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: 19.68). 10/2008; 10(11):1349-55. DOI: 10.1038/ncb1794
Source: PubMed


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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    • "The upregulation of Saa3 on monocytes/macrophages highlights the relevance of an inflammatory microenvironment in leukemia engraftment and progression. SAA3 is known to attract monocytes/macrophages, and it may cooperate with inter- leukin-10 (IL-10) to promote M2-skewed macrophage accumulation (Hao et al., 2012; Hiratsuka et al., 2008; Mantovani et al., 2004), ultimately attracting leukemic cells. Notably, we found several chemokines (e.g., CCL2, CCL17, and CCL22) upregulated in leukemic MEC1 cells consistent with previous gene expression studies of leukemic cells from CLL patients (Burger et al., 2009; Herishanu et al., 2011). "
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