The ultimate goal of all cancer treatments is to destroy tumours without harming normal cells. We have discovered many methods to kill cancer cells — now the goal is to protect as many healthy cells as possible from collateral damage. Researchers are coming up with creative new ways to go about this. On page 420 of this issue, Avi Ashkenazi updates us on methods to induce tumour-cell-specific apoptosis through activation of death-receptor signalling. These tumour-necrosis-factor-receptor family members only activate apoptotic signalling pathways in cancer cells, and treatment with their ligand — APO2L/TRAIL — kills a broad spectrum of human cancer cells.
Although there were initial reports that APO2L/TRAIL was toxic to normal human hepatocytes, this was found to be an artefact of an epitope-tagged recombinant variant of the molecule. Recent improvements in our understanding of APO2L/TRAIL structure and function revealed that the naturally occurring, non-tagged zinc-bound form has little or no effect on normal cells, but still activates apoptosis in cancer cells. The ability of death-receptor signalling to kill cancer cells regardless of p53 status also indicates that APO2L/TRAIL might be one way to attack tumours that are resistant to therapy.
