Rolle der sauren Sphingomyelinase in Thrombozyten bei der Tumormetastasierung
Zusammenfassung der Projektergebnisse
Metastatic dissemination of cancer cells is the ultimative hallmark of malignancy and accounts for approximately 90% of human cancer deaths. Here, we investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of a panel of malignant tumor cells. Intravenous injection of melanoma, lung or colon carcinoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpdl-/- mice) were protected from pulmonary tumor spread. Likewise, the hematogenous metastasis of a local melanoma was almost absent in Asm-deficient mice. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Tumor cells triggered activation and release of platelet Asm, in turn leading to ceramide formation and clustering of α5β1 integrins in tumor cells. Clustering of integrins by applying purified acid sphingomyelinase to malignant tumor cells before intravenous injection restored arrest and metastasis of tumor cells into the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins. These findings indicate that malignant tumor cells employ platelet-derived Asm for integrin activation, adhesion, and metastasis.
