Letter abstract
Nature Cell Biology 10, 1349 - 1355 (2008)
Published online: 28 September 2008 | doi:10.1038/ncb1794
The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase
Sachie Hiratsuka1, Akira Watanabe2, Yoshiko Sakurai1, Sachiko Akashi-Takamura3, Sachie Ishibashi1, Kensuke Miyake3, Masabumi Shibuya4, Shizuo Akira5, Hiroyuki Aburatani2 & Yoshiro Maru1
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-
B 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.
- Department of Pharmacology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
- 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.
- Division of Genetics, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
- Department of Host Defense, Research Institute for Microbial Disease, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-1871, Japan.
Correspondence to: Yoshiro Maru1 e-mail: ymaru@research.twmu.ac.jp
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
S100 chemokines mediate bookmarking of premetastatic nichesNature Cell Biology News and Views (01 Dec 2006)
RESEARCH
Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasisNature Cell Biology Letter (01 Dec 2006)
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic nicheNature Article (08 Dec 2005)
Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasisNature Letters to Editor (01 Jan 2009)
