Last year, the Nobel Prize in medicine was awarded to Sidney Brenner, H. Robert Horvitz, and John Sulston, in part for their elucidation of the genetics of programmed cell death using Caenorhabiditis elegans as a model organism. It is fitting therefore that this issue of ONCOGENE is devoted to reviews on apoptosis, from a cancer perspective. Furthermore, I am honored to have served as organizing editor for this special edition.
The study of programmed cell death, and its morphological equivalent, apoptosis, has emerged as one of the fastest growing areas of biomedical research today, as tracked by the number of publications devoted to the topic, according to the Institute for Scientific Information. 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 in several important ways to tumor pathogenesis and progression, allowing neoplastic cells to survive beyond their normally intended lifespans 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 proto-oncogene activation, as many deregulated oncoproteins that drive cell division also trigger apoptosis (e.g. Myc; E1a; 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 (CTLs) and Natural Killer (NK) 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.
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