Antisense Libraries to Isolate Tumor Suppressor Genes

Apoptosis has become a subject that draws tremendous attention and research efforts in the cancer field, since it has a major impact on tumor initiation, progression, and metastasis. At various stages during the course of tumor development, cells are subjected to stressful conditions that trigger different types of programmed cell death, including the classic type of apoptosis. As a consequence, mutations leading to inhibition of apoptosis confer a selective advantage to cells. In premalignant cells, activation of oncogenes and the consequent hyperproliferation provoke a cellular response that leads to elimination of those cells by apoptosis. Subsequently, transformed cells in the tumor microenvironment are under constant selective death pressure, due to lack of oxygen (hypoxia), depletion of growth/survival factors, attacks by the immune system and often death by anoikis that results from loss of cell-matrix interactions. At later stages, when metastasizing tumor cells enter into circulation, they encounter many additional death-inducing signals, such as superoxides, nitric oxide (NO), killing cytokines, and mechanical shearing forces. Thus, all along the multistage process of tumorigenesis, induction of apoptosis functions as a tumor suppressor mechanism from which cells have to escape in order to survive (reviewed in refs. 1 –3 ). This means that tumor cells should benefit from mutations that either inactivate proteins that positively mediate programmed cell death (PCD) or alternatively abnormally activate antiapoptotic genes.