The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol

Department of Pharmacology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Nature Cell Biology (Impact Factor: 20.06). 10/2008; 10(11):1349-55. DOI: 10.1038/ncb1794
Source: PubMed

ABSTRACT A large number of macrophages and haematopoietic progenitor cells accumulate in pre-metastatic lungs in which chemoattractants, such as S100A8 and S100A9, are produced by distant primary tumours serving as metastatic soil. 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-kappaB 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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Available from: Sachie Ishibashi, Feb 11, 2015
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    • "Many attempts have been made to identify new reagents that may control innate immune reactions [1]–[4]. Although the innate immune system protects the host from continual attacks by pathogens, inflammatory responses may lead to unwanted consequences, such as rheumatoid arthritis [5], [6], diabetes [7], [8], or tumor metastasis [9]–[12], in some cases. Recent studies designated such an imbalance of inflammatory reactions as “homeostatic inflammation”, and suggested that the containment of inflammatory cytokines by neutralizing antibodies may prevent the formation of the pre-metastatic phase in the tumor metastasis process [13]. "
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