Apoptosis and cancer: strategies for integrating programmed cell death

Virtually all human cells are endowed with the capacity to commit suicide using an evolutionarily conserved mechanism that involves activation of caspase-family cell death proteases. Caspase activation culminates in a cell death process known as "apoptosis." The activation of these intracellular proteases is carefully controlled through a delicate balance of anti- and pro-death proteins, serving to precisely regulate cell life span. Defects in the natural death pathway promote tumorigenesis by prolonging cell life span and hence cell accumulation. Low-grade B-cell malignancies, particularly follicular lymphoma and chronic lymphocytic leukemia (CLL) represent quintessential examples of human neoplasms characterized primarily by a problem with cell death rather than cell cycle. Because the cell suicide pathway is also required for tumor eradication by the immune system, anticancer drugs, and irradiation, cancer-associated defects in the cellular apoptosis machinery also play an important role in treatment failures. Monoclonal antibody-based therapies may provide opportunities to either bypass defects in apoptosis pathways or to activate latent apoptotic programs in cancer cells, particularly in lymphoid malignancies where tissue-specific antigens can be exploited for cell-selective activation of apoptosis. Recent knowledge about apoptosis pathways is reviewed, and some examples of opportunities for therapeutic intervention are discussed.