To tumor biologists, defective apoptosis is recognized as one of the six pillars upon which cancer occurs and progresses, along with defective cell-cycle regulation, growth factor autonomy, overcoming senescence, angiogenesis and cell invasion and metastasis. Defects in apoptosis contribute to several important aspects of tumor pathogenesis and progression, allowing neoplastic cells to survive beyond their normally intended life spans and thereby promoting clonal expansion, subverting the need for exogenous survival factors, providing protection from hypoxia and oxidative stress as tumor mass expands, and allowing time for accumulative genetic alterations that deregulate cell proliferation, interfere with differentiation, promote angiogenesis and increase cell motility and invasiveness during tumor progression. Apoptosis defects are also recognized as an important complement to protooncogene activation, as many deregulated oncoproteins that drive cell division also trigger apoptosis (e.g., Myc, E1a and cyclin-D1). Defects in apoptosis facilitate metastasis by allowing epithelial cells to survive in a suspended state, without attachment to extracellular matrix. They also promote resistance to the immune system, in as much as many of the weapons cytolytic T-cells and natural killer cells use for attacking tumors depend on integrity of the apoptosis machinery. Finally, cancer-associated defects in apoptosis play a role in chemoresistance and radioresistance, increasing the threshold for cell death, and thereby requiring higher doses for tumor killing.
Apoptosis is a caspase-driven cell death program requiring the activities of a family of evolutionarily conserved intracellular cysteine proteases. Other forms of cell death that do not meet the criterion for apoptosis and that are caspase-independent have also been recognized recently as important facets of tumor biology. Caspase-independent cell death mechanisms, for instance, are induced in the context of death signaling by mitochondria and endoplasmic reticulum. These caspase-independent cell death programs are relevant to the cytotoxic mechanisms of many anticancer drugs and to hypoxic tumor microenviroments. In addition, autophagy is emerging as a newly recognized feature of tumor biology. This ancient catabolic program in which cells ‘eat’ their own organelles and macromolecules to generate fuel for sustaining energy may be decisive for the survival of cancer cells in hostile tumor microenviroments where nutrient deprivation occurs. And yet, in some scenarios, autophagy may kill cancer cells, perhaps explaining why haploinsufficiency of the autophagy gene, Beclin, is a common occurance in some types of human cancers.
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