Abstract
Aims: Breast cancer patients often experience cognitive impairments, which have been predominantly blamed on the toxic side-effects of chemotherapy. However, memory dysfunction is evident in up to 40% of patients prior to receiving any cancer-directed therapy. This suggests that diagnosis-associated stress and/or tumour growth itself could cause cancer-related cognitive impairment (CRCI). Moreover, the aged brain is likely more susceptible to those stress- and/or tumour-induced changes. The aim of this thesis was to examine the contribution of diagnosis related stress and tumour-associated factors to the development of pre-treatment cognitive impairment in the adult and aged brain.Methods: As the effects of diagnosis-associated stress cannot be distinguished from the tumour-induced impact on the brain in breast cancer patients, an orthotopic syngeneic breast cancer mouse model (3- and 18-month-old) was used. Tumour- and non-tumour-inoculated mice were subjected to novel object recognition memory tests following three weeks of daily restraint stress, to model psychological stress, or non-stress conditions. Subsequently, urinary corticosterone and brain inflammatory cytokine levels were measured using ELISA. Additionally, in-depth mass-spectrometry based proteomic profiling of the hippocampus was performed. Primary hippocampal neuron cultures were used to examine the effects of tumour-secreted factors
on neuronal Ca2+ signalling.
Results: Breast tumour inoculation alone, in the absence of psychological stress, was shown to elicit a glucocorticoid-mediated stress response and to cause long-term memory dysfunction. Cognitive impairment was also observed in tumour-inoculated mice whose primary tumour spontaneously regressed. However, increased expression of the inflammatory cytokine TNF-α was only observed in the brains of 3-month-old tumour-bearing animals. In contrast, in the aged brain, presence of a peripheral tumour decreased the expression of TNF-α. In vitro, cancer-cell conditioned media induced neuronal Ca2+ signalling dysfunction in primary hippocampal neurons which was corroborated ex vivo using mass spectrometry. Compelling changes in relative protein
abundancy were observed for various Ca2+-related proteins in the brains of both young and old tumour-inoculated animals.
Conclusions: Tumour-induced glucocorticoid-mediated signalling and neuronal Ca2+ signalling dysfunction are likely involved in the development of pre-treatment CRCI. Cognitive dysfunction in tumour-inoculated animals, in which the primary tumour underwent spontaneous tumour regression, suggests that an early tumorigenic event is sufficient to induce memory impairments. The observed differences in the inflammatory response in the aged mice
could suggest that divergent mechanisms are at play in young and elderly patients with pretreatment CRCI. Furthermore, hippocampal proteomic profiling indicates that that pretreatment CRCI may be attributable to proteomic changes of Ca2+-related proteins.
| Date of Award | Mar 2021 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Graham Sheridan (Supervisor), Melanie Flint (Supervisor) & Nicolas Stewart (Supervisor) |