Document Detail

Liver acid sphingomyelinase inhibits growth of metastatic colon cancer.
MedLine Citation:
PMID:  23298833     Owner:  NLM     Status:  MEDLINE    
Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine-1-phosphate (S1P). These sphingolipids regulate carcinogenesis and proliferation, survival, and apoptosis of cancer cells. However, the role of ASM in host defense against liver metastasis remains unclear. In this study, the involvement of ASM in liver metastasis of colon cancer was examined using Asm-/- and Asm+/+ mice that were inoculated with SL4 colon cancer cells to produce metastatic liver tumors. Asm-/- mice demonstrated enhanced tumor growth and reduced macrophage accumulation in the tumor, accompanied by decreased numbers of hepatic myofibroblasts (hMFs), which express tissue inhibitor of metalloproteinase 1 (TIMP1), around the tumor margin. Tumor growth was increased by macrophage depletion or by Timp1 deficiency, but was decreased by hepatocyte-specific ASM overexpression, which was associated with increased S1P production. S1P stimulated macrophage migration and TIMP1 expression in hMFs in vitro. These findings indicate that ASM in the liver inhibits tumor growth through cytotoxic macrophage accumulation and TIMP1 production by hMFs in response to S1P. Targeting ASM may represent a new therapeutic strategy for treating liver metastasis of colon cancer.
Yosuke Osawa; Atsushi Suetsugu; Rie Matsushima-Nishiwaki; Ichiro Yasuda; Toshiji Saibara; Hisataka Moriwaki; Mitsuru Seishima; Osamu Kozawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-09
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  834-43     Citation Subset:  AIM; IM    
Department of Pharmacology, Gifu University Graduate School of Medicine, 1-1 Yanagido Gifu 501-1194, Japan.
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MeSH Terms
Cell Line, Tumor
Colonic Neoplasms*
Disease Progression
Liver / enzymology*,  pathology
Liver Neoplasms, Experimental / enzymology*,  pathology,  secondary*
Lysophospholipids / metabolism
Macrophages / pathology
Mice, Inbred C57BL
Mice, Knockout
Myofibroblasts / metabolism,  pathology
Rats, Wistar
Sphingomyelin Phosphodiesterase / deficiency,  genetics,  metabolism*
Sphingosine / analogs & derivatives,  metabolism
Tissue Inhibitor of Metalloproteinase-1 / metabolism
Reg. No./Substance:
0/Lysophospholipids; 0/Timp1 protein, mouse; 0/Tissue Inhibitor of Metalloproteinase-1; 123-78-4/Sphingosine; 26993-30-6/sphingosine 1-phosphate; EC Phosphodiesterase

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