world cancer report - iarc
world cancer report - iarc
world cancer report - iarc
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APOPTOSIS<br />
SUMMARY<br />
> The term apoptosis refers to a type of<br />
cell death that occurs both physiologically<br />
and in response to external stimuli,<br />
including X-rays and anti<strong>cancer</strong> drugs.<br />
> Apoptotic cell death is characterized by<br />
distinctive morphological changes different<br />
from those occurring during<br />
necrosis, which follows ischaemic injury<br />
or toxic damage.<br />
> Apoptosis is regulated by several distinct<br />
signalling pathways. Dysregulation<br />
of apoptosis may result in disordered<br />
cell growth and thereby contribute to<br />
carcinogenesis.<br />
> Selective induction of apoptosis in tumour<br />
cells is among current strategies for the<br />
development of novel <strong>cancer</strong> therapies.<br />
Apoptosis is a mode of cell death that<br />
facilitates such fundamental processes as<br />
development (for example, by removal of<br />
unwanted tissue during embryogenesis)<br />
and the immune response (for example,<br />
by elimination of self-reactive T cells).<br />
This type of cell death is distinguished<br />
from necrosis both morphologically (Fig.<br />
3.33) and functionally. Specifically, apoptosis<br />
involves single cells rather than<br />
areas of tissue and does not provoke<br />
inflammation. Tissue homeostasis is<br />
dependent on controlled elimination of<br />
unwanted cells, often in the context of a<br />
continuum in which specialization and<br />
maturation is ultimately succeeded by<br />
cell death in what may be regarded as the<br />
final phase of differentiation. Apart from<br />
elimination in a physiological context,<br />
cells that have been lethally exposed to<br />
cytotoxic drugs or radiation may be subject<br />
to apoptosis.<br />
The process of apoptosis can be<br />
described by reference to distinct phases,<br />
termed “regulation”, “effector” and<br />
“engulfing” respectively [1]. The regulatory<br />
phase includes all the signalling pathways<br />
that culminate in commitment to<br />
cell death. Some of these pathways regulate<br />
only cell death, but many of them<br />
have overlapping roles in the control of<br />
cell proliferation, differentiation, responses<br />
to stress and homeostasis. Critical to<br />
apoptosis signalling are the “initiator”<br />
caspases (including caspase-8, caspase-9<br />
and caspase-10) whose role is to activate<br />
the more abundant “effector” caspases<br />
(including caspase-3 and caspase-7)<br />
which, in turn, brings about the morphological<br />
change indicative of apoptosis.<br />
Finally, the engulfing process involves the<br />
recognition of cellular “remains” and their<br />
elimination by the engulfing activity of<br />
surrounding cells.<br />
Identification of genes mediating apoptosis<br />
in human cells has been critically<br />
Organelle<br />
disruption<br />
and breakdown,<br />
cell swelling<br />
NECROSIS<br />
Membrane<br />
blebbing,<br />
residual<br />
‘ghost’ cell<br />
APOPTOSIS<br />
dependent on definition of the ced genes<br />
in the nematode Caenorhabditis elegans,<br />
members of this gene family being variously<br />
homologous to human BCL2 (which<br />
suppresses apoptosis), APAF-1 (which<br />
mediates caspase activation) and the<br />
caspases themselves (proteases which<br />
mediate cell death). The centrality of<br />
apoptosis to <strong>cancer</strong> biology is indicated<br />
by excess tumorigenesis in BCL2-transgenic<br />
and p53-deficient mice. An appreciation<br />
of apoptosis provides a basis for the<br />
further development of novel and conventional<br />
<strong>cancer</strong> therapy<br />
The role of cell death in tumour<br />
growth<br />
Apoptosis, or lack of it, may be critical to<br />
tumorigenesis [2]. BCL2, a gene mediating<br />
resistance to apoptotic stimuli, was<br />
discovered at the t(14:18) chromosomal<br />
Condensation and<br />
fragmentation of<br />
chromatin<br />
Fig. 3.33 Apoptosis and necrosis are distinguished by characteristic morphological changes.<br />
Shrinking/<br />
rounding up,<br />
fragmentation<br />
of cell and<br />
nucleus<br />
Engulfing by<br />
neighbouring cell<br />
as ‘apoptoticbody’<br />
Apoptosis 113