Der Transforming Growth Factor-Beta (TGF-β)-Signalweg und seine Bedeutung beim malignen Melanom[*]

Zusammenfassung

Der Transforming Growth Factor-β (TGF-β) stellt einen potenten Wachstumsinhibitor bei normalen Melanozyten dar. Diese Funktion scheint im Verlauf der Tumorgenese zunehmend verloren zu gehen, da viele Melanomzellen durch TGF-β nur sehr schwach oder gar nicht gehemmt werden. Beim Melanom wird der antiproliferative Signalweg des TGF-β häufig aufgehoben, und die Produktion des TGF-β autokrin hochreguliert. Somit kommt es zu einer Reihe parakriner Effekte, wie des extrazellulären Matrixumbaus, der Neoangiogenese, und der Immunsuppression, die letztendlich zum lokalen Tumorwachstum und zur Metastasierung führen. Die Wechselwirkungen der TGF-β-signalübertragenden Smad Proteine mit anderen Signalsystemen, wie der mitogenaktivierten Proteinkinasen, des SKI/SnoN und des Proteinkinase-C-Systems, tragen möglicherweise zum Entweichen der Melanomzellen von der TGF-β-Wachstumskontrolle bei. Die Abklärung der molekularen Interaktionen des TGF-β-Signalweges wird möglicherweise zu der Entwicklung neurer Konzepte für die Therapie des malignen Melanoms beitragen.

Abstract

Transforming growth factor-β is a potent growth inhibitor for normal melanocytes. This function is lost in the course of tumorigenesis, since several melanoma cell lines are only slightly or not at all inhibited by TGF-β. In melanoma, the transduction of antiproliferative signals by TGF-β is often abolished, and the autocrine production of TGF-β increased. By this way, several TGF-β-driven paracrine effects, such as extracellular matrix remodeling, neoangiogenesis, and immunosuppression induce local tumor growth and metastasis. The interaction of Smads, the major TGF-β signaling proteins, with other signaling systems such as the mitogen-activated protein kinases, the SKI/SnoN proteins, and the protein kinase C family, possibly contributes to the escape of melanoma cells from TGF-β growth control. Therefore, the clarification of the molecular interactions of the TGF-β signaling pathway may further promote the development of new treatment concepts for melanoma.

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1 Vortrag anlässlich des Jahressymposiums der Berliner Stiftung für Dermatologie am 31. 5. 2008.