Molecular mechanisms of hematogenous tumor
Duisburg, Essen (2007), 83 S.
Dissertation / Fach: Biologie
ehem. Fakultät für Biologie und Geografie
Gulbins, Erich (Doktorvater, Betreuerin)
Ehrmann, Michael (GutachterIn)
The present manuscript demonstrates that B16F10 melanoma cells activate the enzyme acid sphingomyelinase in thrombocytes via the surface molecule P-selectin, by which ceramide is released. Metastasis of tumor cells in the lung is decreased by up to 95% by genetic deficiency of P-selectin molecule or deficiency of acid sphingomyelinase. After activation of wild type thrombocytes by B16F10 melanoma cells there is a rapid increase in acid sphingomyelinase activity and ceramide production as compared to acid sphingomyelinase-deficient thrombocytes or P-selectin-deficient thrombocytes. A lack of interaction of B16F10 melanoma cells and thrombocytes was excluded by activation of PLCγ, JNK and MAP kinase, indicating that these signaling events are stimulated in both, wild-type and P-selectin-deficient platelets, proving that B16F10 melanoma cells interact with and activate P-selectin-deficient thrombocytes. The molecular mechanisms of tumor metastasis are currently fairly incomplete, though metastasis plays a crucial clinical role in cancer patients. Acid sphingomyelinase is iidentified as a novel target molecule for the inhibition of tumor metastasis. In order to pharmacologically inhibit the thrombocytic P-selectin system, an intravenous injection of fucoidan showed a decrease of tumor metastasis of B16F10 melanoma cells by approximately 75%. This indicates that tumor metastasis can be blocked pharmacologically, which is of great clinical interest.