Doctor of Philosophy
Foster, Paula J.
Ronald, John A.
Introduction: Breast cancer recurrence continues to be a significant challenge in the clinic. Despite successful removal and/or treatment of the original tumour, many patients experience relapse in the breast or at distant sites. Furthermore, the diagnosis of metastatic disease often occurs too late for effective treatment. Methods: In this thesis, we combine iron-based cellular MRI and longitudinal BLI to noninvasively track the fate of cancer cells into overt tumours in the mouse brain. We then apply this imaging model to study the effect of a primary breast tumour on the growth of secondary metastases in an immune competent mouse model. Finally, we utilized dual-luciferase BLI to investigate the potential of self-homing circulating tumour cells (CTCs) as a novel cancer theranostic in both orthotopic and metastatic models of breast cancer. Results: BLI complemented our cellular MRI technologies well by providing longitudinal measures of cancer cell viability. Using in vivo BLI/MRI, we demonstrated the presence of a 4T1 primary tumour significantly enhances total brain tumour burden. Finally, using dual-luciferase BLI, we demonstrated the ability of experimental CTCs to home to and treat primary tumours and disseminated breast cancer lesions. Conclusion: MRI and BLI are complementary technologies to noninvasively study the fate of breast cancer cells, as well as the mechanisms contributing to metastasis including CTR/CTE and tumour self-homing. Furthermore, we provide evidence that CTCs are a novel theranostic platform for the visualization and treatment of pre-established tumour sites throughout the body.
Summary for Lay Audience
Introduction:Metastasis is defined as the spread of cancer cells from the original tumour to other parts of the body and is responsible for the majority of cancer related deaths. Thus, there is a need to better understand the mechanisms that contribute to the progression and spread of cancer. Methods: In this thesis, we used novel molecular imaging tools to study potential mechanisms of breast cancer metastasis in mouse models. We combined two complementary imaging technologies, cellular magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) to get a more complete picture of breast cancer cell fate in the brain over time. We then applied these technologies to study the impact of a primary tumour on the growth of secondary metastases in the body. Finally, we applied non-invasive imaging to investigate the potential of circulating tumour cells as a novel delivery vehicle for anti-cancer therapeutics in mouse models of breast cancer. Results: BLI complemented our cellular MRI technologies well by providing longitudinal measures of cancer cell viability. Using in vivoBLI/MRI, we demonstrated the presence of a primary tumour enhances total brain tumour burden. Finally, using BLI, we demonstrated the ability of circulating tumour cells to home to and treat primary tumours and disseminated lesions. Conclusion: MRI and BLI are complementary technologies to noninvasively study the fate of breast cancer cells, as well as the mechanisms contributing to metastatic spread.
Parkins, Katie, "Investigating the Mechanisms of Breast Cancer Metastasis Using Multimodality Molecular Imaging" (2019). Electronic Thesis and Dissertation Repository. 6509.
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