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 1

ASM deficiency increased, and ASM overexpression decreased, metastatic tumor growth in the liver.

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ASM deficiency increased, and ASM overexpression decreased, metastatic t...
(A and B) Asm+/+ and Asm–/– mice were intrasplenically injected with 2 × 104 SL4 cells (A). Wild-type mice were infected with AdGFP or AdASM 24 hours before inoculation (B). Mice were sacrificed 14 days after inoculation, and livers were excised and photographed. Liver sections were stained with H&E (loupe magnification), and intrahepatic tumor load was presented as hepatic replacement area and maximum diameter, based on measurement of 3 nonsequential sections. (C) GFP+Asm+/+ and GFP+Asm–/– mice were intrasplenically injected with SL4 cells. At 14 days after inoculation, GFP expression in the liver was assessed by fluorescent microscopy, measurement of the GFP+ area was performed, and nuclei were stained with DAPI. Shown are bright field images at the border of the metastatic tumor and liver (left), GFP/DAPI merge in the same bright field images (middle), and higher-magnification views of GFP/DAPI merge in the tumor area (right). Original magnification, ×200 (left and middle); ×400 (right). Results are mean ± SD of data obtained from at least 5 independent experiments. *P < 0.05, 2-tailed Student’s t test.