An emerging problem in the treatment of breast cancer is the increasing incidence of metastases to the brain. Metastatic brain tumours are incurable and can cause epileptic seizures and cognitive impairment, so better understanding of this niche, and the cellular mechanisms, is urgently required. Microglia are the resident brain macrophage population, becoming “activated” by neuronal injury, eliciting an inflammatory response. Microglia promote proliferation, angiogenesis and invasion in brain tumours and metastases. However, the mechanisms underlying microglial involvement appear complex and better models are required to improve understanding of function. Here, we sought to address this need by developing a model to study metastatic breast cancer cell-microglial interactions using intravital imaging combined with ex vivo electrophysiology. We implanted an optical window on the parietal bone to facilitate observation of cellular behaviour in situ in the outer cortex of heterozygous Cx3cr1GFP/+ mice. We detected GFP-expressing microglia in Cx3cr1GFP/+ mice up to 350 μm below the window without significant loss of resolution. When DsRed-expressing metastatic MDA-MB-231 breast cancer cells were implanted in Matrigel under the optical window, significant accumulation of activated microglia around invading tumour cells could be observed. This inflammatory response resulted in significant cortical disorganisation and aberrant spontaneously-occurring local field potential spike events around the metastatic site. These data suggest that peritumoral microglial activation and accumulation may play a critical role in local tissue changes underpinning aberrant cortical activity, which offers a possible mechanism for the disrupted cognitive performance and seizures seen in patients with metastatic breast cancer.

中文翻译：

---

转移性乳腺癌细胞诱导体内小胶质细胞形态和电兴奋性改变

乳腺癌治疗中的一个新问题是脑转移的发生率不断增加。转移性脑肿瘤无法治愈，可导致癫痫发作和认知障碍，因此迫切需要更好地了解这一生态位及其细胞机制。小胶质细胞是大脑中常驻的巨噬细胞群，因神经元损伤而被“激活”，引发炎症反应。小胶质细胞促进脑肿瘤和转移瘤的增殖、血管生成和侵袭。然而，小胶质细胞参与的机制似乎很复杂，需要更好的模型来提高对功能的理解。在这里，我们试图通过开发一种模型来解决这一需求，该模型使用活体成像结合离体电生理学来研究转移性乳腺癌细胞-小胶质细胞相互作用。我们在顶骨上植入了一个光学窗口，以便于原位观察杂合子 Cx3cr1GFP/+ 小鼠外皮层的细胞行为。我们在 Cx3cr1GFP/+ 小鼠中检测到窗口下方 350 μm 处表达 GFP 的小胶质细胞，分辨率没有明显损失。当表达 DsRed 的转移性 MDA-MB-231 乳腺癌细胞在光学窗口下植入基质胶时，可以观察到入侵肿瘤细胞周围活化的小胶质细胞显着聚集。这种炎症反应导致显着的皮质紊乱和转移部位周围异常自发发生的局部场电位尖峰事件。这些数据表明，瘤周小胶质细胞的激活和积累可能在支撑异常皮质活动的局部组织变化中发挥关键作用，这为转移性乳腺癌患者认知功能障碍和癫痫发作提供了可能的机制。