Download Radiobiology Lec:3 Stage:2 3.Cell death after irradiation

Radiobiology
Lec:3
Stage:2
3.Cell death after irradiation
The effects of radiation on the human population can be classified as
either somatic or genetic:
1-Somatic effects are harm that exposed individuals suffer during their
lifetime, such as radiation induced cancers (carcinogenesis), sterility,
opacification of the eye lens and life shortening.
2-Genetic or hereditary effects are radiation induced mutations to an
individual’s genes and DNA that can contribute to the birth of defective
descendants.
- Carcinogenesis expresses itself as a late somatic effect in the form of
acute or chronic myeloid leukaemia or some solid tumours, for example
in the skin, bone, lung, thyroid or breast.
- Radiation is a known teratogen (i.e. it causes birth defects). The effects
of radiation on the foetus depend on two factors: the dose and the stage of
development at the time of exposure. The principal effects of radiation on
a foetus are foetal or neonatal death, malformations, growth retardation,
congenital defects and cancer induction.
-An abortion to avoid the possibility of radiation induced congenital
abnormalities should be considered only when the foetal dose has
exceeded
10cGy.
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3.1.How cells die?
It is now clear that cells can die by many different mechanisms following
irradiation. Increased attention to the mechanisms of cell death occurred
following the discovery of a genetically ‘programmed’ form of cell death
known as apoptosis.
This form of cell death results in rapid and normally complete
destruction and removal of the cell, and is considered as a ‘choice’ made
by the cell itself often as a consequence of damage, stress or as a barrier
against tumorigenesis.
Since the discovery of apoptosis, several other pathways under genetic
control have been identified that can contribute to loss of reproductive
capacity after irradiation, including: autophagy, senescence, and
necrosis.
Each of these pathways can potentially contribute to radiosensitivity.
Importantly, the pathways that control these programmed forms of cell
death are differentially activated in different tissue types, and are
frequently altered in cancer. Consequently, differential activation of cell
death pathways constitutes a main contributor to variation in radiation
response among different cells, tumors, and tissues.
3.2.Apoptosis
Is defined as programmed cell death, which occurs very systematically
and lead to elimination of cells without releasing harmful substances into
the surrounding area.
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Apoptosis plays a crucial role in developing and maintaining the health of
the body by eliminating old cells, unnecessary cells, and unhealthy cells.
Too little or too much apoptosis can play a role in many diseases .
Apoptosis is an important cellular defence against cancer development
and loss of apoptotic sensitivityis recognized as an essential hallmark of
cancer.
Apoptosis can be initiated either as a result of conditions occurring within
the cell itself (such as those after DNA damage) or from signals generated
externally such as those from a surrounding tissue or immune cell.
During apoptosis, the cells are disassembled very systematically. They
detach from the neighboring cells of the tissue and its protoplasm
condenses.
The membrane-bound organelles such as mitochondria disintegrate by
releasing its contents into the cytoplasm.
The enzymes, endonucleases, act on the chromatin materials and break
the DNA into fragments. At the final stage, the cell membrane starts
forming blebs and the cell fragments into apoptosis bodies.
In these cells, p53 induction of BAX is sufficient to cause cytochrome
crelease from the mitochondria and induction of apoptosis. Thus, the
importance of apoptosis and the genes controlling it such as p53 is highly
context dependent.
During this process, cellular contents are also fragmented into many
membrane-enclosed apoptotic bodies, which, in vivo, are taken up by
phagocytes (Figure3.1).
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Figure3.1: Cell surface blebbing and apoptotic bodies phagocytosis
3.3.Necrosis
Is an inappropriate or accidental death that occurs under conditions
that are extremely unfavorable, such as those incompatible with a critical
normal physiological process (like: extreme changes in pH, energy loss
and ion imbalance). It is death by injury, which occurs under pathogenic
conditions or deficiencies.
Necrosis characterized by cellular swelling, membrane deformation,
organelle breakdown and the release of lysosomal enzymes, which attack
the cell (Figure3.2). These conditions can occur following infection,
inflammation. Also, frequently observed in human tumors and can be
induced following treatment with DNA-damaging agents, including
radiation.
Induction of necrosis dependent on cell stress and cell signalling
including oxidative stress, calcium levels and p53 activation have been
shown to influence lysosomal membrane permeability. Permeabilization
leads to intracellular acidification and release of various enzymes that can
promote necrosis.
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Figure3.2:Comparison between apoptosis and necrosis
3.4.Autophagy
Is a term that means ‘self-eating’ and describes a process in which cells
digest parts of their own cytoplasm in order to generate small
macromolecules and energy.
Autophagy initiate the formation of a double-membrane bound structure
that grows and engulfs cytoplasmic components forming cytoplasm-filled
vacuoles called autophagasomes.
These fuse with lysosomes to initiate the degradation of the enclosed
material into primary components and energy that can be used to fuel
metabolism.
Autophagy is activated in response to several different situations, the best
characterized of which occurs in response to growth factor or nutrient
removal (starvation). In some way act as a barrier to cancer formation,
likely in part through its ability to promote cell death in transformed cells.
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Autophagy has also been observed following treatment with many anticancer agents including radiation.
Figure3.3:The Autophagy process
3.5.Senescence
Cellular senescence is the term given to the observation that over time
normal cells permanently lose their ability to divide.
These cells remain present, metabolically intact and may or may not
display functional changes.
In addition to this replicative form of senescence, ‘premature’ senescence
can also be elicited by various cellular stresses such as those caused by
oncogene activation or by radiation-induced DNA damage. In both
situations, the cells enter a permanent cell cycle arrest characterized
morphologically by a flattened cytoplasm and increased granularity or
biochemically by an increase in senescence associated β-galactosidase
expression. Cells that undergo senescence after irradiation are not
metabolically ‘dead’, but because they have permanently ceased
proliferation they are unable to contribute to tissue or tumor recovery.
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