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Discontinuation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis

Bonapace, Laura and coissieux, marie-may and wyckoff, jeffrey and Mertz, Kirsten D. and Varga, Zsuzsanna and Junt, Tobias and Bentires-Alj, Mohamed (2014) Discontinuation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature, 515 (7525). pp. 130-133.

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 mice inhibits metastasis1 by retaining monocytes in the bone marrow. 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, enhancement of cancer cell mobilization from the primary tumor, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an IL-6/VEGF-A-dependent manner. Notably, inhibition of CCL2 and IL-6 dramatically reduced metastases and increased survival of the animals. CCL2 has been implicated in various neoplasias and adopted as a therapeutic target1-3. However, our results call for caution when considering anti-CCL2 as monotherapy in metastatic disease and highlight the tumor microenvironment as a critical determinant of successful anti-metastatic therapy.

Item Type: Article
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23463

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