Proteins selectively killing tumor cells.

All human cells have a genetic program that upon activation will cause cell death, named apoptosis. Cancer cells can grow due to unbalances in proliferation, cell cycle regulation and their apoptosis machinery: genomic mutations resulting in non-functional pro-apoptosis proteins or over-expression of anti-apoptosis proteins form the basis of tumor formation. Surprisingly, lessons learned from viruses show that cancer cannot be regarded simply as the opposite of apoptosis. For instance, adenovirus can only transform cells when both its anti- and pro-apoptotic proteins are produced. Oncolytic viruses are known to replicate selectively in tumor cells resulting in cell death. Proteins derived from viruses, i.e. chicken anemia virus (CAV)-derived apoptosis-inducing protein (apoptin), adenovirus early region 4 open reading frame (E4orf4) and parvovirus-H1 derived non-structural protein 1 (NS1), the human alpha-lactalbumin made lethal to tumor cells (HAMLET), which is present in human milk or the human cytokines melanoma differentiation-associated gene-7 (mda-7) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have all the ability to induce tumor-selective apoptosis. The tumor-selective apoptosis-inducing proteins seem to interact with transforming survival processes, which can become redirected by these proteins into cell death. Transformation-related processes have been identified, which seem to be crucial for the tumor-selectively killing activity of these proteins. For instance, the transformation-related protein phosphatase 2A (PP2A) plays a role in the induction of tumor-selective apoptosis. The proteins mda-7, TRAIL and HAMLET are already successfully tested in first clinical trials. Proteins harboring tumor-selective apoptosis characteristics represent, therefore, a therapeutic potential and a tool for unraveling tumor-related processes. Fundamental molecular and (pre)clinical therapeutic studies of the various tumor-selective apoptosis-inducing proteins apoptin, E4orf4, HAMLET, mda-7, NS1, TRAIL and related proteins will be discussed.