Apoptosis The regulation and maintenance of normal tissue requires a balance between cell proliferation and programmed cell death, or apoptosis. When proliferation exceeds programmed cell death, the result is hyperplasia. When programmed cell death exceeds proliferation, the result is atrophy. Programmed cell death is a crucial concomitant of normal embryologic development. This mechanism accounts for deletion of the interdigital webs, palatal fusion, and development of the intestinal mucosa (16–18). Programmed cell death is also an important phenomenon in normal physiology (19). The reduction in the number of endometrial cells following alterations in steroid hormone levels during the menstrual cycle is, in part, a consequence of programmed cell death (20,21). In response to androgens, granulosa cells undergo programmed cell death (e.g., follicular atresia) (22).
Programmed cell death, or apoptosis, is an energy-dependent, active process that is initiated by the expression of specific genes. This process is distinct from cell necrosis, although both mechanisms result in a reduction in total cell number. In programmed cell death, cells shrink and undergo phagocytosis. Conversely, groups of cells expand and lyse when undergoing cell necrosis. The process is energy independent and results from noxious stimuli. Programmed cell death is triggered by a variety of factors, including intracellular signals and exogenous stimuli such as radiation exposure, chemotherapy, and hormones. Cells undergoing programmed cell death may be identified on the basis of histologic, biochemical, and molecular biologic changes. Histologically, apoptotic cells exhibit cellular condensation and fragmentation of the nucleus. Biochemical correlates of impending programmed cell death include an increase in transglutaminase expression and ﬂuxes in intracellular calcium concentration (23).
Programmed cell death emerged as an important factor in the growth of neoplasms. Historically, neoplastic growth was characterized by uncontrolled cellular proliferation that resulted in a progressive increase in tumor burden. It is recognized that the increase in tumor burden associated with progressive disease reﬂects an imbalance between cell proliferation and cell death. Cancer cells fail to respond to the normal signals to stop proliferating, and they may fail to recognize the physiologic signals that trigger programmed cell death.
Modulation of Cell Growth and Function
The normal cell exhibits an orchestrated response to the changing extracellular environment. The three groups of substances that signal these extracellular changes are steroid hormones, growth factors, and cytokines. The capability to respond to these stimuli requires a cell surface recognition system, intracellular signal transduction, and nuclear responses for the expression of specific genes in a coordinated fashion. Among the genes that participate in control of cell growth and function, proto-oncogenes and tumor suppressor genes are particularly important. More than 100 proto-oncogene products that contribute to growth regulation have been identified (24) (Table 6.1). As a group, proto-oncogenes exert positive effects upon cellular proliferation. In contrast, tumor suppressor genes exert inhibitory regulatory effects on cellular proliferation (Table 6.2).
Steroid Hormones Steroid hormones play a crucial role in reproductive biology and in general physiology. Among the various functions, steroid hormones inﬂuence pregnancy, cardiovascular function, bone metabolism, and an individual’s sense of well-being. The action of steroid hormones is mediated via extracellular signals to the nucleus to affect a physiologic response.