world cancer report - iarc

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