Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

Tomita, Takeshi; Sakurai, Yuko; Ishibashi, Sachie; Maru, Yoshiro

doi:10.1038/onc.2011.53

Cited by 63 publications

(46 citation statements)

References 41 publications

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“…Importantly, various changes which facilitate metastasis have been described in the lung. These pre-formed lung niches encompass cells recruited from the bone marrow and resident cells such as club/Clara cells152 and alveolar macrophages153. Factors produced by resident cells in metastatic niches can enhance the survival and outgrowth of disseminated tumour cells.…”

Section: Resultsmentioning

confidence: 99%

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Greening

Chen

et al. 2016

Sci Rep

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Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets.

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Section: Resultsmentioning

confidence: 99%

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Greening

Chen

et al. 2016

Sci Rep

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“…29 The auto-amplification of SAA3 in lung-specific Club cells may contribute to organotropism in lung metastasis. 43 We more recently reported that SAA3 activates TLR4/MD-2 pathway in a MyD88-dependent, but TRIF-independent manner by using an SAA3 peptide. 28 In contrast, in case of S100A8, RAGE and TLR4 are identified as S100A8/A9 receptors.…”

Section: Introductionmentioning

confidence: 99%

Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment

et al. 2015

Self Cite

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S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.

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“…Collected cells were incubated with anti-CD11b-FITC and anti-Gr-1-PE Abs. The recruitment of CD11b + Gr-1 + cells in the lungs was determined by flow cytometry, as described previously (12). All procedures performed with mice were approved by the Animal Research Committee of Tokyo Women's Medical University.…”

Section: /2mentioning

confidence: 99%

“…An anti-SAA3 neutralizing Ab inhibited lung metastasis. The autoamplification of SAA3 by lung-specific Clara cells may contribute to organotropism in lung metastasis (12).…”

mentioning

confidence: 99%

Serum Amyloid A3 Binds MD-2 To Activate p38 and NF-κB Pathways in a MyD88-Dependent Manner

Deguchi

Tomita

Omori

et al. 2013

The Journal of Immunology

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Serum amyloid A (SAA) 3 is a major component of the acute phase of inflammation. We previously reported that SAA3 served as an endogenous peptide ligand for TLR4 to facilitate lung metastasis. Because these experiments were performed with SAA3 recombinant proteins purified from Escherichia coli or mammalian cells, we could not rule out the possibility of LPS contamination. In this study, we used SAA3 synthetic peptides to eliminate the presence of LPS in SAA3. We found that the SAA3 synthetic peptide (aa 20–86) (20–86) stimulated cell migration and activated p38 in a manner dependent on TLR4, MD-2, and MyD88. SAA3 (20–86) also activated NF-κB and Rho small GTPase. Using surface plasmon resonance analysis, the binding constant KD values between SAA3 (20–86) or SAA3 (43–57) and TLR4/MD-2 protein highly purified by the baculovirus system were 2.2 and 30 μM, respectively. FLAG-tagged SAA3 tightly bound to protein A–tagged MD-2, but not to TLR4 in baculovirus coinfection experiments. Although SAA3 (20–86) caused a low, but appreciable level of endocytosis in TLR4, it induced the upregulation of both IL-6 and TNF-α, but not IFN-β1. An i.v. injection of SAA3 (43–57) induced the lung recruitment of CD11b+Gr-1+ cells at an estimated serum concentration around its KD value toward TLR4/MD-2. Taken together, these results suggest that SAA3 directly binds MD-2 and activates the MyD88-dependent TLR4/MD-2 pathway.

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Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

Cited by 63 publications

References 41 publications

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment

Serum Amyloid A3 Binds MD-2 To Activate p38 and NF-κB Pathways in a MyD88-Dependent Manner

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