Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis

Laura Bonapace, Marie-May Coissieux1, Jeffrey Wyckoff1, Kirsten D. Mertz, Zsuzsanna Varga, Tobias Junt, Mohamed Bentires-Alj

Nature 515, 130-133 (2014)

Speaker: Cheng-Hao Chen (陳正豪)                             Time: 14:00~15:00, May 6, 2015

Commentator: Dr. Hung-Chi Cheng (鄭宏祺老師)     Place: Room 601

Abstract:

Tumor microenvironment plays an essential role in supporting cancer progression, and macrophages are major components in this microenvironment. In previous studies, C-C chemokine ligand 2 (CCL2) secreted by breast tumors recruits monocytes expressing C-C chemokine ligand 2 receptor (CCR2) to facilitate metastasis via a vascular endothelial growth factor-A (VEGF-A)-dependent manner. In clinical patients, high CCL2 expression in the tumors has been correlated to a poor prognosis in breast cancer. (1) Therefore, blocking CCL2 seems to be a potential strategy to inhibit metastasis in patients suffering from breast cancer. However, this study indicates a paradoxical effect of anti-CCL2 therapy in four syngeneic mouse models of metastatic breast cancer. Unexpectedly, interruption of anti-CCL2 treatment accelerated both the development of metastasis and death. This phenomenon was due to released monocytes from bone marrow inducing blood vessel formation as well as metastatic growth-enhancing effects. The authors found that discontinuation of anti-CCL2 therapy upregulated interleukin-6 (IL-6) expression in mouse serum. Furthermore, neutralization of IL-6 or its downstream molecule, VEGF-A, reduced angiogenesis and prevented overshoot of lung metastasis after cessation of anti-CCL2 therapy. Taken together, cessation of anti-CCL2 therapy accelerates breast cancer metastasis by promoting blood vessel formation through IL-6–VEGF-A dependent mechanism. This study highlights the risk of metastatic overshoot after anti-CCL2 therapy.

Reference:

1.         Bonapace, L. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumor metastasis. Nature 515, 130–133 (2014).