Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis

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Abstract

Primary tumours influence the environment in the lungs before metastasis1,2. However, the mechanism of metastasis is not well understood. Here, we show that the inflammatory chemoattractants S100A8 and S100A9, whose expression is induced by distant primary tumours, attract Mac 1 (macrophage antigen 1)+-myeloid cells in the premetastatic lung. In addition, tumour cells use this mechanism, through activation of the mitogen-activated protein kinase (MAPK) p38, to acquire migration activity with pseudopodia for invasion (invadopodia). The expression of S100A8 and S100A9 was eliminated in lung Mac 1+-myeloid cells and endothelial cells deprived of soluble factors, such as vascular endothelial growth factor A (VEGF-A), tumour necrosis factor α (TNFα) and transforming growth factor β (TGFβ) both in vitro and in vivo. Neutralizing anti-S100A8 and anti-S100A9 antibodies blocked the morphological changes and migration of tumour cells and Mac 1+-myeloid cells. Thus, the S100A8 and S100A9 pathway may be common to both myeloid cell recruitment and tumour-cell invasion.

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Figure 1: Upregulation of the expression of S100A8 and S100A9 in premetastatic lungs responding to distant primary tumours.
Figure 2: Distant tumours upregulate S100A8 and S100A9 expression in the lung in the premetastatic phase.
Figure 3: S100A8 and S100A9 induce migration activities of macrophages and tumour cells.
Figure 4: Lung endothelial cells (ECs) and Mac 1+-myeloid cells (Ms) stimulated by S100A8 secrete migration-stimulating factors for tumour cells.
Figure 5: Neutralizing anti-S100A8 and anti-S100A9 antibodies block the migration of macrophages and tumour cells to lungs.

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Acknowledgements

We thank M. Shibuya and T. Noda for preparation of the VEGFR1–TK−/− mouse and H. Meguro and S. Yamamoto for GeneChip analysis and data processing. We are also grateful to O. N. Witte for critical reading of and comments on the manuscript. This study was partly supported by Grants-in-Aid for Scientific Research from the Japanese government (No. 12147210) from the Ministry of Education, Culture, Sports, Science and Technology and the Program for Promotion of Fundamental Studies in Health Sciences of the National Sciences of the National Insititute of Biomedical innovation to Y.M., and from the NFAT project of New Energy and Industrial Technology Development Organization to H.A.

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Correspondence to Yoshiro Maru.

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Supplementary figure S1 and Supplementary methods (PDF 1585 kb)

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