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.

Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5 [S]

“…Additionally, ASM, previously also associated with apoptosis, is emerging as a key tumor promoter (73)(74)(75)). In the pathway described in this study, elevated ceramide may serve as a precursor to higher C-1-P levels which may 'override' the cell intrinsic functions of ceramide by promoting inflammatory and other tumor-promoting effects.…”

Regulation of Arthritis Severity by the Acid Sphingomyelinase

“…Enhanced cell adhesion upon sphingomyelinase- or ceramide treatment has been reported in different cell types, hinting at a general mechanism [50-52]. Particularly relevant to this study are reports on hematogenous metastasis, indicating that platelets secrete Asm to regulate tumor cell extravasation [51]. Subsequently, this process was shown to involve P-selectin, p38 MAPK and ß1-Integrin [53, 54].…”

Blockade of Experimental Multiple Sclerosis by Inhibition of the Acid Sphingomyelinase/Ceramide System

“…Ceramide has been previously shown to mediate cell adhesion to endothelial cells [28]. These studies indicated that ceramide-enriched membrane platforms cluster adhesion molecules such as β 1 -integrin [28] or ICAM-1 [29].…”

“…Ceramide has been previously shown to mediate cell adhesion to endothelial cells [28]. These studies indicated that ceramide-enriched membrane platforms cluster adhesion molecules such as β 1 -integrin [28] or ICAM-1 [29]. Receptor clustering results in a very high local density of cognate receptor molecules, thereby permitting and greatly amplifying signal transduction by this particular receptor.…”