Regulation of hematogenous tumor metastasis by acid sphingomyelinase

EMBO Molecular Medicine

Alexander Carpinteiro²  Katrin Anne Becker²  Lukasz Japtok⁷  Gabriele Hessler²  Simone Keitsch²  Miroslava Požgajovà⁴  Kurt W Schmid¹  Constantin Adams²  Stefan Müller³  Burkhard Kleuser⁷  Michael J Edwards⁵  Heike Grassmé²  Iris Helfrich⁶ 

[1] Department of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany;Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany;Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany;Department of Genetics and Breeding Biology, Slovak University of Agriculture, Nitra, Slovakia;Department of Surgery, University of Cincinnati, Cincinnati, OH, USA;Department of Dermatology, University of Duisburg-Essen, Essen, Germany;Institute for Nutritional Science, University of Potsdam, Nuthetal, Germany

关键词: acid sphingomyelinase;    ceramide;    integrins;    platelets;    tumor‐metastasis;   

DOI  :  10.15252/emmm.201404571

来源: Wiley

【 摘 要 】

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.

Synopsis

Melanoma cells induce acid sphingomyelinase (Asm) release from platelets, which in turn induces ceramide in melanoma cells, clustering of α5β1 integrin, and tumor cell trapping. Asm loss or inhibition protects mice from hematogenous tumor metastasis.

• Activation of the acid sphingomyelinase (Asm)/ceramide system is required for hematogenous metastasis of melanoma cells in mouse models.
• Interaction of melanoma cells with platelets results in secretion of Asm from platelets to induce clustering and activation of β1-integrin in ceramide-enriched membrane domains on tumor cells.
• Ceramide-mediated activation of β1-integrin induces melanoma cell adhesion in the lung and thereby metastasis.
• Pharmacological inhibition of the Asm is sufficient to reduce hematogenous melanoma metastasis by 75%.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.