Investigating the Impact of a Primary Tumor on Metastasis and Dormancy Using MRI: New Insights into the Mechanism of Concomitant Tumor Resistance

Dormant cancer cells, also referred to as quiescent, slowly cycling or “nonproliferative” cells, are believed to contribute to tumor recurrence and present a therapeutic problem because they are nonresponsive to current therapies that target proliferating cells. Concomitant tumor resistance (CTR) is the ability of a primary tumor to restrict the growth of secondary metastases. In this paper, we investigate these 2 cancer concepts using cellular magnetic resonance imaging (MRI). A new model for CTR is presented where a primary mammary fat pad tumor is generated using a human breast cancer cell line (231) and breast cancer brain metastases are generated using a cell line derived from 231 to be brain metastatic (231-BR). Iron oxide particles are used to label the 231BR cells to allow for tracking of the proliferating cells, which form metastases, and the nonproliferating cells, which remain dormant in the brain. Bioluminescence and fluorescence-activated cell sorting are used to validate the MRI data. The presence of a primary 231 mammary fat pad tumor inhibited the formation of MRI-detectable 231BR brain metastases. More iron-retaining cells persisted in the brains of mice with a primary tumor. Bioluminescence and fluorescence-activated cell sorting provide evidence that signal voids detectable by MRI on day 0 represent live, iron-labeled cells in the brain. This work shows that retention of iron by nonproliferative cancer cells can be exploited to monitor the fate of this important cell population in vivo, and it points to a new mechanism for CTR, the enhancement of dormancy by a primary tumor.