Abstract
BackgroundAn 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.MethodsHere, 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.ResultsWe 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.ConclusionsThese 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.
Highlights
Metastasis, the spreading of primary tumours to secondary sites, is responsible for 90% of deaths from cancer and is a leading cause of morbidity in cancer patients [1]
In order to accurately determine the effect of imaging depth on visualisation of key parameters of microglial morphology, we quantified the extent of arborisation of microglial processes using Sholl analysis [41, 42]
We found that the accumulation of microglia persisted for the 13-day duration of the experiment following implantation of the breast cancer cells
Summary
Metastasis, the spreading of primary tumours to secondary sites, is responsible for 90% of deaths from cancer and is a leading cause of morbidity in cancer patients [1]. Most breast cancer brain metastases occur in the frontal lobe, with cerebellum and parietal lobe being common sites [4]. Patients with metastatic brain tumours present with neurological symptoms including cognitive impairment and epileptic seizures [8, 9], and this can have a significant impact on quality of life. There is an urgent need to better understand the mechanisms regulating seeding and expansion of brain metastases and their neurological sequelae in order to develop new effective therapies. 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. The mechanisms underlying microglial involvement appear complex and better models are required to improve understanding of function
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