The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase (original) (raw)
- Letter
- Published: 28 September 2008
- Akira Watanabe2,
- Yoshiko Sakurai1,
- Sachiko Akashi-Takamura3,
- Sachie Ishibashi1,
- Kensuke Miyake3,
- Masabumi Shibuya4,
- Shizuo Akira5,
- Hiroyuki Aburatani2 &
- …
- Yoshiro Maru1
Nature Cell Biology volume 10, pages 1349–1355 (2008)Cite this article
- 7085 Accesses
- 533 Citations
- 6 Altmetric
- Metrics details
Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).
Article CAS PubMed Google Scholar - Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
Article CAS PubMed PubMed Central Google Scholar - Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated lung metastasis. Nature Cell Biol. 8, 1369–1375 (2006).
Article CAS PubMed Google Scholar - Paget, S. The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev. 8, 98–101, (1989).
CAS PubMed Google Scholar - Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2, 161–174 (2002).
Article CAS Google Scholar - Liang, T. S., Wang, J. M., Murphy, P. M. & Gao, J. L. Serum amyloid A is a chemotactic agonist at FPR2, a low-affinity N-formylpeptide receptor on mouse neutrophils. Biochem. Biophys. Res. Commun. 270, 331–335 (2000).
Article CAS PubMed Google Scholar - He, R., Sang, H. & Ye, R. D. Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. Blood 101, 1572–1581 (2003).
Article CAS PubMed Google Scholar - Larson, M. A., Wei, S. H., Weber, A., Weber, A. T. & McDonald, T. L. Induction of human mammary-associated serum amyloid A3 expression by prolactin or lipopolysaccharide. Biochem. Biophys. Res. Commun. 301, 1030–1037 (2003).
Article CAS PubMed Google Scholar - Meek, R. L. & Benditt, E. P. Rat tissues express serum amyloid A protein-related mRNAs. Proc. Natl Acad. Sci. USA 86, 1890–1894 (1989).
Article CAS PubMed PubMed Central Google Scholar - Meek, R. L., Eriksen, N. & Benditt, E. P. Murine serum amyloid A3 is a high density apolipoprotein and is secreted by macrophages. Proc. Natl Acad. Sci. USA 89, 7949–7952 (1992).
Article CAS PubMed PubMed Central Google Scholar - Wang, H. & Liao, W. S. Functional analysis of a minimal mouse serum amyloid A3 promoter in transgenic mice. Amyloid 8, 250–256 (2001).
Article CAS PubMed Google Scholar - Lin, Y. et al. Hyperglycemia-induced production of acute phase reactants in adipose tissue. J. Biol. Chem. 276, 42077–42083 (2001).
Article CAS PubMed Google Scholar - Son, D. S., Roby, K. F. & Terranov, P. F. Tumor necrosis factor induces serum amyloid A3 in mouse granulosa cells. Endocrinology 145, 2245–2252 (2004).
Article CAS PubMed Google Scholar - Huang, B. et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 65, 5009–5014 (2005).
Article CAS PubMed Google Scholar - Verghese, M. W. & Snyderman, R. Endotoxin (LPS) stimulates in vitro migration of macrophages from LPS-resistant mice but not from LPS-sensitive mice. J. Immunol. 128, 608–613 (1982).
CAS PubMed Google Scholar - Beutler, B. Toll-like receptors: how they work and what they do. Curr. Opin. Hematol. 9, 2–10 (2002).
Article PubMed Google Scholar - Ogawa, T. et al. Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4- and myeloid differentiation factor 88-dependent signaling pathway. Int. Immunol. 14, 1325–1332 (2002).
Article CAS PubMed Google Scholar - Miyake, K., Yamashita, Y., Ogata, M., Sudo, T. & Kimoto, M. RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family. J. Immunol. 154, 3333–3340 (1995).
CAS PubMed Google Scholar - Akashi, S. et al. Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14. J. Exp. Med. 198, 1035–1042 (2003).
Article CAS PubMed PubMed Central Google Scholar - Vogl, T. et al. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Natue Med. 13, 1042–1049 (2007).
Article CAS Google Scholar - Akira, S. & Takeda, K. Toll-lke receptor signaling. Nature Rev. Immunol. 4, 499–511 (2004).
Article CAS Google Scholar - Beutler, B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257–263 (2004).
Article CAS PubMed Google Scholar - Vabulas, R. M. et al. HSP70 as endogenous stimulus of the Toll/Interleukin-1 receptor signal pathway. J. Biol. Chem. 277, 15107–15112 (2002).
Article CAS PubMed Google Scholar - Termeer, C. et al. Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J. Exp. Med. 195, 99–111 (2002).
Article CAS PubMed PubMed Central Google Scholar - Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Med. 11, 1173–1179 (2005).
Article CAS PubMed Google Scholar - Smiley, S. T., King, J. A. & Hancock, W. W. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J. Immunol. 167, 2887–2894 (2001).
Article CAS PubMed Google Scholar - Marx, J. Cancer research. Inflammation and cancer: the link grows stronger. Science 306, 966–968 (2004).
Article CAS PubMed Google Scholar - Greten, F. R. et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).
Article CAS PubMed Google Scholar - Hoshino, K. et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to Lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162, 3749–3752 (1999).
CAS PubMed Google Scholar - Dong, Q. G. et al. A general strategy for isolation of endothelial cells from murine tissues. Characterization of two endothelial cell lines from the murine lung and subcutaneous sponge implants. Arterioscler. Thromb. Vasc. Biol. 17, 1599–1604 (1997).
Article CAS PubMed Google Scholar
Acknowledgements
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
Authors and Affiliations
- 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 - 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 - 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 - Division of Genetics, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
Masabumi Shibuya - Department of Host Defense, Research Institute for Microbial Disease, Osaka University, 3-1 Yamada-oka, Suita, Osaka, 565-1871, Japan
Shizuo Akira
Authors
- Sachie Hiratsuka
You can also search for this author inPubMed Google Scholar - Akira Watanabe
You can also search for this author inPubMed Google Scholar - Yoshiko Sakurai
You can also search for this author inPubMed Google Scholar - Sachiko Akashi-Takamura
You can also search for this author inPubMed Google Scholar - Sachie Ishibashi
You can also search for this author inPubMed Google Scholar - Kensuke Miyake
You can also search for this author inPubMed Google Scholar - Masabumi Shibuya
You can also search for this author inPubMed Google Scholar - Shizuo Akira
You can also search for this author inPubMed Google Scholar - Hiroyuki Aburatani
You can also search for this author inPubMed Google Scholar - Yoshiro Maru
You can also search for this author inPubMed Google Scholar
Contributions
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.
Corresponding author
Correspondence toYoshiro Maru.
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Hiratsuka, S., Watanabe, A., Sakurai, Y. et al. The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase.Nat Cell Biol 10, 1349–1355 (2008). https://doi.org/10.1038/ncb1794
- Received: 28 July 2008
- Accepted: 10 September 2008
- Published: 28 September 2008
- Issue Date: November 2008
- DOI: https://doi.org/10.1038/ncb1794