Abstract
Brain metastasis is a common complication of cancer patients and is associated with poor survival. Histological data from patients with brain metastases suggest that microglia are the major immune population activated around the metastatic foci. Microglia and macrophages have the ability to polarize to different phenotypes and to exert both tumorigenic and cytotoxic effects. However, the role of microglia/macrophages during the early stages of metastatic growth in the brain has not yet been determined. The aim of this study was to profile microglial/macrophage activation in a mouse model of breast cancer brain metastasis during the early stages of tumor growth, and to assess the role of the anti-inflammatory microglial/macrophage population, specifically, during this phase. Following intracerebral injection of 5 × 103 4T1-GFP mammary carcinoma cells into female BALB/c mice, robust microglial/macrophage activation around the 4T1 metastatic foci was evident throughout the time-course studied (28 days) and correlated positively with tumor volume (R2 = 0.67). Populations of classically (proinflammatory) and alternatively (anti-inflammatory) activated microglia/macrophages were identified immunohistochemically by expression of either induced nitric oxide synthase/cyclooxygenase 2 or mannose receptor 1/arginase 1, respectively. Temporally, levels of both pro- and anti-inflammatory cells were broadly stable across the time-course. Subsequently, selective depletion of the anti-inflammatory microglia/macrophage population by intracerebral injection of mannosylated clodronate liposomes significantly reduced metastatic tumor burden (p < 0.01). Moreover, increased levels of apoptosis were associated with tumors in clodronate liposome treated animals compared to controls (p < 0.05). These findings suggest that microglia/macrophages are important effectors of the inflammatory response in the early stages of brain metastasis, and that targeting the anti-inflammatory microglial/macrophage population may offer an effective new therapeutic avenue for patients with brain metastases.
Highlights
IntroductionIt is estimated that 20–40% of cancer patients will develop metastases in the brain; this percentage is increasing due to better control of the systemic disease and improved diagnosis
Brain metastasis is a common complication in cancer
Microglial/macrophage infiltration increased significantly over time as intracranial tumor volume increased (ANOVA p < 0.001; Figure 1C) and a strong positive correlation was evident between the Iba1 immunostained area and the volume of the 4T1-GFP metastases (R2 = 0.671; Figure 1D)
Summary
It is estimated that 20–40% of cancer patients will develop metastases in the brain; this percentage is increasing due to better control of the systemic disease and improved diagnosis. Anti-inflammatory Microglia/Macrophages in Brain Metastasis is beneficial when used early in the course of the disease [1, 2]. Clustering of microglial cells around metastatic tumors has been described for both experimental and human brain metastases [4,5,6]. Histological analysis of autopsy samples from patients with brain metastases suggests that microglia are the major immune population activated around the metastatic foci. The histological study of another cohort of patients with breast cancer brain metastasis revealed the presence and close association of CD68+ microglia/macrophages with GFAP expressing astrocytes between clusters of carcinoma cells [7]. Low numbers of scattered B and T lymphocytes were associated with human brain metastases [5], and minimal neutrophil infiltration of brain metastases in the mouse 4T1 mammary carcinoma model has been reported [8]
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