Abstract
Treatment options are limited for patients with breast cancer presenting with metastatic disease. Targeting of tumor-associated macrophages through the 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 levels of serum G-CSF, increased frequency of neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased numbers of neutrophils and Ly6C(hi) monocytes in the peripheral blood. Neutralizing antibody against the G-CSF receptor, which regulates neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers that resulted from 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.
Highlights
The link between chronic inflammation and the onset and progression of many cancers is well established [1]
We described an isogenic series of spontaneous mammary tumors, including 67NR, 66cl4, and the highly metastatic 4T1.2, that mimics the course of human breast cancer, with primary tumor formation from a small inoculum, invasion of cells through the stroma into the circulation, and colonization at distant organs, including the lung and bone [31, 32]
We have shown, using two different metastatic tumors and four different treatments, that blockade of colony-stimulating factor-1 receptor (CSF-1R)/CSF-1 signaling, while not affecting primary tumor growth, can enhance spontaneous metastasis of breast carcinoma to both the lung and the bone
Summary
The link between chronic inflammation and the onset and progression of many cancers is well established [1]. Tumorassociated macrophages (TAM), which have been subjected to extensive study, can execute several key roles required for tumor growth and progression [1, 2]. Colony-stimulating factor-1 (CSF-1/M-CSF) regulates the recruitment, differentiation, survival, and proliferation of macrophages [3]. CSF-1 activity is mediated through its interaction with the receptor tyrosine kinase, CSF-1 receptor 3), which is expressed primarily on mononuclear phagocytic cells and their precursors [4]. Interleukin-34 (IL34) is a second ligand for CSF-1R; it controls the development of specific macrophage lineages, such as microglia and Langerhans cells [5]. IL34 and CSF-1 have distinct expression patterns [6]
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