Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  Google Scholar 

  2. Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).

    Article  CAS  Google Scholar 

  3. Couzin, J. Medicine. Tracing the steps of metastasis, cancer's menacing ballet. Science 299, 1002–1006 (2003).

    Article  CAS  Google Scholar 

  4. Kang, Y. & Massague, J. Epithelial–mesenchymal transitions: twist in development and metastasis. Cell 118, 277–279 (2004).

    Article  CAS  Google Scholar 

  5. Toda, K. et al. Establishment and characterization of a tumorigenic murine vascular endothelial cell line (F-2). Cancer Res. 50, 5526–5530 (1990).

    CAS  PubMed  Google Scholar 

  6. Lackmann, M. et al. Identification of a chemotactic domain of the pro-inflammatory S100 protein CP-10. J. Immunol. 150, 2981–2991 (1993).

    CAS  PubMed  Google Scholar 

  7. Devery, J. M., King, N. J. & Geczy, C. L. Acute inflammatory activity of the S100 protein CP-10. Activation of neutrophils in vivo and in vitro. J. Immunol. 152, 1888–1897 (1994).

    CAS  PubMed  Google Scholar 

  8. Hobbs, J. A. et al. Myeloid cell function in MRP-14 (S100A9) null mice. Mol. Cell. Biol. 23, 2564–2576 (2003).

    Article  CAS  Google Scholar 

  9. Roth, J., Vogl, T., Sunderkotter, C. & Sorg, C. Chemotactic activity of S100A8 and S100A9. J. Immunol. 171, 5651 (2003).

    Article  CAS  Google Scholar 

  10. Barleon, B. et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87, 3336–3343 (1996).

    CAS  PubMed  Google Scholar 

  11. Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. & Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. USA 95, 9349–9354 (1998).

    Article  CAS  Google Scholar 

  12. Muraoka, R. S. et al. Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 109, 1551–1559 (2002).

    Article  CAS  Google Scholar 

  13. Fan, J. & Malik, A. B. Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nature Med. 9, 315–321 (2003).

    Article  CAS  Google Scholar 

  14. Huang, C., Jacobson, K. & Schaller, M. D. MAP kinases and cell migration. J. Cell Sci. 117, 4619–4628 (2004).

    Article  CAS  Google Scholar 

  15. Watanabe, T. et al. Monocyte chemotactic protein-1 regulates leukocyte recruitment during gastric ulcer recurrence induced by tumor necrosis factor-α. Am. J. Physiol. Gastrointest. Liver Physiol. 287, 919–928 (2004).

    Article  Google Scholar 

  16. Chen, S. et al. Transforming growth factor-β1 increases CXCR4 expression, stromal-derived factor-1α-stimulated signalling and human immunodeficiency virus-1 entry in human monocyte-derived macrophages. Immunology 114, 565–574 (2005).

    Article  CAS  Google Scholar 

  17. Ohira, S. et al. Possible regulation of migration of intrahepatic cholangiocarcinoma cells by interaction of CXCR4 expressed in carcinoma cells with tumor necrosis factor-α and stromal-derived factor-1 released in stroma. Am. J. Pathol. 168, 1155–1168 (2006).

    Article  CAS  Google Scholar 

  18. Marx, J. Cancer research. Inflammation and cancer: the link grows stronger. Science 306, 966–968 (2004).

    Article  CAS  Google Scholar 

  19. Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    Article  CAS  Google Scholar 

  20. Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).

    Article  CAS  Google Scholar 

  21. Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    Article  CAS  Google Scholar 

  22. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    Article  CAS  Google Scholar 

  23. Folkman, J. The role of angiogenesis in tumor growth. Semin. Cancer Biol. 3, 65–71 (1992).

    CAS  PubMed  Google Scholar 

  24. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  Google Scholar 

  25. Dong, Q. G. et al. A general strategy for isolation of endothelial cells from murine tissues. Characterization of two endothelial cell lines from the murine lung and subcutaneous sponge implants. Arterioscler. Thromb. Vasc. Biol. 17, 1599–1604 (1997).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yoshiro Maru.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figure S1 and Supplementary methods (PDF 1585 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hiratsuka, S., Watanabe, A., Aburatani, H. et al. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8, 1369–1375 (2006). https://doi.org/10.1038/ncb1507

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1507

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing