Apoptosis and Programmed Cell Death in Health and Disease

https://doi.org/10.1016/S0065-2423(08)60336-4Get rights and content

Introduction

Apoptosis is a concept that may be considered as one of the most formidable in biology, whose significance is equivalent to that of the cell cycle.

L. D. Tomei and F. O. Cope (T7)

Death is one of life’s only two certainties. This fact is applicable to all living organisms, as it is to individual cells. Traditionally, biologists considered cell death to be the result of aging or accidental damage, including hypoxia and a wide variety of chemical or physical insults. Pathologists use for the phenomenon of cell death the classical term “necrosis” for cell degradation caused by any form of insult to the integrity of the cell.

The concept of a deliberate cell death, due to activation of an energyconsuming endogenous cell suicide mechanism, has only recently been recognized U1, W16. Such a physiological death of cells was described originally in the normal development of vertebrates in 1951 by Glücksmann (G3) and of invertebrates in 1966 by Saunders (S7). These authors postulated from their observations about cell deletion, during metamorphosis of amphibia and during regression of larval organs, the existence of a concerted cell death program. They recognized programmed cell death as an adaptive mechanism by which unwanted or useless cells are eliminated. In the past one has become aware that extensive programmed cell death occurs not only during normal embryonic and fetal development; it appears to be a widespread phenomenon, a dynamic balance between cell proliferation and cell elimination, to which the homeostatic control of cell numbers is attributed. Programmed cell death is responsible for the discrete deletion of useless, unwanted, or crippled cells in every tissue, in organ remodeling, in canalization of ducts, and in fashioning of the body (e.g., formation of the digits, or fusion of the palatal shelves).

Kerr et al. (K9) in 1972 were the first to describe the ultrastructural changes that can be observed in cases of cell necrosis and programmed cell death. They introduced the term “apoptosis” as opposite that of mitosis. Apoptosis is derived from the Greek word that indicates the “falling off” of leaves from trees or petals from flowers. At present the term “apoptosis” is often considered synonymous with programmed cell death such as it occurs during embryonic and morphogenetic development. Although it appears to be a matter of semantics, the casual transposition of the two concepts may lead to undesirable confusion. Programmed cell death is an operational definition of the concerted program of cell elimination necessary in the development of individuals and organs during the processes of metamorphosis, embryogenesis, and morphogenesis. Apoptosis is a morphological and biochemical description of a physiological cell death mechanism, which does not necessarily include programming.

Apoptosis is implicated in cell turnover in normal adult tissues such as intestinal crypts and in the hematopoietic system. It occurs during the evolution of hormone-dependent organs e.g., (prostrate, endometrium, and mammary tissue). Neutrophils undergo apoptosis during resolution of the inflammatory reaction, lymphocytes in the regulation of the immune system. Cell injury due to a variety of agents e.g., (radiation, viruses, thermic injuries, and chemotherapeutic cytotoxic insults) may also lead to apoptosis. Finally, apoptosis has also been demonstrated in premalignant and malignant tissues (K7).

Necrosis, or accidental cell death, occurs in response to harmful insults such as physical damage, hypoxia, hyperthermia, complement attack, and chemical injury. The earliest morphological changes which occur are swelling of the cytoplasm and organelles, including the mitochondria. These changes are the expression of the loss of selective permeability of the cytoplasmic membrane, due to depletion of cellular energy, membrane ion-pumping activities, or direct physical or chemical membrane damage. This demolition results in total dissolution of the organelles, leaking of cellular contents into the extracellular space, and finally complete rupture and disappearance of the cytoplasmatic membranes. Activation of enzymes such as hydrolases, phospholipases, proteases, RNases, and DNases results in degradation of membranes, proteins, RNA, and DNA, which accelerates the cellular disintegration. Necrosis affects tissue areas or at least groups of contiguous cells and elicits an inflammatory reaction in the adjacent viable tissues in response to the released cell debris (Table 1).

In contrast to necrosis, apoptosis shows a morphologically distinct pattern of cell resolution. The earliest changes of apoptosis include the loss of cell junctions and specialized membrane structures such as the microvilli. The cytoplasma condenses and the nucleus coalesces into several large masses, which then break up into fragments. The mitochondria initially remain apparently intact. The endoplasmic reticulum transforms into vesicles that fuse with the cytoplasma membrane and void their contents extracellularly. These processes result in contraction of the cytoplasmic volume, associated with the loss of intracellular fluid and ions. The cell transiently adopts a convoluted outline and subsequently breaks up into several apoptotic bodies that contain a variety of intact cytoplasmic organelles and some nuclear fragments. These apoptotic bodies vary in size and are phagocytosed by nearby cells. The engulfing cells belong mostly to the mononuclear-phagocyte system, but also epithelial, endothelial, and even tumor cells may be involved in the phagocytosing of the apoptotic bodies. It has been recognized that apoptotic bodies themselves provide a stimulus for phagocytosis by exposure of normally hidden sugar moieties or by movement of inner membrane phospholipids such as phosphatidylserine to the external surface of the membrane. Once ingested, the apoptotic bodies undergo rapid degradation.

The cellular fragmentation occurs within several minutes. The rapid cell degradation, along with the facts that apoptosis affects only single cells in an asynchronous fashion and that the process does not induce any inflammatory reaction, makes it difficult to observe the process and explains why apoptosis has not been recognized earlier. A cell undergoing necrosis or apoptosis exhibits typically distinctive morphological and biochemical characteristics, as reviewed by Wyllie et al. (W16) and Trump et al. (T9). The most prominent features are schematically presented in Fig. 1.

Apoptosis takes place during embryogenesis, during the development of the nervous and immune systems, in the course of normal tissue turnover, and after withdrawal of a trophic hormone from the target tissue. Furthermore, apoptosis can also be produced by various pathological stimuli. In general, any event that produces necrosis by direct cell destruction e.g., (toxins or radiation) can induce apoptosis if the cell initially survives.

Recently, comprehensive reviews have been published by Ellis et al. (E3), Raff (R2), Schwartzman and Cidlowski (S20), and Carson and Ribeiro (C2). In Table 1 the most prominent features of apoptosis and necrosis are summarized, together with the ultrastructural and biochemical differences between these two modes of cell death.

An important characteristic of apoptosis is that it is induced by withdrawal of tissue or cell-specific mitogens B17, B18, K27, K29, W16. Otherwise, the occurrence of apoptosis is inhibited by cell-specific hormones, growth factors, and mitogens. In mammals apoptosis is observed during tissue involution, for example, in the uterus after delivery, in the breast gland after weaning, in a liver lobe after ligation of the portal blood supply, and in the whole liver after starvation or during regression of liver hyperplasia (B19). Apoptosis is also prominent in certain tissues undergoing atrophy as a result of withdrawal of hormones. Hypophysectomy induces apoptosis in the adrenal cortex, the thyroid gland, and other endocrine organs. Apoptosis occurs in endometrial cells deprived of steroid hormones (S4) and in the prostatic glandular acini after orchidectomy K27, W16. Some types of neurons die in response to deprivation of nerve growth factor (NGF) (L9). Mature T lymphocytes undergo apoptosis when deprived of interleukin-2 (IL-2) B13, D20. While some hormones act to prevent the apoptotic death of susceptible cells, others trigger apoptosis, such as corticosteroids in thymocytes and lymphocytes W10, W16. In all of these examples, the signals that either trigger or prevent the apoptotic death also control other aspects of the growth and development of susceptible cells. In other words, both cell replication and cell death are regulated in concert to produce growth and cell regression and balance the size of organs (Fig. 2).

Cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and tumor necrosis factor secreted by lymphocytes and macrophages are able to trigger apoptosis in many cell types. Otherwise, various types of growth factors, such as hematopoietic colony-stimulating factors, fibroblast growth factor, platelet-derived growth factor, NGF, insulin-like growth factor-III, and IL-2, inhibit susceptible cells to undergo apoptosis. The factors that characteristically induce or inhibit the occurrence of apoptosis are summarized in Table 2.

One may speculate about the advantages of cell survival, dependent on signals produced by other cells. One is that it could provide a mechanism for eliminating cells that end up in an abnormal location. For example, when a needle is inserted into the skin or when tissue is lacerated, cells are displaced or eventually may become transported to the lung, where they could cause trouble if they survived and proliferated. The same mechanism may prevent hematopoietic stem cells from proliferating outside the bone marrow or cancer cells from establishing metastases. Another advantage of cell survival being dependent on the presence of specific growth factors is the control of the total number of distinct cell types, because they must compete for limiting amounts of growth factors, establishing a continuous selection for the most competitive and vital cells. The present knowledge about the regulators of apoptosis is summarized in Table 3.

It is obvious that this introduction provides only a simplified model of a very complicated system that triggers or inhibits the occurrence and regulates the extent of apoptosis in the various tissues. Excellent reviews with more detailed information have recently been published by Anilkumar et al. (A9), Alison and Sarraf (A4), Bursch et al. (B19), and Schwartzman and Cidlowski (S20).

Section snippets

PROGRAMMED CELL DEATH IN Caenorhabditis elegans

The most direct evidence that cell death in animals may be initiated by the activation of a suicide program, coded in the DNA, comes from studies in the nematode Caenorhabditis elegans E3, Y4. The patterns of cell divisions and cell death in this nematode have been studied by direct observations of the living C. elegans K10, S40, S41. Four features of C. elegans make it an excellent organism for the study of cell death: (1) the cell divisions and cell death of individual cells can be observed

Mechanism of Apoptosis

As discussed earlier, apoptosis was originally defined on the basis of its morphology. However, the similarities in the morphology of cell death in different examples of apoptosis suggest that the biochemical mechanisms might also be common in all cell types. Unfortunately, our understanding of the common biochemical events of apoptosis is still fragmentary. This knowledge gap between morphology and biochemistry is partly due to a methodological problem: the lack of a general experimental model

Measurement of Apoptosis

Pathologists have repeatedly reported individual cell disintegration with the characteristic morphology of apoptosis as a constant finding in malignant tissues (W15). Still, there is surprisingly little quantitative information about the relative frequency and significance of apoptosis in human neoplastic tissues, in contrast to the large amount of data about the proliferative activity in all types of malignancies (L8). The very nature of apoptotic cell death promotes the underrecognition of

Clinical Significance of Apoptosis

The mechanism of apoptosis has long been neglected in clinical research and in clinical thinking. Nevertheless, programmed cell death offers an understanding of a number of pathological syndromes and clinical observations, which otherwise cannot be explained by well-known biological processes. Such phenomena relate to the involution of certain tissues after hormonal deprivation, ineffective hematopoiesis in myelodysplastic syndromes, lymphocytolysis after adrenocorticoid therapy, massive cell

Future Developments

Apoptosis is an efficient system in cell biology to eliminate superfluous, unwanted, altered, aged, or transformed cells without eliciting damage to adjacent normal cells or surrounding tissues. Apoptosis serves for the selective

deletion of cells whose survival would compromise the consistency of the organism as a whole. It warrants, during embryogenesis, the molding of tissues, fashioning of limbs, coring of vessels and channels, and optimal development of the nervous system. In adult life it

ACKNOWLEDGMENTS

We are indebted to Sia Timmerman and Nicole Bossink for their unfailing assistance in the preparation of the manuscript. Their dedication and expert skill are gratefully acknowledged.

First page preview

First page preview
Click to open first page preview

REFERENCES (347)

  • P.L. Cohen et al.

    The lpr and gld genes in systemic autoimmunity: Life and death in the Fas lane

    Immunol. Today

    (1992)
  • J.E. Coligan et al.

    Structure of thrombospondin

    J. Biol. Chem.

    (1984)
  • M.M. Compton et al.

    Identification of a glucocorticoid-induced nuclease in thymocytes. A potential “lysis gene” product

    J. Biol. Chem.

    (1987)
  • M.M. Compton et al.

    Thymocyte apoptosis. A model of programmed cell death

    Trends Endocrinol. Metab.

    (1992)
  • E.H. Cooper et al.

    Cell death in normal and malignant tissues

    Adv. Cancer Res.

    (1975)
  • W.M. Cowan

    Neuronal death as a regulative mechanism in the control of cell number in the nervous system

  • M. Dean et al.

    Regulation of c-myc transcription and mRNA abundance by serum growth factors and cell contact

    J. Biol. Chem.

    (1986)
  • G. DelBino et al.

    The S-phase cytotoxicity of camptothecin

    Exp. Cell Res.

    (1991)
  • C.W. Distelhorst

    Glucocorticosteroids induce DNA fragmentation in human lymphoid leukemia cells

    Blood

    (1988)
  • C. Dive et al.

    Analysis and discrimination of necrosis and apoptosis programmed cell death) by multiparameter flow cytometry

    Biochim. Biophys. Acta

    (1992)
  • S. Durant et al.

    Calcium and A23187-induced cytolysis of mouse thymocytes

    Biochem. Biophys. Res. Commun.

    (1980)
  • H.M. Ellis et al.

    Genetic control of programmed cell death in the nematode

    C. elegans. Cell

    (1986)
  • G.I. Evan et al.

    Induction of apoptosis in fibroblasts by c-myc protein

    Cell

    (1992)
  • A. Facchinetti et al.

    An improved method for the detection of DNA fragmentation

    J. Immunol. Methods

    (1991)
  • A.I. Farbman

    Electron microscope study of palate fusion in mouse embryos

    Dev. Biol.

    (1968)
  • L. Fesus

    Apoptosis

    Immunol. Today

    (1992)
  • V.N. Afanasyev et al.

    Flow cytometry and biochemical analysis of DNA degradation characteristics of two types of cell death

    FEBS Lett.

    (1986)
  • V.N. Afanasyev et al.

    The use of flow cytometry for the investigation of cell death

    Cytometry

    (1993)
  • J.E. Albina et al.

    Nitric oxide-mediated apoptosis in murine peritoneal macrophages

    J. Immunol.

    (1993)
  • M.R. Alison et al.

    Apoptosis: A gene-directed programme of cell death

    J. R. Coll. Physicians London

    (1992)
  • R.D. Allen et al.

    Differences defined by bone marrow transplantation suggest that 1pr and gld are mutations of genes encoding an interacting pair of molecules

    J. Exp. Med.

    (1990)
  • E.S. Alnemri et al.

    Involvement of BCL-2 in glucocorticoid-induced apoptosis of human pre-B-leukemias

    Cancer Res.

    (1992)
  • J.C. Ameisen

    Programmed cell death and AIDS: From hypothesis to experiment

    Immunol. Today

    (1992)
  • J.C. Ameisen et al.

    Cell dysfunction and depletion in AIDS: The programmed cell death hypothesis

    Immunol. Today

    (1991)
  • T.V. Anilkumar et al.

    The biology and pathology of programmed cell death apoptosis)

    Vet. Hum. Toxicol.

    (1992)
  • M.J. Arends et al.

    Apoptosis. The role of the endonuclease

    Am. J. Pathol.

    (1990)
  • A.S. Asch et al.

    Isolation of the thrombo-spondin membrane receptor

    J. Clin. Invest.

    (1987)
  • S.J. Baker et al.

    Suppression of human colorectal carcinoma cell growth by wild-type p53

    Science

    (1990)
  • A. Bakhshi et al.

    Cloning the chromosomal breakpoint of t14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18

    Cell

    (1985)
  • K.J. Ballard et al.

    Cytological and cytochemical studies on cell death and digestion in foetal rat foot: The role of macrophages and hydrolytic enzymes

    J. Cell Sci.

    (1968)
  • M.A. Barry et al.

    Etoposide-induced apoptosis in human HL-60 cells is associated with intracellular acidification

    Cancer Res.

    (1993)
  • D.V. Basile et al.

    Programming of cells for death under defined experimental conditions: Relevance to the tumor problem

    Proc. Natl. Acad. Sci. U.S.A.

    (1973)
  • G.D. Baxter et al.

    Cell death by apoptosis in acute leukaemia

    J. Pathol.

    (1989)
  • A.C. Begg et al.

    A method to measure the duration of DNA synthesis and the potential doubling time from a single sample

    Cytometry

    (1985)
  • S. Bettuzzi et al.

    Identification of an androgen-repressed mRNA in rat ventral prostate as coding for sulphated glycoprotein 2 by cDNA cloning and sequence analysis

    Biochem. J.

    (1989)
  • C.J. Bishop et al.

    T lymphocytes in infectious mononucleosis. II. Response in vitro to interleukin-2 and establishment of T cell lines

    Cin. Exp. Immunol.

    (1985)
  • S. Brenner

    The genetics of

    Caenorhabditis elegans. Genetics

    (1974)
  • S. Bruno et al.

    Apoptosis of rat thymocytes triggered by prednisolone, camptothecin, or teniposide is selective to G0 cells and is prevented by inhibitors of proteases

    Oncol. Res.

    (1992)
  • P.E. Budtz et al.

    Epidermal tissue homeostasis: Apoptosis and cell migration as mechanisms of controlled cell deletion in the epidermis of the toad

    Bufo bufo. Cell Tissue Res.

    (1989)
  • W. Bursch et al.

    Controlled death apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters

    Carcinogenesis

    (1984)
  • Cited by (0)

    View full text