Uveale Melanomzellen unter oxidativem Stress – Einfluss von VEGF und VEGF-Inhibitoren

Zusammenfassung

Hintergrund Die Rolle des oxidativen Stresses bei Krebserkrankungen ist komplex. Während die durch ihn ausgelösten pathologischen Veränderungen an der Krebsentstehung beteiligt sind, kann er in späteren Stadien das Absterben von Tumorzellen fördern und sogar Metastasierungen eindämmen. Krebszellen zeigen durch ihren veränderten Metabolismus häufig eine verstärkte Bildung von radikalen Sauerstoffspezies, was sie anfällig für zusätzlichen oxidativen Stress macht. Dies ist ein wichtiger Wirkmechanismus von verschiedenen Chemotherapeutika und von therapeutisch eingesetzter ionisierender Strahlung. Das uveale Melanom ist der häufigste primäre Tumor im adulten Auge. Für die bei etwa 50 % der Patienten auftretenden Metastasen sind zurzeit leider keine wirksamen Behandlungsoptionen verfügbar. Der Primärtumor kann aber mit gutem Erfolg mit ionisierender Strahlung behandelt werden. Eine wichtige Nebenwirkung ist hierbei die Strahlenretinopathie, die wiederum mit VEGF-Antagonisten (VEGF: Vascular endothelial Growth Factor) behandelt wird. Eine Therapie des Primärtumors mit Anti-VEGF-Substanzen wird ebenfalls in der Literatur diskutiert. Über eine solche Anwendung liegen bisher nur wenige Daten vor, es ist aber eine paradoxe Verschlechterung der Situation bei einem uvealen Melanommodell in der Maus unter Anti-VEGF-Therapie berichtet worden.

Methoden In einer Studie haben wir den Einfluss von VEGF und dem VEGF-Antagonisten Bevacizumab auf das Überleben von 5 unterschiedlichen uvealen Melanomzelllinien, die mit oxidativem Stress (Wasserstoffperoxid) behandelt worden sind, untersucht. Im Weiteren haben wir uns die Expression relevanter Proteine sowie den Einfluss von Bevacizumab auf das Proliferationsverhalten der Zellen und auf das Angiogeneseverhalten von Endothelzellen in einer Kokultur mit uvealen Melanomzellen angesehen.

Ergebnisse Wir konnten in dieser Studie zeigen, dass nicht nur VEGF, sondern paradoxerweise auch der VEGF-Antagonist Bevacizumab uveale Melanomzellen vor einem Zelltod durch oxidativen Stress schützen kann. Bevacizumab zeigt darüber hinaus keinen Einfluss auf die Proliferation der Zellen und ist nur bedingt in der Lage, angiogene Strukturen in diesem System zu verhindern.

Schlussfolgerungen Die Protektion der uvealen Melanomzellen vor oxidativem Stress durch Bevacizumab ist, gerade in Anbetracht des Wirkprinzips der ionisierenden Strahlung, durch oxidativen Stress in den Tumorzellen einen Zelltod auszulösen, ein besorgniserregender Befund, der gegen eine Verwendung von Anti-VEGF bei uvealem Melanom spricht.

Abstract

Background The role of oxidative stress in cancer is complex. While the pathological alterations induced by oxidative stress may be involved in the induction of tumours, in the late stages of tumour development, it can facilitate the loss of tumour cells and might even prevent metastasis. Tumour cells show metabolic alterations, often inducing an increased production of reactive oxygen species, which makes these cells particularly vulnerable to additional oxidative stress. This is an important mode of action in the use of many chemotherapeutics and in the application of ionizing radiation. Uveal melanoma is the most frequent primary tumour in the adult eye. For metastasis of this tumour, which affects about 50 % of the patients, no appropriate treatment is currently available. However, the primary tumour can efficiently be treated with ionizing radiation. A frequent side effect of this treatment is radiation retinopathy, which is treated with vascular endothelial growth factor (VEGF) antagonists. A therapy of the primary tumour with VEGF antagonists is under discussion. So far, little data is available on this subject, however, a paradoxical worsening of the situation has been found in a mouse model of uveal melanoma treated with bevacizumab.

Methods We have investigated the effect of VEGF and of the VEGF-antagonist bevacizumab on the survival of five different melanoma cell lines under oxidative stress treatment with hydrogen peroxide. In addition, we investigated the expression of relevant proteins and the effect of bevacizumab on the proliferation of the cells as well as its effect on the angiogenic behaviour of endothelial cells, co-cultured with uveal melanoma cells.

Results Our study showed that not only VEGF but also, paradoxically, the VEGF-antagonist bevacizumab is able to protect uveal melanoma cells from oxidative stress-induced cell death. Bevacizumab did not influence the proliferation of the cells and showed only limited effectiveness to reduce angiogenic structures.

Conclusion Considering that oxidative stress is the mode of action for ionizing radiation to induce cell death, a protective effect of bevacizumab on uveal melanoma cells against oxidative stress is worrisome and argues against the use of VEGF in uveal melanoma.

Schlüsselwörter

uveales Melanom - VEGF - oxidativer Stress - Bevacizumab

Key words

uveal melanoma - VEGF - oxidative stress - bevacizumab

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