title: Regulation of hematogenous tumor metastasis by acid sphingomyelinase.
abstract: Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were 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 activation and release of platelet secretory Asm, 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 peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis.
authors: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany Department of Hematology, University of Duisburg-Essen, Essen, Germany.
authors: Alexander
authors: A
authors: Carpinteiro
authors: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors: Katrin Anne
authors: KA
authors: Becker
authors: Institute for Nutritional Science University of Potsdam, Nuthetal, Germany.
authors: Lukasz
authors: L
authors: Japtok
authors: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors: Gabriele
authors: G
authors: Hessler
authors: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors: Simone
authors: S
authors: Keitsch
authors: Department of Genetics and Breeding Biology, Slovak University of Agriculture, Nitra, Slovakia.
authors: Miroslava
authors: M
authors: Požgajovà
authors: Department of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
authors: Kurt W
authors: KW
authors: Schmid
authors: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors: Constantin
authors: C
authors: Adams
authors: Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany.
authors: Stefan
authors: S
authors: Müller
authors: Institute for Nutritional Science University of Potsdam, Nuthetal, Germany.
authors: Burkhard
authors: B
authors: Kleuser
authors: Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors: Michael J
authors: MJ
authors: Edwards
authors: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors: Heike
authors: H
authors: Grassmé
authors: Department of Dermatology, University of Duisburg-Essen, Essen, Germany.
authors: Iris
authors: I
authors: Helfrich
authors: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany Department of Surgery, University of Cincinnati, Cincinnati, OH, USA erich.gulbins@uni-due.de.
authors: Erich
authors: E
authors: Gulbins
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D008545:Melanoma / Q000556:secondary*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000378:metabolism*
chemical_list: C577975:ASMase, mouse; D013108:Sphingomyelin Phosphodiesterase
keywords: acid sphingomyelinase; ceramide; integrins; platelets; tumor‐metastasis