Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Medical Biophysics


Dr. Ann Chambers

Second Advisor

Dr. Ian MacDonald


Metastatic disease is responsible for the majority of cancer related deaths. However, most anti-cancer drugs are not designed or tested for efficacy against this heterogeneous cancer cell population. This is in part due to the technical challenges involved in imaging and quantifying individual cells, or even large metastases, in common non-superficial sites of metastasis including lung, brain, bone marrow and liver. The purpose of the studies presented here was to develop and utilize imaging techniques capable of assessing metastatic cell progression and quantifying the effect of treatment on the majority of metastatic

cell population, inclusive of solitary cells. Quantification of the solitary metastatic cells in whole mouse liver was

achieved using an MRI technique in which iron labeled cells were visible as

areas of signal void. Signal void area was found to be highly correlated with the

number of MPIO labeled cell injected into the liver. The MR scanning protocol

used here resulted in images in which both signal void (due to iron labeled cells)


and hyperintensity due to metastases (>200 |j,m) were apparent and could be quantified. This technique was subsequently utilized to assess the effect of doxorubicin and the synthetic triterpenoid CDDO-lm on experimental liver metastases in mice. It was found that despite significantly inhibiting the growth of large metastases, neither treatment decreased the number of solitary cells present in the same liver. In order to better understand the effect of treatment on the metastatic cell population at a cellular level, cells that express a cell cycle reporter system that changes colour as cell cycle progresses (fudci) were used in 2D and 3D cell culture. It was found that initial cell density and CDDO-lm treatment altered cell growth, and that cell cycle progression could be monitored longitudinally in individual and groups of cells within the same enclosed culture system.

It is expected that the techniques presented here will enable the screening of therapeutic strategies for their efficacy against not just a subset of the metastatic cell population, but the population as a whole



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