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. 2014 Nov 6;515(7525):130-3.
doi: 10.1038/nature13862. Epub 2014 Oct 22.

Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis

Laura Bonapace  1 , Marie-May Coissieux  2 , Jeffrey Wyckoff  2 , Kirsten D Mertz  3 , Zsuzsanna Varga  4 , Tobias Junt  5 , Mohamed Bentires-Alj  2
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Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis

Laura Bonapace et al. Nature. .

Abstract

Secretion of C-C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. Here we report a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin (IL)-6- and vascular endothelial growth factor (VEGF)-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals. CCL2 has been implicated in various neoplasias and adopted as a therapeutic target. However, our results call for caution when considering anti-CCL2 agents as monotherapy in metastatic disease and highlight the tumour microenvironment as a critical determinant of successful anti-metastatic therapy.

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