Autokrine und parakrine Wachstumsregulation des malignen Melanoms durch Zytokine

Zusammenfassung

In der vorliegenden Arbeit wird die autokrine und parakrine Wirkung von Zytokinen auf das Wachstum des malignen Melanoms zusammengefasst. Maligne Melanomzellen sind in der Lage, eine Vielzahl von Zytokinen zu synthetisieren. Zu diesen zählen der Basic Fibroblast Growth Factor (bFGF) und die Melanoma Growth Stimulatory Activity (MGSA)/Interleukin-8 (IL-8), die autokrin das Wachstum der Melanomzellen stimulieren. Der Transforming Growth Factor-β (TGF-β) und das IL-6, die ebenfalls autokrin von Melanomzellen produziert werden, erwiesen sich als potente Wachstumsinhibitoren normaler Melanozyten, während sie die Proliferation von Melanomzellen nicht beeinflussten oder sogar stimulierten. Der Tumor Necrosis Factor-α (TNF-α) erwies sich als potenter Wachstumsinhibitor normaler Melanozyten, während der antiproliferative Effekt bei Melanomzellen geringer war. Demgegenüber zeigte IFN-β eine konstant starke antiproliferative Wirkung auf normale Melanozyten und maligne Melanomzellen. Andererseits hemmten IFN-α und IFN-γ, welche auf normale Melanozyten kaum antiproliferativ wirksam waren, das Wachstum von Melanomzellen stark. Diese Befunde zeigen eine selektive, antiproliferative Funktion von IFN-α und IFN-γ auf maligne Melanomzellen. Die immunmodulatorische Wirkung der untersuchten Zytokine mit Veränderung der Expression von HLA-Klasse I und II sowie von ICAM-1 war nach Behandlung von Melanozyten mit IFN-γ und TNF-α besonders ausgeprägt. Die bis heute gewonnenen Erkenntisse stellen ein komplexes Zytokinnetzwerk dar, welches Proliferation und Differenzierung von Melanomzellen steuert, und bilden die Grundlage für neuere Therapieansätze des malignen Melanoms. Diese Ansätze zentrieren sich in den letzten Jahren auf Wachstumsfaktorinhibitoren und Signaltransduktionsinhibitoren, und in der Erprobung neuer Zytokinkombinationen oder in Zusammenhang mit Multipeptidvakzinen.

Abstract

The present work summarizes data on the autocrine and paracrine growth regulation of melanoma by cytokines. Melanoma cells produce several cytokines, including the basic fibroblast growth factor (bFGF), and the melanoma growth stimulatory activity (MGSA) / Interleukin 8 (IL-8) which stimulate the growth of melanoma cells in an autocrine fashion. Transforming growth factor-β (TGF-β) and IL-6, which are also produced by melanoma cells, potently inhibited normal melanocyte growth, whereas they did not influence or even stimulated the proliferation of melanoma cells. Tumor necrosis factor-α (TNF-α) was shown to be a potent inhibitor of normal melanocyte growth, whereas the antiproliferative effect on melanoma cells was moderate. On the contrary, IFN-β showed a constantly strong antiproliferative action on normal melanocytes and melanoma cells. On the other hand, IFN-α and IFN-γ which exerted minor effects on normal melanocyte proliferation, strongly suppressed melanoma cell growth. These findings demonstrate a selective, antitumoral activity of IFN-α and IFN-γ against melanoma cells. The immunomodulatory action of the investigated cytokines with modulation of HLA class I expression and of ICAM-1 was more pronounced in the case of IFN-γ and TNF-α. These findings show that melanoma cell growth and differentiation are regulated by a complex cytokine network, and form the basis for newer treatment strategies in melanoma. These recently focus on growth factor inhibitors and signal transduction inhibitors, as well as on new cytokine combinations either alone or together with multipeptide vaccines.

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