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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Collaborative Specialization

Molecular Imaging

Supervisor

Foster, Paula J.

Abstract

Introduction: Breast cancer remains a leading cause of mortality among women due to the propensity of breast tumours to spread and metastasize to distant sites, including the brain. Early detection of metastatic disease has been challenging, and typical methods of treatment often fail. A significant roadblock in advancing the detection and treatment of breast cancer brain metastases is the lack of representative experimental preclinical models and methods of studying its progression in vivo. Methods: First, we use iron-based cellular MRI to noninvasively track the progression of a brain metastatic breast cancer cell line in murine models with varying immune competencies. We then employ longitudinal BLI and MPI to visualize the tumour progression of a patient-derived xenograft (PDX) model of breast cancer brain metastasis. Finally, we used MPI to evaluate the magnetic performance of iron oxide particles following cell labeling with a brain metastatic breast cancer cell line to optimize cellular detection and cell tracking techniques. Results: Cellular MRI revealed significant differences in tumour progression throughout the brain and body between murine models. We then developed a novel method for labeling PDX cells with iron oxide particles and use MPI and BLI to provide measures of iron content and cellular viability. Finally, we demonstrate that cell labeling can change the magnetic performance of iron agents used for cell tracking with MPI. Conclusion: Comprehensive analysis of cancer cell arrest, clearance, and tumour progression with cellular imaging is important for understanding the metastatic cascade of a model of breast cancer brain metastasis in both cell lines and PDX models. Furthermore, we provide evidence that iron oxide particles are valuable tracers for MPI cell tracking, but their MPI performance may be altered following cell labeling.

Summary for Lay Audience

Introduction: The majority of cancer related deaths are due metastasis, which is the spread of cancer from the original tumour to distant locations in the body. For breast cancer, this is often the brain, lungs, liver, and bones. When breast cancer spreads to the brain, the prognosis is poor. Therefore, there is an urgent need to understand and develop new tools to study the progression of this disease. Methods: In this thesis, we study models of breast cancer that spread to brain using novel cellular imaging techniques. First, we use magnetic resonance imaging (MRI) to compare how cancer cells arrive in the mouse brain and grow and progress over time. We then used two complementary imaging technologies called bioluminescence imaging (BLI) and magnetic particle imaging (MPI) that allowed us to visualize how cells derived from patient brain metastases grows in a mouse model. Finally, we assessed different iron agents that are used for cell tracking and determined how they behave alone and once taken up by breast cancer cells. Results: Using MRI allowed us to measure and examine differences in cancer cell fate over time in different strains of mice. Using BLI and MPI was a complementary approach to study the development of a tumour formed from patient tumour cells, allowing us to measure both cell viability and iron content. Lastly, we demonstrated that some iron agents significantly change their behaviour and affect their utility for cell tracking once they have been taken up by breast cancer cells. Conclusion: Cellular imaging technologies, like MRI, BLI, and MPI, are critical in providing a comprehensive understanding of the progression of breast cancer and can be used to improve detection of cancer cells in the body.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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