Lung cancer is still the most common cause of death from cancer worldwide with over 900,000 deaths per year. In most cases, by the time it is detected, it is incurable. In Nature Cell Biology, Yoshiru Maru and colleagues identify two chemokines in the lungs of tumour-bearing mice that directly regulate the migration of cancer cells to this organ. These findings not only provide further evidence that soluble factors released from primary tumours prepare distant tissues for malignant cell engraftment, but also indicate that the chemokines S100A8 and S100A9 might serve as prognostic indicators of metastasis or even, as targets for anticancer drug design.

Examination of the gene expression profile in lungs derived from normal, benign and malignant tumour-bearing mice revealed that the inflammatory chemoattractants S100A8 and S100A9 are strongly expressed in lung cells before tumour cells metastasize. Moreover, exposure to serum from tumour-bearing mice was sufficient to induce the upregulation of S100A8 and S100A9 in normal lung tissue. Using neutralizing antibodies and recombinant proteins, the authors showed that a combination of factors, including tumour necrosis factor (TNF), transforming growth factor- (TGF-) and vascular endothelial growth factor-A (VEGF-A), is responsible for the upregulation of these chemokines in premetastatic lungs.

S100A8 and S100A9-stimulated lung conditioned medium (S100-stimulated LCM) induced the migration of both macrophages and tumour cells in Boyden chamber assays by activating the mitogen-activated protein kinase p38, and promoting the formation of invading pseudopods. Further experiments showed that S100A8 and S100A9 induce the secretion of factors that function as migration-stimulatory factors (MSFs) such as TNF, MIP2, TGF- or VEGF-A, from lung endothelial cells and Macrophage antigen-1 (Mac1⁺)-myeloid cells. Depletion of these molecules from S100-stimulated LCM or inhibition of p38 partially blocked tumour-cell migration indicating that S100A8 and S100A9 induce the secretion of several MSFs, and that p38 signalling is required for the migration of both myeloid and cancer cells.

Finally, Yoshiru Maru and colleagues generated anti-S100A8 and anti-S100A9 antibodies, which suppressed cancer-cell migration in vitro and the formation of metastasis in vivo by decreasing the number Mac1⁺-myeloid cells, and thereby the secretion of MSFs, in the lungs of tumour-bearing mice.

Taken together, these findings indicate that the secretion of TNF, TGF- and VEGF-A from primary tumours upregulate S100A8 and S100A9 in the lungs which in turn, leads to the recruitment of Mac1⁺-myeloid cells and the secretion of MSFs. These factors activate p38 and promote tumour-cell migration. The ability of anti-S100A8 and anti-S100A9 antibodies to protect lungs from circulating tumour cells holds promise for future cancer therapies.

Author: Monica Hoyos-Flight