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Acute versus chronic hypoxia in tumors

Controversial data concerning time frames and biological consequences

Akute versus chronische Hypoxie in Tumoren

Kontroverse Daten über Zeitverläufe und biologische Konsequenzen

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Abstract

Background

Many tumors contain hypoxic regions. Hypoxia, in turn, is known to increase aggressiveness and to be associated with treatment resistance. The two most frequently described and investigated subtypes of tumor hypoxia are acute and chronic. These two subtypes can lead to completely different hypoxia-related responses within the tumor, which could have a direct effect on tumor development and response to treatment. In order to accurately assess the specific biological consequences, it is important to understand which time frames best define acute and chronic hypoxia.

Materials and methods

This article provides an overview of the kinetics of in vitro and in vivo acute and chronic tumor hypoxia. Special attention was paid to differentiate between methods to detect spontaneous in vivo hypoxia and to describe the biological effects of experimental in vitro and in vivo acute and chronic tumor hypoxia.

Results and conclusions

There are large variations in reported spontaneous fluctuations in acute hypoxia that are dependent on the cell lines investigated and the detection method used. In addition to differing hypoxia levels, exposure times used to induce in vitro and in vivo experimental acute and chronic hypoxia range from 30 min to several weeks with no clear boundaries separating the two. Evaluation of the biological consequences of each hypoxia subtype revealed a general trend that acute hypoxia leads to a more aggressive phenotype. Importantly, more information on the occurrence of acute and chronic hypoxia in human tumors is needed to help our understanding of the clinical consequences.

Zusammenfassung

Hintergrund

Viele Tumoren weisen Areale mit einer O2-Mangelversorgung (Hypoxie) auf, die zur Entwicklung eines aggressiven Phänotyps und zu Therapieresistenzen führen kann. Die hierbei am häufigsten experimentell untersuchten Subtypen sind die akute und chronische Hypoxie, die ganz unterschiedliche hypoxieinduzierte biologische Reaktionen der Tumoren zur Folge haben können. Um diese Effekte genauer erfassen zu können, ist insbesondere eine Festlegung der hierbei diskutierten zeitlichen Rahmen der beiden Hypoxieformen von Bedeutung.

Material und Methoden

Dieser Diskussionsbeitrag analysiert im Wesentlichen die zeitlichen Verläufe von in-vitro- und in-vivo-Untersuchungen zur akuten und chronischen Tumorhypoxie, wobei auch die jeweils eingesetzten Methoden zur Erfassung von Spontanhypoxien in vivo detailliert beschrieben werden. Weiterhin werden die biologischen Konsequenzen der akuten und chronischen Hypoxie in vivo und in vitro diskutiert.

Ergebnisse und Schlussfolgerungen

Die beobachteten Spontanfluktuationen bei der Akuthypoxie scheinen Zelllinien- und Methoden-abhängig zu sein. Weiterhin sind unterschiedliche Hypoxiegrade und Expositionszeiten zur Auslösung einer experimentellen Akut- und Langzeithypoxie in vitro und in vivo äußerst variabel, ohne bislang deutlich erkennbare „Zeitfenster“ zur Abgrenzung der beiden Hypoxieformen. Bei der Bewertung der biologischen Konsequenzen der beiden Hypoxiesubtypen wird deutlich, dass vor allem die Akuthypoxie zur Entwicklung eines aggressiven Phänotyps beiträgt. Für eine abschließende Bewertung der beiden Hypoxieformen in der klinischen Onkologie ist die gegenwärtige Datenlage jedoch noch nicht ausreichend.

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Acknowledgments

This study has been supported in part by the Bundesministerium für Bildung und Forschung (BMBF: 01EZ0826).

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  1. Department of Radiotherapy and Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

    C. Bayer Ph.D. & P. Vaupel

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Bayer, C., Vaupel, P. Acute versus chronic hypoxia in tumors. Strahlenther Onkol 188, 616–627 (2012). https://doi.org/10.1007/s00066-012-0085-4

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