Growth Factors, Cell Proliferation, and Apoptosis

Abstract

It has been known for several years that the number of cells in any population, whether normal or abnormal, depends on both the rate of cell division and the rate of cell death [1]. When the two rates are equal, the cell population is said to be in a steady state; when the rate of cell death exceeds the rate of cell division, atrophy ensues, and conversely, the cell population will increase when the number of cells produced per unit time exceeds the number of cells that die in the same period. More precisely, the three mechanisms that produce an increase in cell number of any given cell population are 1) a shortening of the cell cycle, i.e., the cells divide more frequently; 2) an increase in the number of cells participating in the cell cycle, i.e., the G0 fraction decreases; and 3) a decrease in the rate of cell death. The third mechanism was all but neglected until recently, when apoptosis suddenly became the fashionable way for cells to die. But it was clear several years ago that the rate of cell proliferation was not suf~cient to explain the growth of tumors. When Baserga and Kisieleski [2] showed that one of the fastest-growing tumors of mice did not proliferate faster than the normal cells of the epithelial lining of the small intestine, their results brought home not only an important fact but also a concept. The concept was that the cells of the epithelial lining of the small intestine, while proliferating vigorously, also continuously die, so that, at least in the adult animal, this population is in a steady state. Later, Bresciani et al. [3] showed that, in human squamous cell carcinomas of the skin, tumor cells died in large amounts—unfortunately, not large enough to cause the tumors to regress. These tumors grew because the rate of cell division always exceeded the rate of cell death. Cell death in general and apoptosis in particular occur not only in tumors but also during normal development and aging [4], consequently, we can say that the growth of a cell population, in development or in abnormal growth, always rests on a delicate balance between cell division and cell death. How is this balance achieved? The size of any population of cells, whether normal or abnormal, depends on environmental signals, among which growth factors are the most important. But, until recently, growth factors were looked upon merely as mitogenic agents, or, in the case of inhibitory growth factors, as antimitogenic agents. It is only in recent years that two new aspects of growth factors have been emerging: 1) the association of growth factors with viral oncogenes [5] in mediating the action of these oncogenes; and 2) the ability of growth factors to protect cells from apoptosis [6]. This last property will be the subject of the present article. Since growth factors invariably act through their receptors in determining their effects on cell survival, the terms ligands and receptors will be used interchangeably. This article will place particular emphasis on the role of the insulin-like growth factor 1 (IGF-I) receptor activated by its ligands, since that this receptor seems to transmit not the only but certainly the most effective antiapoptotic signal among the growth factor receptors.