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Cessation of CCL2 Inhibition Precipitates Breast Cancer Metastases and Death

Bonapace, Laura and wyckoff, Jeffrey and Mertz, Kirsten D. and Varga, Zsuzsanna and coissieux, marie-may and Junt, Tobias and Bentires-Alj, Mohamed (2014) Cessation of CCL2 Inhibition Precipitates Breast Cancer Metastases and Death. Nature.

Abstract

Here we report a paradoxical effect of the CC chemokine ligand 2 (CCL2) in metastatic breast cancer. Secretion of CCL2 by mammary tumors recruits CCR2-expressing inflammatory monocytes to primary tumors and metastatic sites and CCL2 neutralization in mouse models inhibits metastasis1 by retaining monocytes in the bone marrow. Surprisingly, interruption of CCL2 inhibition leads to an overshoot in metastatic load and precipitates death of the animals. This is the result of sudden monocyte release from the bone marrow, enhancement of cancer cell mobilization from the primary tumor, increased proliferation of metastatic cells, and blood vessel formation in the lungs in an IL-6/VEGF-dependent manner. Of note, inhibition of IL-6 following cessation of anti-CCL2 treatment dramatically reduced metastases and increased overall survival of the animals. CCL2 has been functionally implicated in various neoplasias and has been positioned as an attractive therapeutic target1-3. However, our results call for extreme caution when considering anti-CCL2 as single therapy in metastatic disease and highlight the tumor microenvironment as a critical determinant of successful anti-metastatic therapy.

Item Type: Article
Keywords: CCL2, breast cancer, metastasis
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/20600

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