title: Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis.
abstract: BACKGROUND
  Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm) from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis.
  
  
  METHODS
  We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K), phospholipase Cx03B3; (PLCx03B3;), ezrin, and extracellular signal-regulated kinases.
  
  
  RESULTS
  Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K), phospholipase Cx03B3; (PLCx03B3;), ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of β1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis.
  
  
  CONCLUSIONS
  Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates β1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel target to prevent tumor metastasis.
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Carpinteiro
authors.forename: Nadine
authors.initials: N
authors.lastname: Beckmann
authors.forename: Aaron
authors.initials: A
authors.lastname: Seitz
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hessler
authors.forename: Barbara
authors.initials: B
authors.lastname: Wilker
authors.forename: Matthias
authors.initials: M
authors.lastname: Soddemann
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
authors.forename: Bärbel
authors.initials: B
authors.lastname: Edelmann
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Katrin Anne
authors.initials: KA
authors.lastname: Becker
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics*; D014184:Transplantation, Homologous; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D019012:Integrin beta1; D051966:Phospholipase C gamma; D047428:Protein Kinase Inhibitors; D013108:Sphingomyelin Phosphodiesterase; D048051:p38 Mitogen-Activated Protein Kinases; D000099149:Ezrin; C112980:acid sphingomyelinase-1