Stefanie Galbán1, Yong Hyun Jeon2, Lisa M. Sharkey2, Ben Hoff2, Craig J. Galbán2, Brian D. Ross2 and Alnawaz Rehemtulla1
Departments of Radiation Oncology1 and Radiology2 University of Michigan, Ann Arbor, MI
The importance of the apoptotic machinery is exemplified in a number of disease processes. For example, inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. Cancer is characterized by dysregulated cell proliferation and altered cell death, which constitutes a common basis for neoplastic evolution. The most implicit and clinically attractive anticancer strategies, therefore, consist of eliminating tumor cells by preventing their expansion and ultimately inducing apoptotic cell death.
We have developed a transgenic mouse model wherein Caspase 3 mediated cell death can be imaged in real time and non-invasively utilizing a luciferase based biosensor. Upon Cre-mediated recombination, transgene expression containing the Caspase 3 biosensor is achieved in a cell or tissue specific manner. Here we show that expression of the Caspase 3 biosensor can be achieved in several tissues. In addition, we demonstrate in mouse models of cancer, that the ability to dynamically and sensitively image the activation of the Caspase 3 provides an opportunity to understand the dynamics of cell death in response to specific drugs or combination therapies.
We also provide results demonstrating the utility of the technology in evaluating the efficacy of cancer therapeutics in cancer stem cells, a population that is rare and transient.