Anchorage dependence, integrins, and apoptosis

Abstract

Understanding of the anchorage-dependent phenomenon may be closer; two papers (Meredith et al., 1993; Frisch and Francis, 1994) show that cells denied anchorage can undergo apoptosis and implicate integrin-mediated signaling as the controlling factor in this phenomenon. It has long been known that most types of normal cells require attachment to a substrate to be able to grow and that this dependence on anchorage is reduced in malignantly transformed cells (Folkman and Moscona, 1978). Recent work indicates that anchorage-dependent cells grown in suspension are arrested in the Gl phase and that failure to induce cyclin A may be responsible for the growth block (Guadagno et al., 1993). As integrins are primarily responsible for adhesion to extracellular matrices, it is not surprising that they would be involved in anchorage dependence. However, the novel and exciting results relate to apoptosis and the role of integrin signaling in controlling the apoptotic response. Apoptosis is an important homeostatic mechanism that maintains correct cell numbers in the body by balancing cell production with cell death. Tumor cells can gain a selective growth advantage by blocking the apoptotic pathway (Reed, 1994). Conversely, increased apoptosis leads to organ involution that is sometimes physiological, as in the postlactating breast gland, or pathological, as in various degenerative diseases of the central nervous system. The findings in Meredith et al. (1993) and Frisch and Francis (1994) suggest that apoptosis may also control cell positioning. They show that normal endothelial and epithelial cells undergo apoptosis when the cells are detached from substrate with RGD peptides or attachment is prevented by growing the cells in suspension (Figure 1). Frisch and Francis (1994) name this phenomenon anoikis (pronounced an-o-EE-kis), a term derived from the Greek word for homelessness. The anoikis phenomenon implies that once a differentiated epithelial cell loses contact with its underlying matrix, it dies. This may prevent detached cells from establishing themselves in a new and perhaps inappropriate position or location. In agreement with the idea that anchoragedependent apoptosis would be important to cell positioning, the apoptotic response appears to be limited to epithelial and endothelial cells to the exclusion of fibroblasts. This mechanism may operate in the normal maturation of the skin, where the cells that abut the basement membrane proliferate, while the ones that move away from it to the more superficial layers become apoptotic (Adams and Watts, 1993). Given that bcC2 cDNA transfer was shown by Frisch and Francis (1994) to block anoikis, it Minireview