Zusammenfassung
Ein von Makrophagen auch in Pankreaskarzinomen gebildetes Zytokin, der Tumornekrosefaktor α (TNF-α), moduliert auf Pankreastumorzellen u.a. die Expression sowohl eines seiner Rezeptoren als auch der Wachstumsfaktoren PDGF-B (“platelet-derived growth factor”), TGF-α und TGF-β (“transforming growth factor”) sowie des epidermalen Wachstumsfaktorrezeptors (EGF-R). Die Stimulation der mRNA- und Proteinexpression des EGF-R bzw. seines Liganden TGF-α durch TNF-α erfolgt über die Bindung an die TNF-Rezeptoren mit einem Molekulargewicht von 55 (TNF-RI) bzw. 75kD (TNF-RII). Die beobachtete Verstärkung der Expression des TNF-RII involviert dabei ebenso die Botenstoffe Proteinkinase C und Phospholipasen. Eine gleichzeitig durch den TNF-RI ausgelöste Verminderung der Rezeptorexpression des ERBB2 führte zu einer erhöhten TNF-α-Sensitivität bzgl. dessen Zytotoxizität. Für den TNF-RII konnte mittels spezifischer monoklonaler Antikörper (MAK) ein selektiver Signalübertragungsweg für eine TGF-α-Induktion nachgewiesen werden. Darüber hinaus bietet die Erhöhung der EGF-R-Antigendichte auf Pankreastumorzellinien einen Angriffspunkt für die durch Antikörper vermittelte Zytotoxizität. Eine teilweise komplette Remission von Xenotransplantaten der Pankreastumorzellinien in vivo schließt eine durch den Fc-Teil des Antikörpers vermittelte zelluläre Abwehr ein und eröffnet neue therapeutische Ansatzpunkte.
Summary
Tumor necrosis factor α (TNF-α), a macrophage-synthesised cytokine not only modifies the expression of one of its own receptors on pancreatic tumor cells, it also regulates the expression of the platelet-derived growth factor (PDGF-B), of the transforming growth factors TGF-α and TGF-β and of the epidermal growth factor receptor (EGF-R). Stimulation of mRNA and protein expression of EGF-R respectively of its ligand TGF-α is effected by TNF-α binding to TNF-receptors with a molecular weight of 55 (TNF-RI), respectively 75kD (TNF-RII). The registered increase of TNF-RII involves the second messengers proteinkinase C and phospholipases as well. Simultaneously TNF-RII induces a decrease of the ERBB2 receptor expression which heightened TNF-α-sensitivity regarding its cytotoxicity.
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Schmielau, J., Kalthoff, H., Roeder, C., Schmiegel, W. (1995). Tumor-Wirt-Interaktion (Zytokine). In: Beger, H.G., Manns, M.P., Greten, H. (eds) Molekularbiologische Grundlagen der Gastroenterologie. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79782-8_1
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DOI: https://doi.org/10.1007/978-3-642-79782-8_1
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