Letter | Published:

The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase

Nature Cell Biology volume 10, pages 13491355 (2008) | Download Citation



A large number of macrophages and haematopoietic progenitor cells accumulate in pre-metastatic lungs1,2 in which chemoattractants, such as S100A8 and S100A9, are produced by distant primary tumours serving as metastatic soil3. The exact mechanism by which these chemoattractants elicit cell accumulation is not known. Here, we show that serum amyloid A (SAA) 3, which is induced in pre-metastatic lungs by S100A8 and S100A9, has a role in the accumulation of myeloid cells and acts as a positive-feedback regulator for chemoattractant secretion. We also show that in lung endothelial cells and macrophages, Toll-like receptor (TLR) 4 acts as a functional receptor for SAA3 in the pre-metastatic phase. In our study, SAA3 stimulated NF-κB signalling in a TLR4-dependent manner and facilitated metastasis. This inflammation-like state accelerated the migration of primary tumour cells to lung tissues, but this was suppressed by the inhibition of either TLR4 or SAA3. Thus, blocking SAA3–TLR4 function in the pre-metastatic phase could prove to be an effective strategy for the prevention of pulmonary metastasis.

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We thank P. E. Scherer for providing the anti-mouse SAA3 antibody and pGEX-SAA3 vector, and T. Noda for preparation of the VEGFR1TK−/− mouse. We are grateful to B. Panda for checking the manuscript and also O. N. Witte for critical reading of manuscript and providing comments. This study was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, 12147210 (Y.M.) and 16101006 (H.A.) the NIBIO program and NFAT project of New Energy and Industrial Technology Development Organization (H.A.) and Uehara foundation (S.H.)

Author information


  1. Department of Pharmacology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.

    • Sachie Hiratsuka
    • , Yoshiko Sakurai
    • , Sachie Ishibashi
    •  & Yoshiro Maru
  2. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.

    • Akira Watanabe
    •  & Hiroyuki Aburatani
  3. Division of Infectious Genetics, Department of Microbiology and immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Sachiko Akashi-Takamura
    •  & Kensuke Miyake
  4. Division of Genetics, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Masabumi Shibuya
  5. Department of Host Defense, Research Institute for Microbial Disease, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-1871, Japan.

    • Shizuo Akira


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S.H., Y.S. mainly contributed to animal studies; A.W. and S.I. contributed to molecular analysis; S.A.T., K.M., M.S. and S.A. supplied animals and materials; Y.M. designed and organized the work; H.A. and Y.M. supervised the work.

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The authors declare no competing financial interests.

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Correspondence to Yoshiro Maru.

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