Fatal attraction: How macrophages participate in tumor metastases

Insight from Dmitry Gabrilovich

Macrophages are critically important for the regulation of tumor growth and metastases. They contribute to tumor angiogenesis, tumor cell extravasation, and survival at the sites of metastases. Now, Kitamura et al., using mouse models of breast cancer, have uncovered a major role for a CCL2-induced chemokine cascade that supports macrophage recruitment and retention in metastatic sites in the lung.

Macrophages found in metastatic sites have a distinct phenotype and are referred to as metastasis-associated macrophages (MAMs). Similar to other tumor-associated macrophages, MAMs originate from circulating inflammatory monocytes, which are recruited to the tumor site in response to the chemokine CCL2. This raised the attractive possibility of controlling metastasis by targeting CCL2. However, an anti-CCL2 antibody was found to be ineffective in humans. Furthermore, loss of CCL2 signaling reduced the numbers of circulating monocytes, leading to an increased susceptibility to infection in mouse models. This necessitated the search for more precise mechanisms regulating MAM migration, as addressed by Kitamura et al. in the current study.

Representative fluorescence microscopy images of lung 24 hours after injection of mouse breast cancer cells. Green, CMFDA-labeled E0771-LG breast cancer cells; red, CD11b; blue, nuclei; arrow head, interaction between myeloid cells and cancer cells. Dotted line indicates the interaction between macrophage and tumor cell. Bars, 10 μm.

Kitamura et al. found that MAMs expressed the CCL2 receptor CCR2, and activation of CCR2 signaling prompted MAMs to secrete another chemokine, CCL3. The increased CCL3 secretion resulted in enhanced MAM–cancer cell interaction, at least in part through integrin α4, and prolonged the retention of MAMs in the metastatic sites, resulting in extravasation of cancer cells. The authors implicated the CCL3 receptor CCR1 on MAMs as the main mechanism responsible for CCL3-mediated retention of MAMs in metastatic sites.

This study identifies a novel prometastatic chemokine cascade that promotes lung metastasis in breast cancer. Although the concept of chemokine crosstalk has been described previously, this work demonstrates, for the first time, the existence of the CCL2–CCL3 cascade in vivo and its contribution to tumor metastases. It appears that CCL2 is primarily responsible for macrophage migration, whereas CCL3 is primarily responsible for macrophage retention. It also seems likely that CCL2-induced CCL3 expression is specific to the prometastatic macrophage, which raises the exciting possibility of more effective identification and targeting of MAMs. However, the molecular mechanism by which CCL3 activates macrophages and promotes their interaction with tumor cells needs to be elucidated. CCL3 is known to have potent effects on neutrophil extravasation and activation. Although neutrophils may not play a major role in the breast tumor models used in this study, the potential involvement of neutrophils in other models and in patients requires further analysis.

This study presents a more refined picture of the role of macrophages in metastases than has been appreciated to date, and it suggests that more precise targeting of macrophages may allow us to curtail the development of metastases.