CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.
Bottom Line: Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice.Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions.These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.
Affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.Show MeSH
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Mentions: We thus investigated the role of CCL3 in extravasation, one of the rate-limiting steps of metastasis, using an experimental metastasis model that enables cancer cells to avoid the early metastatic steps from the primary tumor such as local invasion and intravasation. Namely, we injected E0771-LG cells into the tail vein of mice that received BM transplantation (BMT) from WT, Ccl3−/−, or Ccr2−/− mice. Consistent with our other experimental models, transplantation of Ccl3−/− BM cells reduced number of foci without affecting the size of foci (Fig. 4 A). The suppressive effect of Ccl3 gene ablation was comparable with that of Ccr2 knockout. To investigate the requirement of CCL3 in lung metastasis of another cell line, we performed experimental metastasis assays with Met-1 mouse mammary tumor cells. Because the cells are derived from the PyMT tumor in FVB mice (Borowsky et al., 2005), we used anti-CCL3 neutralizing antibody instead of Ccl3−/− mice (C57BL/6). Consistent with the genetic model, pretreatment with anti-CCL3 antibody significantly suppressed the number of foci (Fig. 4 B). Although the suppressive effect of the antibody treatment was smaller than that of genetic Ccl3 deletion, we are unable to compare the two models (Met-1 and E0771) in the mutant because of the genetic background. The lower effect caused by the antibody treatment may also due to the very high dose of the antibody (ND50 = 5–25 µg/ml) required to achieve complete neutralization of CCL3 in mice that is greater than the amount of antibody available to us for this experiment. Nevertheless the effects were highly significant compared with the control antibody.
Affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.