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

Sachie Hiratsuka¹, Akira Watanabe², Hiroyuki Aburatani² & Yoshiro Maru¹

¹  Department of Pharmacology, Tokyo Women's Medical University School of Medicine, Shinjyuku-ku, Tokyo 162–8666, Japan.

²  Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Meguro-ku, Tokyo 153–8904, Japan.

Primary tumours influence the environment in the lungs before metastasis^{1, 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 (TNF) and transforming growth factor (TGF) 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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