Abstract
Discontinuation of anti-CCL2 therapy augments lethal breast cancer metastasis in mice.
Major finding: Discontinuation of anti-CCL2 therapy augments lethal breast cancer metastasis in mice.
Mechanism: Monocyte influx into the lung promotes metastatic growth and induces angiogenesis via IL6 and VEGFA.
Impact: Treatments that only sequester monocytes in the bone marrow may enable metastatic rebound posttherapy.
Intratumoral macrophage infiltration is associated with metastatic spread and poor prognosis in breast cancer and is mediated by secretion of C-C chemokine ligand 2 (CCL2) by tumor cells. Inhibition of CCL2 suppresses macrophage recruitment and metastasis in mice, supporting CCL2 as a potential antimetastatic therapeutic target. Bonapace, Coissieux, and colleagues found that, consistent with previous findings, treatment with a CCL2-neutralizing antibody decreased the number of circulating tumor cells (CTC) and intratumoral macrophages and reduced lung metastasis in syngeneic mouse models of metastatic breast cancer. Intriguingly, however, discontinuation of anti-CCL2 treatment triggered a rebound in CCL2 expression in lung tissue and resulted in a significant and rapid increase in CTCs, accelerated lung metastasis, and decreased survival of tumor-bearing mice. This prometastatic effect was dependent on the release of monocytes from sequestration in the bone marrow and increased migration of monocytes to the primary tumor and lungs following cessation of anti-CCL2 therapy. Infiltrating monocytes enhanced lung metastasis by promoting the proliferation of metastatic tumor cells and increasing blood vessel formation in the metastatic microenvironment in response to the proangiogenic cytokine IL6, which induced expression of VEGFA in monocytes via phosphorylated STAT3. Inhibition of IL6 in mice following anti-CCL2 therapy reduced angiogenesis and the proliferation of metastatic tumor cells in the lungs, prevented the rebound in lung metastasis, and prolonged survival. Similarly, neutralization of VEGFA or depletion of monocytes and macrophages via inhibition of colony-stimulating factor 1 receptor decreased vascular density and metastatic proliferation in the lung after discontinuation of anti-CCL2 therapy. Furthermore, elevated CCL2 levels correlated with increased macrophage infiltration and vascularization in human breast cancer, and high expression of both CCL2 and IL6 was associated with decreased patient survival. These results support the use of caution in the application of antimetastatic therapies such as anti-CCL2 that sequester but do not deplete macrophages from the tumor microenvironment.
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