Apoptosis in Cancer

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Apoptosis in Cancer Background

Apoptosis is a gene-directed process of organized cellular death and disassembly that occurs in individual cells, separate and distinct from necrosis, in which acute cellular injury. Unlike apoptosis, necrosis causes rapid swelling and lysis in groups of affected cells, accompanied by the release of cellular debris, inflammation and the perturbation of neighboring tissues.
Apoptosis has been reported in many cell types. During normal mammalian development, apoptosis participates in the elimination of interdigital webbing, the formation of intestinal villi and in the involution of the spleen and thymus. Differentiation of the retina, deletion of redundant epithelium after fusion of palantine processes, and resorption of connecting tissue around erupting teeth all depend on apoptosis to remove cells that are no longer essential. Apoptosis also occurs in slowly proliferating adult tissues such as the pancreas, prostate, adrenal cortex and liver epithelium, as well as rapidly proliferating adult tissues such as seminiferous tubules, lymphoid germinal centers, and crypts of the gastrointestinal mucosa. The involution of certain endocrine-dependent tissues rely on apoptosis, for example the progesterone-induced involution of the cat oviduct. It also stimulates the involution of endocrine-dependent tissues following the withdrawal of hormone stimulus, such as human premenstrual endometrium tissue, ovarian blood vessels, uterine luminal epithelium and breast tissue.

In response to a multitude of inducers, apoptosis is critical to cellular repair following trauma. Hypoxia-induced cell death in neuronal cells and cardiomyocytes, ischemia-induced cell death in liver tissue, and atrophy of exocrine pancreatic tissue following duct obstruction all demonstrate apoptotic cell death during the pathogenesis of human disease. Apoptosis has also been observed in human malignant neoplasms, such as gastric carcinoma, squamous cell carcinoma of the oral cavity, basal cell carcinoma, primary central nervous system lymphoma, and several melanomas .
Apoptosis has many crucial purposes in the body, including the maintenance of tissue homeostasis, supporting embryo and tissue development, limiting cellular proliferation in endocrine-dependent tissues and removing senescent, diseased or damaged cells in response to injury or mutation. The consequence of these diverse cellular circumstances is apoptosis, a coordinated cellular program of morphological and biochemical events that direct programmed cell death. During this programmed cell death or apoptosis, individual cells undergo a series of morphological changes that culminate with an organized removal of apoptotic bodies by phagocytes.

Initially, protein and RNA synthesis within the apoptotic cell increase and internucleosomal DNA cleavage occurs inside the nucleus. The internucleosomal cleavage of double-stranded DNA by a calcium- and magnesium-dependent (Ca²⁺/Mg²⁺) endogenous endonuclease occurs in the short linker regions of DNA between nucleosomes resulting in numerous double stranded DNA fragments 200 base pairs in length. The nuclear accumulation of Ca²⁺ is a requirement for the activation of the endogenous endonuclease and depends upon an ATP- and calmodulin-dependent Ca²⁺ uptake system in the cell. The linker regions are not within the nucleosome and therefore are not protected by histone proteins from cleavage by the endonuclease, such that cleavage results in a characteristic apoptotic DNA ladder during agarose gel electrophoresis. When DNA from apoptotic cells undergoes agarose gel electrophoresis, a ladder of bands results in which each rung of the ‘ladder’ corresponds to DNA fragments that are multiples of the 200 base pair fragment length, for example, DNA fragments representing 400, 600, 800 and 1000 base pairs in length appear.

Subsequently, the DNA fragments compact and segregate into masses that appear to cluster along the inner nuclear envelope. During this process, nuclear and cytoplasmic condensation occurs via the extrusion of water from the cell causing an increase in cell density. Cytoplasmic condensation causes the cell to round up and pull away from adjacent cells thereby interrupting cell-to-cell contact. The redistribution of cytoplasmic microfilaments causes protuberances to form on the cell surface during cell shrinkage, followed by the fragmentation of the cell into apoptotic bodies.
Cellular fragmentation results in the formation of many membrane-bound, dense apoptotic bodies. Some apoptotic bodies contain structurally and biochemically intact mitochondria, while others contain cellular components such as condensed nuclear chromatin, organelle remnants and cytoplasmic vacuoles. The contents of the apoptotic bodies depends upon the cellular constituents present in the area proximal to the protuberance that gave rise to the particular apoptotic body.

Apoptosis-specific carbohydrate moieties on the surface of the apoptotic bodies enable their rapid recognition and subsequent removal by phagocytosis. Apoptotic bodies that have been engulfed by phagocytes are degraded by secondary necrosis within the phagosomes. Secondary necrosis is similar to necrosis, with swelling and bursting of organelles and degradation by enzymes of the apoptotic body constituents.

The complete dismantling of an apoptotic cell over the course of several hours occurs in an orderly, efficient manner that is dependent upon the execution of apoptotic pathways. The pathways are stimulated by pro-apoptotic stimuli and culminate in the activation of proteases that demolish the cell. The signaling events that lead to apoptosis are subject to inhibition by numerous genes, although once stimulated, apoptosis is an irreversible cellular event.

Apoptosis pathways

Apoptosis may be initiated by two different pathways, the extrinsic pathway which responds to extracellular signals or the intrinsic pathway activated by intracellular modulators. The two independent pathways converge into a central effector pathway termed the caspase cascade. Within the cascade, the activation of numerous proteases dismantle the cell to complete the apoptosis paradigm.

The activation of apoptosis occurs in large, specialized protein complexes, the death inducing signal complexes (DISCs) of the extrinsic pathway or in the mitochondria for the intrinsic pathway, as discussed in detail later in this section. The binding of extracellular ligands to their specific transmembrane receptors stimulates the assembly of DISCs in the extrinsic pathway which activate the caspase cascade. In the intrinsic pathway, intracellular signals stimulate the release of cytochrome c into the cytosol from the intermembrane space of the mitochondria, initiating the assembly of the apoptosome, where, analogous in function to DISC, the apoptosome activates the caspase cascade. A third apoptosis pathway exists in the cell, yet it is distinct from the extrinsic and intrinsic pathways of interest in this research. Within this third pathway, cytotoxic granules containing granzyme B released from cytotoxic T lymphocytes (CTL) and Natural Killer (NK) cells during encounters with transformed or virally-infected cells infiltrate the cell, where intracellular granzyme B activates the caspase cascade via tBid, a member of the Bcl2 oncogene family.

The caspase cascade, whether activated by the extrinsic apoptosis pathways or the intrinsic apoptosis pathway is a hierarchical system. Specific proteases, known as initiator or apical caspases, recruit and activate downstream proteases called executioner caspases. Executioner caspases form the molecular demolition crew that interrupt the cell cycle and dismantle the cellular constituents.

 

Apoptosis reference

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