Treatment options are limited for breast cancer patients presenting with metastatic disease. Targeting of tumor-associated macrophages through inhibition of colony stimulating factor-1 receptor (CSF-1R), a key macrophage signaling pathway, has been reported to reduce tumor growth and metastasis, and these treatments are now in clinical trials. Here we report that, surprisingly, treatment with neutralizing anti-CSF-1R and anti-CSF-1 antibodies, or with two different small molecule inhibitors of CSF-1R, could actually increase spontaneous metastasis, without altering primary tumor growth in mice bearing two independently derived mammary tumors. The blockade of CSF-1R or CSF-1 led to increased serum G-CSF levels, increased neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased neutrophils and Ly6Chi monocytes in peripheral blood. Neutralizing antibody against the granulocyte-colony stimulating factor receptor (G-CSFR), a key receptor controlling neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers seen after CSF-1R blockade. These results indicate that the role of the CSF-1R/CSF-1 system in breast cancer is far more complex than originally proposed, and requires further investigation as a therapeutic target.
- Received October 25, 2013.
- Revision received March 27, 2014.
- Accepted April 17, 2014.
- Copyright © 2014, American Association for Cancer Research.