Resistance to chemotherapy treatment not only limits its usefulness but also frequently results in the survival of highly aggressive tumor cells. The cancer cells, the surrounding stromal cells, and immune cells are all participants in cancer progression. Acharyya et al. followed up on the report that expression of the gene encoding the chemokine CXCL1 was associated with lung-metastasized breast cancer. They found that CXCL1 and the related gene CXCL2 (collectively CXCL1/2) were amplified in a subset of primary breast tumors (7.5%) and in metastases (20%). In two mouse mammary tumor models and a xenograft model based on a human lung metastatic cell line (LM2) derived from the mammary tumor cell line MDA-MB-231, knocking down CXCL1/2 reduced tumor volume and lung metastasis. The receptor for CXCL1/2 was not detected in the tumors, so the authors performed immunostaining and fluorescence-activated cell sorting to identify the cells in the tumor microenvironment that responded to these tumor cell–produced chemokines. Tumors from the CXCL1/2-knockdown cells had fewer CD11b+Gr1+ myeloid cells, specifically the granulocytic neutrophil population. Analysis of gene expression, limited to those that encode secreted or cell-surface proteins associated with CXCL1 expression in human breast tumors, revealed 43 genes, and the genes encoding S100A8 and S100A9 (S100A8/9) were expressed in tumor-derived CD11b+Gr1+ myeloid cells. S100A8/9 form a dimer, are calcium-binding proteins that activate Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), and have been implicated in cancer and inflammation. Implantation of LM2 cells into mice in which the bone marrow had been transplanted with that of S100a9–/– cells resulted in reduced mammary tumor growth and lung metastasis and increased apoptotic cells in the tumor and lung. In patients with breast cancer, greater abundance of S100A8/9 in the lung metastases correlated with shorter survival. Tumors of LM2 cells exhibited increased expression of CXCL1/2 and increased recruitment of S100A9-positive myeloid cells after cytotoxic chemotherapy treatment of the mice. A similar increase in S100A8/9-positive cells was also observed in breast tumors from patients that received chemotherapy compared with those that had not. Exposure of the LM2 cells to cytotoxic chemotherapy drugs failed to induce CXCL1/2 expression; however, conditioned media from primary endothelial cells or primary bone marrow–derived cells exposed to the drugs did induce expression in the LM2 cells. Chemotherapy treatment stimulated the expression the gene encoding tumor necrosis factor–α (TNF-α) in endothelial cells from the lungs of mice with the LM2 tumors. TNF-α activated the NF-κB (nuclear factor κB) pathway, which stimulated CXCL1 expression, in cultured LM2 cells. Treatment of the mice with an antibody inhibitor of TNF-α reduced recruitment of S100A8/9-positive cells. In mice that had developed lung metastases from implantation of one of two different human breast cancer cell lines, combining an antagonist of CXCR2 (the receptor for CXCL1/2) with cytotoxic chemotherapy synergistically reduced or eliminated detectable lung metastases, suggesting that disrupting this stromal-tumor survival pathway may prove successful at limiting chemoresistance.
S. Acharyya, T. Oskarsson, S. Vanharanta, S. Malladi, J. Kim, P. G. Morris, K. Manova-Todorova, M. Leversha, N. Hogg, V. E. Seshan, L. Norton, E. Brogi, J. Massagué, A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012). [Online Journal]