Aims: Cognitive impairment in cancer patients often presents before treatment, called “cancer brain”. Anxiety of diagnosis is usually identified as the source of cancer brain but the tumour itself may also play a role. We aimed to use a breast cancer mouse model to identify the mechanisms and biomarkers of cancer brain in the absence of anxiety related to diagnosis, which is unavoidable in patient studies.
Methods: Mice were injected with a syngenic breast cancer cell line or vehicle into the orthotopic site. Bioluminescence imaging was used to monitor cancer progression. Memory impairment was assessed using validated behavioural tests for memory in mice. To determine whether secreted factors from tumour cells were sufficient to induce memory impairment, a second group of mice were treated with daily injections of tumour-conditioned media and assessed for memory impairment. Inflammatory profiles of tumour bearing vs control mice were assessed in the brain, spleen and plasma.
Results: Mice exhibited memory impairment as early as 3 days after tumour cell injection (p < 0.05). Injection of secreted factors was sufficient to induce memory impairment in the absence of tumour cells (p < 0.05). Increased splenic and plasma proinflammatory cytokines and reduced anti-inflammatory IL-10 was also observed in the brains of tumour-bearing mice compared to controls and in the tumour-conditioned media (p < 0.05).
Conclusions: These mouse models of breast cancer show that a peripheral tumour can drive cognitive impairment via neuroinflammation in addition to the psychosocial factors usually associated with cancer brain. Peripheral markers of inflammation directly matched those in the memory centres of the brain suggestive that measurement of the inflammatory profile of cancer patients in blood may serve as a valuable prognostic indicator of cognitive impairment and susceptibility. NSAIDs may serve as an early preventative measure against cancer brain.
This work was supported by the National Breast Cancer Foundation (PF-15-014).