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.

Download full-text


Available from: Sachie Ishibashi, Feb 11, 2015
29 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Celastramycin A, a small molecule that inhibits the production of antibacterial peptides in an ex vivo culture system of Drosophila, suppresses the TNFα-mediated induction of IL-8 in mammalian cells. To understand its molecular mechanism, we examined Celastramycin A binding proteins and investigated their biological functions. Our screening and subsequent pull-down assay revealed ZFC3H1 (also known as CCDC131 or CSRC2), an uncharacterized zinc finger protein, as a Celastramycin A binding protein. The knockdown of ZFC3H1 reduced IL-8 expression levels in the TNFα-stimulated lung carcinoma cell line, LU99, and UV-irradiated HeLa cells. Based on reporter assay results, we concluded that ZFC3H1 participates in the transcriptional activation of IL-8. The findings of our UV-irradiation experiments implied that ZFC3H1 may indirectly interact with ERCC1 in an activated DNA repair complex. Thus, we designated ZFC3H1 as a mammalian target of Celastramycin A (mTOC).
    PLoS ONE 09/2014; 9(9):e108957. DOI:10.1371/journal.pone.0108957 · 3.23 Impact Factor
  • Source
    • "S100A8, S100A9 and SAA3 are TLR4 agonists and induce the activation of MyD88- dependent pathways as well as ERK1/2, p38, mitogenactivated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and protein kinase C (PKC). Stimulation of TLR4 induces the release of proinflammatory cytokines, chemokines and reactive oxygen species necessary for the activation of potent host defences (Ehrchen et al., 2009; Hiratsuka et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce interferon-gamma, H99γ, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with wild type (WT) Cryptococcus. Considering that individuals with suppressed T CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether or not antimicrobial peptides were produced in mice inoculated with H99γ. Thus, we measured the levels of antimicrobial peptides Lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors TLR4 and the receptor for advanced glycation end products [RAGE] in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of Lipocalin-2, S100A8, S100A9, and SAA3 as well as TLR4+ and RAGE+ macrophages and dendritic cells in mice inoculated with H99γ compared to WT H99. Similar results were observed in the lungs of H99γ-immunized, compared to heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22 deficient mice inoculated with H99γ demonstrated antimicrobial peptide production and no change in survival rates compared to WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional.
    Microbiology 04/2014; 160(Pt_7). DOI:10.1099/mic.0.073445-0 · 2.56 Impact Factor
  • Source
    • "The known factors synthesized by the tumor and regulating the development of the niche (LOX, MIP-2, VEGFA, TGFβ, TNFα) are not organpreferential . Nevertheless, Kaplan et al. ( 2005 ) and Hiratsuka et al. ( 2008 ) have attempted to study this problem experimentally. Mice with grafted Lewis lung carcinomas were injected with conditioned medium from melanoma B16 cells characterized by generalized non-selective metastasis, and as a result metastatic niches and micrometastases developed in various organs and tissues, including such atypical locations as the oviducts (Psaila and Lyden 2009 ). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hypothesis of metastatic niches (advanced kind of “seed and soil” hypothesis) is very promising concept. It has been proposed to supplement the metastatic niche concept with a stage of “preniche” that determines the site of development of a premetastatic niche and of a subsequent metastasis. The “preniche” includes all cellular and molecular events in the site of a prospective metastasis preceding the entrance of myeloid progenitor cells. The preniche integrates an activation of vascular endothelium of the microcirculatory vessels of target organs in the site of a future metastasis under conditions of chronic persistent productive inflammation that can be induced by cytokines from the primary tumor and independently of it. The endothelium activation is responsible for adhesion and clustering of the recruited myeloid progenitor cells and also for the retention of cells of malignant tumors. The preniche easily arises in organs enriched with organ-specific macrophages (lungs, liver, brain, etc.) where the endothelium is predisposed for intensive recruiting of myeloid progenitor cells of macrophages, especially under conditions of inflammation. The feature of CNS is especial population of macrophage cells (microglia) which could be activated and to form metastatic niches without recruiting myeloid progenitor cells and preniche formation as well as bone morrow. Nevertheless, inflammatory prenicha seems to be the factor enhancing brain metastases by the recruiting of additional niche cells and cells of a tumor. Introduction of the preniche concept allows us to avoid difficulties associated with the development of the metastatic niche concept, especially concerning the problem of organ-preferential localization of metastases, and to make potential approaches for preventing metastasizing in some oncologic patients.
    Tumors of the Central Nervous System, Volume 13, 01/2014: pages 93-106;
Show more