Regulation hämatogener und lymphatischer Metastasierung von Tumoren durch die saure Sphingomyelinase
Zusammenfassung der Projektergebnisse
Our data demonstrate that intravenous injection of B16F10 melanoma cells into wild type mice resulted in multiple lung metastases, while acid sphingomyelinase (Asm)-deficient mice (Smpd1-/- mice) or P-selectin-deficient mice are protected from pulmonary tumor spread. Transplanting wild type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered a P-selectin-dependent activation of platelets followed by a release of secretory Asm from platelets, in turn leading to ceramide formation, clustering and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid (RGD) peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. Asm triggered the activation of several signalling molecules within tumor cells including p38-K, ERK, PLCγ and Ezrin. In particular, inhibition of p38-K in tumor cells prevented adhesion and B16F10 tumor metastasis in vivo indicating its significance for tumor metastasis in vivo. These findings indicate that human and mouse melanoma cells employ platelet-derived Asm for adhesion and metastasis.
