Liver acid sphingomyelinase inhibits growth of metastatic colon cancer
Yosuke Osawa, … , Mitsuru Seishima, Osamu Kozawa
Yosuke Osawa, … , Mitsuru Seishima, Osamu Kozawa
Published January 9, 2013
Citation Information: J Clin Invest. 2013;123(2):834-843. https://doi.org/10.1172/JCI65188.
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Research Article Gastroenterology

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

Yosuke Osawa, Atsushi Suetsugu, Rie Matsushima-Nishiwaki, Ichiro Yasuda, Toshiji Saibara, Hisataka Moriwaki, Mitsuru Seishima, Osamu Kozawa

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Figure 5

S1P promoted macrophage migration and Timp1 mRNA expression in hMFs.

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S1P promoted macrophage migration and Timp1 mRNA expression in hMFs. (...
(A) Wild-type mice were infected with AdGFP or AdASM, and S1P was examined by MS analysis 3 days after infection. (B) After addition of CD11b+ peritoneal macrophages and 1 μM S1P to the upper and lower chambers, respectively, of transwell plates, cells were incubated for 4 hours. The number of macrophages that migrated to the underside of the chamber was determined. (C) Primary rat hMFs were incubated with or without 1 μM S1P on plastic dishes for 72 hours before determination of Timp1 mRNA levels by quantitative real-time RT-PCR. (D) Wild-type mice were intrasplenically injected with 2 × 104 SL4 cells, infected with AdGFP or AdASM 5 days after inoculation, and sacrificed 14 days after infection (i.e., 19 days after inoculation). Images of livers after excision and liver sections stained with H&E (loupe magnification) are shown. Intrahepatic tumor load is presented as hepatic replacement area, based on measurement of 3 nonsequential sections. Results are mean ± SD of data collected from 4 (A) or at least 5 (B–D) independent experiments. *P < 0.05, 2-tailed Student’s t test.