Exploitation of Apoptotic Regulation in Cancer

David S. Ucker, Jerrold S. Levine

Within an organism, environmental stresses can trigger cell death, particularly apoptotic cell death. Apoptotic cells, themselves, are potent regulators of their cellular environment, involved primarily in effecting homeostatic control. Tumors, especially, exist in a dynamic balance of cell proliferation and cell death. This special feature of the tumorous microenvironment-namely, the prominence and persistence of cell death-necessarily entails a magnification of the extrinsic, postmortem effects of dead cells. In both normal and malignant tissues, apoptotic regulation is exerted through immune as well as non-immune mechanisms. Apoptotic cells suppress the repertoire of immune reactivities, both by attenuating innate (especially inflammatory) responses and by abrogating adaptive responses. In addition, apoptotic cells modulate multiple vital cell activities, including survival, proliferation (cell number), and growth (cell size). While the microenvironment of the tumor may contribute to apoptosis, the postmortem effects of apoptotic cells feature prominently in the reciprocal acclimatization between the tumor and its environment. In much the same way that pathogens evade the host's defenses through exploitation of key aspects of innate and adaptive immunity, cancer cells subvert several normal homeostatic processes, in particular wound healing and organ regeneration, to transform and overtake their environment. In understanding this subversion, it is crucial to view a tumor not simply as a clone of malignant cells, but rather as a complex and highly organized structure in which there exists a multidirectional flow of information between the cancer cells themselves and the multiple other cell types and extracellular matrix components of which the tumor is comprised. Apoptotic cells, therefore, have the unfortunate consequence of facilitating tumorigenesis and tumor survival.