title: Melanoma cell metastasis via P-selectin-mediated activation of acid sphingomyelinase in platelets.
abstract: Metastatic dissemination of cancer cells is one of the hallmarks of malignancy and accounts for approximately 90 % of human cancer deaths. Within the blood vasculature, tumor cells may aggregate with platelets to form clots, adhere to and spread onto endothelial cells, and finally extravasate to form metastatic colonies. We have previously shown that sphingolipids play a central role in the interaction of tumor cells with platelets; this interaction is a prerequisite for hematogenous tumor metastasis in at least some tumor models. Here we show that the interaction between melanoma cells and platelets results in rapid and transient activation and secretion of acid sphingomyelinase (Asm) in WT but not in P-selectin-deficient platelets. Stimulation of P-selectin resulted in activation of p38 MAPK, and inhibition of p38 MAPK in platelets prevented the secretion of Asm after interaction with tumor cells. Intravenous injection of melanoma cells into WT mice resulted in multiple lung metastases, while in P-selectin-deficient mice pulmonary tumor metastasis and trapping of tumor cells in the lung was significantly reduced. Pre-incubation of tumor cells with recombinant ASM restored trapping of B16F10 melanoma cells in the lung in P-selectin-deficient mice. These findings indicate a novel pathway in tumor metastasis, i.e., tumor cell mediated activation of P-selectin in platelets, followed by activation and secretion of Asm and in turn release of ceramide and tumor metastasis. The data suggest that p38 MAPK acts downstream from P-selectin and is necessary for the secretion of Asm.
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
authors.forename: Katrin Anne
authors.initials: KA
authors.lastname: Becker
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Beckmann
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Adams
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hessler
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.|Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0558, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany. alexander.carpinteiro@uni-due.de.|Clinic for Hematology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany. alexander.carpinteiro@uni-due.de.
authors.forename: Alexander
authors.identifier: 0000-0002-3316-9166
authors.initials: A
authors.lastname: Carpinteiro
mesh_terms: D000818:Animals; D001792:Blood Platelets; D002518:Ceramides / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
chemical_list: D002518:Ceramides; D019007:P-Selectin; D048051:p38 Mitogen-Activated Protein Kinases; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase
keywords: Acid sphingomyelinase; Ceramide; Metastasis; P-selectin; Platelets; p38 MAPK