Received 6/15/97 Accepted 6/28/97

The study of apoptosis is relevant to many aspects of tumor biology which include tumorigenesis, tumor homeostasis, angiogenesis, metastasis, and clinical treatment. Malignant cells often harbor mutations in critical components of the apoptotic pathway which may correlate with poor prognosis. Solid tumors must circumvent the apoptotic pathways which regulate their anchorage-dependent survival in order to metastasize and establish secondary tumor sites. Although chemotherapy was long thought to kill tumor cells by inactivating critical metabolic pathways, it is now recognized that many effective chemotherapeutics trigger the tumor into killing itself by activation of an apoptotic pathway. It is therefore of prime importance for the discovery of improved treatments to better understand the molecular underpinnings of the apoptosis machinery. It is crucial to remember, however, that much of the knowledge we have gained has been derived from the study of 'developmental apoptosis' - or programmed cell death - in primitive organisms amenable to genetic manipulation. Given the highly conserved nature of the apoptosis machinery (at least parts of it), uncovering its molecular details using a variety of in vitro and genetic systems will likely provide useful information for cancer therapy.

Apoptosis is a morphologically and biochemically distinct form of cell death which can be likened to 'cellular suicide.' The apoptotic cell actively destroys itself in a manner which will neither harm neighboring cells nor induce an inflammatory response. This physiological process is distinct from necrotic cell death, which occurs as a result of severe cell injury and results in swelling and lysis. The genetically programmed death of cells during normal development is sometimes referred to as "programmed cell death," an example of apoptosis in normal physiology. During the development of most, if not all, multicellular organisms, programmed cell death provides an efficient mechanism whereby unwanted cells are eliminated. Its relevance has been documented in a number of instances which include thymocyte maturation, formation of the (wrongly named) inter digital "necrotic zones" during limb morphogenesis, mammary gland involution, spermatogonial and follicular development, and synaptogenesis during neural development among others. Whereas the death triggers specific for each of these systems are as diverse as the systems themselves, common apoptosis "effector pathways" appear to be conserved throughout evolution from nematodes to vertebrates. Pathways leading to and responsible for this widespread phenomenon have been incessantly populated with new trigger, effector, and inhibitor molecules. Accrued interest in deciphering these pathways has, in part, been sparked by the recent understanding that successful antineoplastic therapies may also operate through induction of tumor cell-specific apoptosis.

This review focuses on aspects of apoptosis research which have gained particular attention in recent years. Advances in the 'executioner' machinery, its substrates, the Bcl-2 family, Fas-induced death, and the PI3-K/Akt pathway are described with particular focus on the use of genetic and in vitro systems to identify new participants. We subsequently provide an overview of the relevance of these topics in understanding issues specific to tumor biology such as tumorigenesis, anchorage-independent survival and metastasis, tumor-induced angiogenesis, and chemotherapy.