Andrew G Renehan
Cancer Research Campaign Department of Epithelial Biology,
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester
Correspondence to: C S Potten, EpiStem Ltd, Incubator Building,
Manchester M13 9XX [log in to unmask]
Summary points Apoptosis
is a genetically regulated form of cell death It has a
role in biological processes, including embryogenesis, ageing, and many
diseases The
molecular mechanisms involved in death signals, genetic regulation,
activation of effectors have been identified Many
existing treatments (such as non-steroidal anti-inflammatories and anticancer
treatments) act through apoptosis New
treatments aimed at modifying apoptosis are being developed and are likely to
be used to manage common diseases in the next decade |
|
Biological
mechanisms |
The term apoptosis is often used interchangeably with programmed
cell death. In the strictest sense, programmed cell death may be
applied to other forms of cell death that require gene expression
without fulfilling some, or all, of the morphological criteria of
apoptosis.2
Whatever the definition, studies clearly show that apoptosis is genetically
regulated.
In its simplest model, the stages of apoptosis may be considered
as initiation, genetic regulation, and effector mechanisms (figure).3 Initiators
of apoptosis include anticancer drugs, gamma and ultraviolet
irradiation, deprivation of survival factors such as interleukin-1,
and various other cytokines that activate "death
receptors" such as Fas and tumour necrosis factor receptors. Through
a variety of pathways, these stimuli in turn generate a
characteristic pattern of gene expression.
The bcl-2 family of genes is the best studied and includes at
least 20 members; some are pro-apoptotic or "death genes" and
some are anti-apoptotic or "survival genes," including bcl-2
itself. The tumour suppressor gene p53 is also a well characterised
apoptotic agent. The principal effectors are a family of proteases
termed caspases. Studies in the nematode Caenorhabditis elegens, the fruitfly Drosophila, and the mouse indicate that
the molecular machinery of apoptosis is evolutionarily conserved and
intrinsic to all metazoan cells.
|
Assessment
of apoptosis |
Morphological assessment is the standard method for identifying
and quantifying apoptosis. Other approaches include the use of
fluorescence dyes to stain for condensed nuclei or exposed cell
surface phosphatidylserine and the detection of fragmented DNA by
terminal transferase mediated dUTP-biotin nick end labelling (TUNEL).
Levels of cell death in a tissue are often expressed as an apoptotic
index. This approach has serious limitations, mainly because of
uncertainty about the duration of apoptosis (which may be less than
six hours).4
Thus, for instance, a small number of apoptotic cells observed in a
static analysis may reflect a considerable contribution to cell
turnover.
|
Physiological
role |
The first role of apoptosis is during intrauterine development. It
helps to sculpture organ shape and carve out the interdigital webs
of the fingers and toes. Apoptotic mechanisms are important determinants
of fetal abnormalities; experiments have shown that wild type p53
mouse embryos will readily abort after radiation induced
teratogenesis, whereas p53 null embryos will not.5 Both
the nervous system and the immune system arise through overproduction of
cells followed by the apoptotic death of those that fail to establish
functional synaptic connections or productive antigen specificities.
Such massacre or altruistic behaviour requires a tightly regulated
system. In adulthood, about 10 billion cells die every day
simply to keep balance with the numbers of new cells arising from
the body's stem cell populations. This normal homoeostasis is not
just a passive process but regulated through apoptosis. The same
mechanisms serve to "mop up" damaged cells. With ageing, apoptotic
responses to DNA damage may be less tightly controlled and
exaggerated, contributing to degenerative disease. Alternatively, the
apoptotic responses may show reduced sensitivity, contributing to
susceptibility to cancer.6
|
|
Altered
apoptosis and disease |
There is now a long list of diseases associated with altered cell
survival.7
Increased apoptosis is characteristic of AIDS; neurodegenerative
diseases such as Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis; ischaemic injury after myocardial
infarction, stroke, and reperfusion; and in autoimmune diseases such
as hepatitis and graft versus host disease. Decreased or inhibited
apoptosis is a feature of many malignancies, autoimmune disorders
such as systemic lupus erythematosus, and some viral infections.
|
The role of apoptosis in cancer has probably received the greatest
research effort.8
Observations that patterns of spontaneous and induced apoptosis
differ between the small and large intestine has led to a plausible
explanation for the differences in incidence of cancer between these
two sites.9
Studies in p53 null mice show an increased preponderance of
premature tumours and offer strong evidence that such apoptotic
related genes are pivotal to development of tumours.
In addition, tumours develop methods to evade elimination by the
immune system; one such mechanism involves tumours expressing Fas,
which enables them to delete (by apoptosis) antitumour lymphocytes. This
phenomenon is known as the "tumour counterattack."10 There
is also increasing evidence that systemic stimuli such as insulin-like
growth factor I (anti-apoptotic) and insulin-like growth factor binding
protein 3 (pro-apoptotic) may influence the development and
progression of many common cancers.11
|
Potential
treatments |
This brief review has shown that many human diseases may result
when cells die that shouldn't or others live that should die. Modulation
of apoptotic processes may thus offer valuable methods of treatment.
It is now known that many existing drugs (for example, non-steroidal
anti-inflammatories) act by altering the levels of apoptosis.
Virtually all cytotoxic drugs and radiotherapy programmes induce
apoptosis in tumour cells, and resistance to apoptosis is associated
with treatment failure. These therapies also induce apoptosis in
normal cells, and side effects on bone marrow, gut, and oral mucosa
limit the dose that can be used. Many more new treatment strategies
are currently in preclinical trials and show promise (box). 3 12 If
future clinical studies are fruitful, this translation from basic
science to clinical practice will be unique as it will affect not
just one, but a broad range of disordersand many patients will benefit.
|
Footnotes |
Competing interests: None declared.
|
References |
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2. |
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.