title: Liver acid sphingomyelinase inhibits growth of metastatic colon cancer.
abstract: 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.
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, 1-1 Yanagido Gifu 501-1194, Japan. osawa-gif@umin.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Osawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suetsugu
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yasuda
authors.forename: Toshiji
authors.initials: T
authors.lastname: Saibara
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D018450:Disease Progression; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology / Q000556:secondary*; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C060506:sphingosine 1-phosphate; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine