Apoptosis in tumorigenesis and cancer therapy.
Apoptosis is a morphologically and biochemically distinct form of cell death which can be triggered by a variety of extracellular agents during both normal development as well as in adult pathological states. Much progress has recently been made in understanding the molecular pathways which regulate this process as well as new intersections between these. A direct interaction between components of the 'executioner'--the ICE-family of cysteine proteases--and the Bcl-2 family of proteins, which modulate a cell's propensity to undergo apoptosis, has recently been demonstrated. New pathways to cell survival, like the PI3-K/Akt signal transduction pathway, are also providing new clues as to the regulation of cell death by growth factors and extracellular matrix for example. The links which exist between apoptosis and cancer research are several. Genetic alterations in components of the apoptosis pathway occur during tumorigenesis and confer resistance to a variety of physiological (oncogene-induced cell death, loss of adhesion, growth under hypoxia) as well as therapeutic (chemotherapy and radiation) death triggers. Similarly, antineoplastic therapies are thought to induce tumor cell apoptosis, and consequently, common mutations in apoptosis-regulatory genes carry a poor prognosis for the patient. A more detailed understanding of the biochemistry of apoptosis and the ways in which it is disabled in tumors will likely reveal new transformation selective death triggers which stimulate cell death in ways independent of components like p53 and increase the therapeutic window of these drugs in the clinics.
McGill
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Division of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Children's Hospital, Harvard Medical School, 44 Binney St., Boston, MA 02115, USA.
Fisher
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D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015687:Cell Hypoxia; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D009389:Neovascularization, Pathologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D019014:fas Receptor
D000970:Antineoplastic Agents; C491901:FAS protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt