Liver acid sphingomyelinase inhibits growth of metastatic colon cancer
Yosuke Osawa, Atsushi Suetsugu, Rie Matsushima-Nishiwaki, Ichiro Yasuda, Toshiji Saibara, Hisataka Moriwaki, Mitsuru Seishima, Osamu Kozawa
Yosuke Osawa, Atsushi Suetsugu, Rie Matsushima-Nishiwaki, Ichiro Yasuda, Toshiji Saibara, Hisataka Moriwaki, Mitsuru Seishima, Osamu Kozawa
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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 2

Macrophage depletion increased metastatic tumor growth in the liver.

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Macrophage depletion increased metastatic tumor growth in the liver. (A)...
(A) GFP+ mice were intrasplenically injected with 2 × 104 SL4 cells. GFP fluorescence was visualized with fluorescent microscopy, and macrophages were detected in metastatic tumor and liver by immunofluorescent staining for F4/80 (blue). Original magnification, ×400. (B and C) Asm+/+ and Asm–/– mice (B) and AdGFP- and AdASM-infected wild-type mice (C) were intrasplenically injected with 2 × 104 SL4 cells. Expression of F4/80 in the liver and metastatic tumor was examined by immunohistochemistry with an anti-F4/80 antibody to assess the number of macrophages. Original magnification, ×100 (left and middle); ×400 (right). (D) Wild-type mice were injected with SL4 cells and treated with PBS or alendronate before sacrifice 14 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 at least 5 independent experiments. *P < 0.05, 2-tailed Student’s t test.