Research Area

Cancer and Apoptosis


Introduction of apoptosis

Apoptosis is a type of programmed cell death. With respect to cell necrosis, apoptosis is actively performed by cells. Apoptosis is generally induced by physiological or pathological factors, which in turn trigger a series of cellular changes. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. And they lead to characteristic cell changes (morphology) and death. For common multicellular organisms, apoptosis is a normal physiological phenomenon. For example, the average adult human loses between 50 and 70 billion cells each day due to apoptosis; and human child between the ages of 8 and 14, approximately 20 to 30 billion cells die a day. Owing to apoptosis as a physiological process of a determinant of cell fate, its balance is of great importance to the body. For instance, excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. Therefore, apoptosis is rigorously regulated by suppressor and pro-apoptotic factors.

In contrast to necrosis, which is a type of traumatic cell death that results from acute cellular injury, apoptosis is a highly regulated and controlled process that confers advantages during an organism’s life cycle. Specifically, apoptosis is generally brought about by physiological or pathological factors, the necrosis is mainly caused by lack of oxygen, and the two can be readily distinguished by observation. In the process of apoptosis, the cells shrink and the DNA is degraded into 180bp-200bp fragments by endonucleases. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and remove before the contents of the cell can spill out onto the surrounding cells and cause damage to them. When the cells are necrotic, the cells swell, the cell membrane is destroyed, and the permeability changes. The organelles are scattered into the intercellular substance and require removal of macrophages, resulting in inflammation of the local tissue. According to previous studies, apoptosis is a more common form of cell death than cell necrosis. For example, separation fingers and toes in a developing human embryo occur because cells between the digits undergo apoptosis.

Activation Mechanisms

The initiation of apoptosis is tightly regulated by activation mechanisms, because once apoptosis has begun, it inevitably results in the death of the cell. Two best-understood activation mechanisms are the intrinsic pathway (also called the mitochondrial pathway) and the extrinsic pathway. The intrinsic pathway is activated by intracellular signals generated when cells are stressed and depend on the release of proteins from the intermembrane space of mitochondria. The extrinsic pathway is triggered by extracellular ligands binding to cell-surface death receptors, which lead to the formation of the death-inducing signaling complex.

Extrinsic Pathway:

The extrinsic pathway begins with the binding of the receptor to the ligand of the TNF receptor family. These ligands have cancer necrosis factor (TNF), and other cytokines, which can be secreted by T lymphocytes. With the help of FADD (Fas-associated death domain protein), the receptor continuously collects procaspase 8 in the cytoplasm. The latter activates itself through high density autocatalysis. Activated caspase 8 will trigger the so-called caspase cascade.

Intrinsic Pathway:

The intrinsic pathway begins with a tumor suppressor gene such as p53, a transcription factor that is stimulated by DNA damage. P53 stimulates the expression of members of the Bcl-2 family that function before apoptosis, such as Bax, Bad. This will result in the release of substances between the outer and inner mitochondrial membranes, such as cytochrome C and Smac/DIABLO, which are substances that act before apoptosis. Cytochrome C and Apaf-1 and Procaspase 9 in the cytoplasm together form the so-called apoptotic body, which is actually the activated form of caspase 9. It causes the caspases cascade like Caspase 8.

Caspase cascade and effect:

Caspases play the central role in the transduction of ER apoptotic signals. Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases, caspase 2,8,9,10,11,12, and effector caspases, caspase 3,6,7. The activation of initiator caspases requires binding to specific oligomeric activator protein. Effector caspases are then activated by these active initiator caspases through proteolytic cleavage. The active effector caspases then proteolytically degrade a host of intracellular proteins to carry out the cell death program.

Cytochrome C overflows from the mitochondria to the cytoplasm, which is one of the hallmarks of apoptosis. This occurs in the later stages of the apoptotic process in the episodic pathway, where it is instead the result of apoptosis rather than the initiating role played by the intrinsic pathway.

Inhibition

Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. It was originally believed that the associated accumulation of cells was due to an increase in cellular proliferation, but it is now known that it is also due to a decrease in cell death. The most common of these diseases is cancer, the disease of excessive cellular proliferation, which is often characterized by an overexpression of IAP (apoptosis) family members. As a result, the malignant cells experience an abnormal response to apoptosis induction: Cycle-regulating genes (such as p53, ras or c-myc) are mutated or inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in tumors. Some apoptotic factors are vital during mitochondrial respiration e.g. cytochrome C. Pathological inactivation of apoptosis in cancer cells is correlated with frequent respiratory metabolic shifts toward glycolysis.

The Function of Apoptosis

Apoptosis is a necessary path in animal development. Known examples include:

  • Transmutation of insects;
  • Metamorphosis from tadpole to frogs;
  • The apoptosis of the vitreous and crystalline lens cells in the eye is an important step for the eye to penetrate the light;
  • The separation of high mammal’s fingers and toes. Such as, the development of human embryos, the embryo develops flat disc-like limbs sprouting at the 5th week, and the cristae between the fingers and toes disappear and the limbs can form its final shape.

Even in mature individuals, apoptosis is essential:

  • Remove lesions' cells;
  • Cell number and tissue size control;
  • Updates of tissues (eg. nasal olfactory epidermis, replacement of skin epidermal cells);
  • Selection of germ cells (approximately 95% of germ cells will be cleared by apoptosis prior to their maturation);
  • The immune system selects and removes dysfunctional or potentially dangerous cells, such as non-specific cytotoxic effects of natural killer cells (NK) on cancer cells;
  • Gives the nervous system plasticity. For example, the researchers tried to activate the mouse bcl-2 gene during embryonic development. This gene blocks the apoptotic process of nerve cells. As a consequence, the number of neurons in the brain of mice born in mice is greater than that in normal mice, and the volume becomes larger. However, it appeared to be duller than normal mice in the test.

Clinical Significance

Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the down regulation or mutation of proapoptotic proteins such as BAX. At present, there are numerous studies on the relationship between apoptosis and cancer occurrence and various autoimmune diseases. People hope to inspire apoptosis of cancer cells in order to delete cancer.

In addition, the role of apoptosis in neurodegenerative diseases (eg, Alzheimer's disease), Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) is currently a hot topic of research. People are also conducting a lot of research in this field.

References:

  1. Alberts B., et al. Chapter 18 Apoptosis: Programmed Cell Death Eliminates Unwanted Cells. Molecular Biology of the Cell. Garland Science.2008, p. 1115.
  2. Wajant H., The Fas signaling pathway: more than a paradigm. Science.2002, 296 (5573): 1635–6.
  3. Mohamed H., et al. Apoptosis and Molecular Targeting Therapy in Cancer, BioMed Research International.2014, ID 150845.

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