Imaging of cell death in malignancy: Targeting pathways or phenotypes?

Cell death is fundamental in health and disease and resisting cell death is a hallmark of cancer. Treatment of malignancy aims to cause cancer cell death, however current clinical imaging of treatment response does not specifically image cancer cell death but assesses this indirectly either by changes in tumor size (using x-ray computed tomography) or metabolic activity (using 2-[¹⁸F]fluoro-2-deoxy-glucose positron emission tomography). The ability to directly image tumor cell death soon after commencement of therapy would enable personalised response adapted approaches to cancer treatment that is presently not possible with current imaging, which is in many circumstances neither sufficiently accurate nor timely. Several cell death pathways have now been identified and characterised that present multiple potential targets for imaging cell death including externalisation of phosphatidylserine and phosphatidylethanolamine, caspase activation and La autoantigen redistribution. However, targeting one specific cell death pathway carries the risk of not detecting cell death by other pathways and it is now understood that cancer treatment induces cell death by different and sometimes multiple pathways. An alternative approach is targeting the cell death phenotype that is "agnostic" of the death pathway. Cell death phenotypes that have been targeted for cell death imaging include loss of plasma membrane integrity and dissipation of the mitochondrial membrane potential. Targeting the cell death phenotype may have the advantage of being a more sensitive and generalisable approach to cancer cell death imaging. This review describes and summarises the approaches and radiopharmaceuticals investigated for imaging cell death by targeting cell death pathways or cell death phenotype.