Apoptosis, senescence, immortalization and cancer

Abstract

Apoptosis is a definite cellular genetic programme, like quiescence, proliferation or differentiation. Some organs or tissues of the embryo are necessariIy restricted to a determinate period of development, and they have to be eliminated, like mammalian brachial arcs during embryogenesis, tadpole tails in amphibians during metamorphosis, etc. (for a general review see Arends et al. [l]). However, the phenomenon is far from being limited to development and many adult tissues, with high cell turn-over, continuously use this mechanism for cell renewal, like gut mucosa, immunohematopoietic system and skin. At a molecular genetic level, the phenomenon has been well studied in the nematode Caenorhabditis efegans. This worm is composed of only 1090 cells, 13 1 of which are destined to apoptosis. Apoptosis inducing (ted-3 and ted-4), as well as apoptosis protection (ted-9) genes, have been identified and cloned [2]. Ced-9 is so similar to the vertebrate apoptosis protector gene bcl-2, that the latter can substitute for ted-9 in the worm, with identical aoptosis protection functions [3]. The final events of apoptosis are rapid evolving processes, lasting less than 1 h [l]: the most relevant of them are the loss of specialized surface structures, the reduction of the volume (determining a high increase in cell density), surface blebbing, elimination of apoptotic bodies, transformation of the plasma membrane in a kind of rigid shell owing to protein cross-link by transglutaminase, nuclear picnosis, fragmentation and eventually elimination. As opposed to necrosis (see Table I), in the early stages, apoptotic cells are impermeable to vital dyes such as Trypan blue [4]. In vivo, the final event is the engulfment by a neighbouring cell and elimination by phagocytosis without release of inflammatory substances which are characteristic of necrotic cell death. There are reasons to believe that these short-lasting events may be preceded by the expression of genetically programmed changes before they occur 12 h later.