Regulation of hematogenous tumor metastasis by acid sphingomyelinase
Autor: | Iris Helfrich, Stefan P. Müller, Alexander Carpinteiro, Heike Grassmé, Burkhard Kleuser, Erich Gulbins, Simone Keitsch, Miroslava Požgajová, Constantin Adams, Michael J. Edwards, Kurt Werner Schmid, Lukasz Japtok, Gabriele Hessler, Katrin Anne Becker |
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Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Ceramide
Pathology medicine.medical_specialty Melanoma Integrin Medizin Spleen respiratory system Sphingomyelin phosphodiesterase Biology musculoskeletal system medicine.disease respiratory tract diseases Metastasis chemistry.chemical_compound medicine.anatomical_structure chemistry Cancer cell medicine biology.protein Molecular Medicine Institut für Ernährungswissenschaft Acid sphingomyelinase medicine.drug |
Popis: | 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 51 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C-16 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 1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis. |
Databáze: | OpenAIRE |
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