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Biology of cancer
Kevin J Harrington
Abstract
Cancer is caused by aberrant patterns of gene expression. Most common
cancers are caused by acquired mutations in somatic cells. In contrast,
specific germline mutations can account for rare hereditary cancer
syndromes. In general, the genes affected in cancers can be divided into
two groups: oncogenes and tumour suppressor genes. Oncogenes undergo
activation and are phenotypically dominant, while tumour suppressor genes
undergo inactivation and are phenotypically recessive. Oncogenic activation
can occur by specific point mutations within the sequence of a gene, by
amplification of the number of copies of the gene or by translocation of
DNA to a site where transcription is more active or where the formation of
a new fusion gene generates a protein with enhanced biological activity.
Tumour suppressor genes are inactivated by mutations that destroy the function of the protein encoded by the gene. The biological behaviour of cancer
can be considered in terms of eight specific hallmarks and two additional socalled enabling characteristics. Improved understanding of the mechanistic
basis of these processes has resulted in rapid progress in diagnosis, treatment and prognostication in cancer medicine.
Introduction
Cancer is a genetic disease that occurs when the information in
cellular DNA becomes corrupted, leading to abnormal patterns of
gene expression. As a result, the effects of normal genes that
control normal cellular functions, such as growth, survival and
spread, are enhanced and those of genes that suppress these
effects are repressed. The main mechanism by which this
corruption of the genetic code occurs is through the accumulation of mutations, although there is increasing recognition of the
role of non-mutational (epigenetic) changes in the process.
Aberrant gene expression leads to a number of key changes in
fundamental biological processes within cancer cells e the
so-called hallmarks and enabling characteristics of cancer1,2
(Figure 1).
deoxyR
deoxyR
deoxyR
P
G
deoxyR
deoxyR
Cancer genes
deoxyR
deoxyR
P
A
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deoxyR
3
Figure 1
689
Intracellular domain
undergoes phosphorylation
Cell
membrane
P-
Intracellular
domain
Normal protein in
normal amount
Phosphorylated
receptor activates
signal transduction
pathways
Normal mRNA
Abnormal
DNA
Normal DNA
a
-P
Angiogenesis
Invasion
Anti-apoptosis
Gene transcription
mRNA
Figure 3
Protein
Mutant protein Amplified normal protein
Fusion protein
Figure 2
Table 1
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Avoidance of apoptosis
Normal cells continually audit their viability by assessing the
balance of survival (anti-apoptotic) and death (pro-apoptotic)
signals that they receive. In normal cells, DNA damage leads to
a block in proliferation (cell cycle arrest) while the potential for
repair is assessed. If the level of damage exceeds the capacity for
repair, the balance of anti- and pro-apoptotic signals tips and the cell
undergoes programmed cell death (apoptosis). This prevents
maintenance of DNA damage and avoids the risk that mutations will
be passed to the progeny of cell division. As such, this mechanism
represents a very powerful barrier to the development of cancer.
Loss of normal apoptotic pathway signalling is an extremely
common event in cancer. Indeed, two of the best-known cancerassociated genes (p53 (TSG) and bcl-2 (oncogene)) are intimately
involved in apoptosis. The two main mechanisms of apoptotic
signalling (intrinsic and extrinsic pathways) are illustrated in
a simplified form in Figure 4. Cancer cells are able to evade
apoptosis through an ability to ignore signals sent through the
extrinsic pathway, or by re-setting the balance of intracellular proand anti-apoptotic molecules in favour of inhibition of apoptosis. By
circumventing apoptosis, cancer cells can sustain DNA damage
without it causing cell death (unless the damage is to a gene that is
absolutely necessary for cell survival). Therefore, cancer cells that
Cellular immortalization
Normal somatic cells can undergo only a finite number of cell
divisions (Hayflick limit) before they enter a period of permanent
growth arrest, known as replicative senescence. This process
occurs as a result of the cells inability to replicate the ends of
their chromosomes (the telomeres) fully at each division.
Therefore, over time the telomeres get progressively shorter,
effectively acting as molecular clocks that count down the cells
lifespan. In contrast, stem cells and malignant cells have
acquired immortality by maintaining the length of their telomeres. In most tumours, this occurs through upregulation of the
enzyme telomerase, but in 10e15% of cases a different mechanism e the alternative lengthening of the telomeres (ALT) e is
responsible. Telomerase enzymatic activity involves a large
number of proteins but its two main components are an RNA
template (hTR) and a reverse transcriptase enzyme (hTERT); the
reverse transcriptase uses the hTR RNA template as a guide in
the resynthesis of the DNA sequence of the telomere. Therefore,
tumours that have reactivated the expression of telomerase are
Death receptor
Extrinsic
pathway
signalling
molecule
(caspase 8)
Mitochondrion
Intrinsic pathway
signalling
molecule
(cytochrome C)
Caspase 3
Cell
membrane
Pro-apoptotic
signal
Anti-apoptotic
signal
Damage
sensor (p53)
Anti-angiogenic
C
Angiostatin
C
Endostatin
C
Thrombospondin-1 and -2 (TSP-1, TSP-2)
C
Interleukins (IL-1b, IL-12, IL-18)
C
Anti-thrombin III
Genotoxic
insult
INTRINSIC PATHWAY
Table 2
Figure 4
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Lung
Liver
Tumour cell
invades lymphatic
or blood vessel
Bone
Metastasis specifically to
tissues expressing high
levels of cognate ligand
(chemokine)
Brain
Figure 5
able to re-build the parts of their telomeres that they lose with
each round of cell division and thereby avoid being sidelined into
replicative senescence.
Invasion and metastasis (Figure 5)
Distant metastases cause 90% of cancer deaths. Invasion and
metastasis involves careful orchestration of a series of complex
biological processes:
detachment from immediate neighbours and stroma at the
local site
enzymatic digestion of the extracellular matrix followed by
specific directional motility
penetration (intravasation) of blood or lymphatic vessels
and tumour embolization
survival in the circulation until arrival at the metastatic
site, which may be chosen on the basis of provision of
a favourable supply of appropriate growth factors
adherence of the metastasis to the endothelium of blood
vessels at its destination and extravasation from the vessel
proliferation and invasion of the new location and
recruitment of a new blood supply.
One of the key processes underlying invasion and metastasis of
epithelial tumours is the epithelial-to-mesenchymal transition
(EMT). This multifaceted programme can be engaged transiently
or stably by invading cancer cells. The patterns of metastasis of
different cancers to specific organs (e.g. breast cancer to liver,
bone and brain; lung cancer to brain and adrenal gland) are not
random, but appear to be driven by expression of chemokine
receptors by tumour cells that allow them to seek a suitable
environment in which to establish a colony.4
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FURTHER READING
1 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57e70.
2 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation.
Cell 2001; 144: 646e74.
3 Rogers SJ, Harrington KJ, Rhys Evans P, O-Charoenrat P, Eccles SA.
Biological significance of c-erbB family oncogenes in head and neck
cancer. Cancer Metastasis Rev 2005; 24: 47e69.
4 Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors
in breast cancer metastasis. Nature 2001; 410: 50e6.
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