the clinic for better individualization of tumor treatment.

Zusammenfassung

Hintergrund und Fragestellung

Der Laktatgehalt humaner Tumorxenotransplantate ist ein prognostischer, aber kein prädiktiver prätherapeutischer Marker für das Therapieansprechen bei Bestrahlung. Diese Einschränkung hinsichtlich der Vorhersagekraft von Laktat könnte auf Veränderungen des Tumorstoffwechsels während einer Strahlentherapie beruhen.

Material und Methode

Grundlage der Studie waren Xenotransplantate von 4 humanen Plattenepithelkarzinomlinien des Kopf-Hals-Bereichs, die sich in ihrer Strahlenresistenz unterschieden. Die Tumoren wurden mit bis zu 15 Fraktionen mit 2 Gy über einen Zeitraum von 3 Wochen bestrahlt. Mittels induzierter metabolischer Biolumineszenzmessung wurden der ATP- und Laktatgehalt im vitalen Tumorgewebe bestimmt. Zusätzlich erfolgten Messungen der parallelen Veränderungen der mRNA-Expression glykolyserelevanter Gene mit quantitativer RT-PCR.

Ergebnisse

Unabhängig von der zelllinienspezifischen Strahlenresistenz nahm in 3 von 4 Linien der Laktatgehalt im Laufe der fraktionierten Bestrahlung ab. Strahleninduzierte Änderungen des ATP-Gehalts oder der mRNA-Expression waren hingegen mit der Strahlensensitivität der jeweiligen Tumore korreliert. Im Gegensatz zu strahlenresistenten Xenografts zeigten radiosensitive Tumore oder Xenotransplantate mit einer mittleren Strahlenresistenz signifikante Änderungen im ATP-Gehalt und auf transkriptioneller Ebene.

Schlussfolgerung

Die Ergebnisse weisen auf Unterschiede in der transkriptionellen Antwort der Tumoren nach Bestrahlung hin, die sich im klinischen Alltag für eine bessere personalisierte Tumorbehandlung nutzen lassen könnten.

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Conflict of interest

On behalf of all authors, the corresponding author states that there are no conflicts of interest.

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Authors and Affiliations

  1. Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany

    K. Goetze, S.S. Meyer & W. Mueller-Klieser

  2. OncoRay – National Center for Radiation Research in Oncology, Department of Radiation Oncology, Experimental Radiotherapy, Technical University Dresden, Dresden, Germany

    A. Yaromina & M. Baumann

  3. Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany

    D. Zips

  4. Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany

    M. Baumann

Authors
  1. K. Goetze
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  2. S.S. Meyer
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  3. A. Yaromina
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  4. D. Zips
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  5. M. Baumann
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  6. W. Mueller-Klieser
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Correspondence to K. Goetze.

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Goetze, K., Meyer, S., Yaromina, A. et al. Glycolysis-related gene induction and ATP reduction during fractionated irradiation. Strahlenther Onkol 189, 782–788 (2013). https://doi.org/10.1007/s00066-013-0371-9

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  • DOI: https://doi.org/10.1007/s00066-013-0371-9

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