Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo

Ayumi Taguchi, Kei Kawana, Kensuke Tomio, Aki Yamashita, Yosuke Isobe, Kazunori Nagasaka, Kaori Koga, Tomoko Inoue, Haruka Nishida, Satoko Kojima, Katsuyuki Adachi, Yoko Matsumoto, Takahide Arimoto, Osamu Wada-Hiraike, Katsutoshi Oda, Jing X. Kang, Hiroyuki Arai, Makoto Arita, Yutaka Osuga, Tomoyuki Fujii

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Abstract

Cancer associated fibroblasts (CAFs) are responsible for tumor growth, angiogenesis, invasion, and metastasis. Matrix metalloproteinase (MMP)-9 secreted from cancer stroma populated by CAFs is a prerequisite for cancer angiogenesis and metastasis. Omega-3 polyunsaturated fatty acids (omega-3 PUFA) have been reported to have anti-tumor effects on diverse types of malignancies. Fat-1 mice, which can convert omega-6 to omega-3 PUFA independent of diet, are useful to investigate the functions of endogenous omega-3 PUFA. To examine the effect of omega-3 PUFA on tumorigenesis, TC-1 cells, a murine epithelial cell line immortalized by human papillomavirus (HPV) oncogenes, were injected subcutaneously into fat-1 or wild type mice. Tumor growth and angiogenesis of the TC-1 tumor were significantly suppressed in fat-1 compared to wild type mice. cDNA microarray of the tumors derived from fat-1 and wild type mice revealed that MMP-9 is downregulated in fat-1 mice. Immunohistochemical study demonstrated immunoreactivity for MMP-9 in the tumor stromal fibroblasts was diffusely positive in wild type whereas focal in fat-1 mice. MMP-9 was expressed in primary cultured fibroblasts isolated from fat-1 and wild type mice but was not expressed in TC-1 cells. Co-culture of fibroblasts with TC-1 cells enhanced the expression and the proteinase activity of MMP-9, although the protease activity of MMP-9 in fat-1-derived fibroblasts was lower than that in wild type fibroblasts. Our data suggests that omega-3 PUFAs suppress MMP-9 induction and tumor angiogenesis. These findings may provide insight into mechanisms by which omega-3 PUFAs exert anti-tumor effects by modulating tumor microenvironment.

Original languageEnglish
Article numbere89605
JournalPloS one
Volume9
Issue number2
DOIs
Publication statusPublished - 2014 Feb 27

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Taguchi, A., Kawana, K., Tomio, K., Yamashita, A., Isobe, Y., Nagasaka, K., Koga, K., Inoue, T., Nishida, H., Kojima, S., Adachi, K., Matsumoto, Y., Arimoto, T., Wada-Hiraike, O., Oda, K., Kang, J. X., Arai, H., Arita, M., Osuga, Y., & Fujii, T. (2014). Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo. PloS one, 9(2), [e89605]. https://doi.org/10.1371/journal.pone.0089605