Journal of Clinical Oncology, Vol 17, Issue 9
(September), 1999: 2941
© 1999 American Society for Clinical Oncology
Dysregulation of Apoptosis in Cancer
John C. Reed
From the The Burnham Institute, La Jolla, CA.
Address reprint requests to John C. Reed, MD, PhD, The Burnham Institute, 10901 North Torrey Pines Rd, La Jolla, CA 92037
ABSTRACT
ABSTRACT: Each day, approximately 50 to 70 billion cells perish in the average adult because of programmed cell death (PCD). Cell death in self-renewing tissues, such as the skin, gut, and bone marrow, is necessary to make room for the billions of new cells produced daily. So massive is the flux of cells through our bodies that, in a typical year, each of us will produce and, in parallel, eradicate a mass of cells equal to almost our entire body weight. The morphologic ritual cells go through when experiencing PCD has been termed apoptosis and is executed by a family of intracellular proteases, called caspases. Unlike accidental cell deaths caused by infarction and trauma, these physiologic deaths culminate in fragmentation of cells into membrane-encased bodies which are cleared through phagocytosis by neighboring cells without inciting inflammatory reactions or tissue scarring. Defects in the processes controlling PCD can extend cell life span, contributing to neoplastic cell expansion independently of cell division. Moreover, failures in normal apoptosis pathways contribute to carcinogenesis by creating a permissive environment for genetic instability and accumulation of gene mutations, promoting resistance to immune-based destruction, allowing disobeyance of cell cycle checkpoints that would normally induce apoptosis, facilitating growth factor/hormone–independent cell survival, supporting anchorage-independent survival during metastasis, reducing dependence on oxygen and nutrients, and conferring resistance to cytotoxic anticancer drugs and radiation. Elucidation of the genes that constitute the core machinery of the cell death pathway has provided new insights into tumor biology, revealing novel strategies for combating cancer.
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