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CANCER BIOLOGY AND IMAGING

Biology of cancer

Oncogenes are derived from mutated versions of normal


cellular genes (called proto-oncogenes) that control cell proliferation, survival and spread. In normal cells, the expression of
proto-oncogenes is very tightly regulated to avoid uncontrolled
cell growth. In cancer, activating mutations of proto-oncogenes
are responsible for uncontrolled cell division, enhanced
survival (even in the face of anti-cancer treatment) and dissemination. Oncogenes are described as being phenotypically dominant e a single mutated copy of a proto-oncogene is sufficient to
promote cancer e and are generally not associated with inherited
cancer syndromes. Two exceptions to this rule are mutations in
the ret proto-oncogene that are associated with multiple endocrine neoplasia (MEN) syndromes (types 2A and 2B) and germline mutations in H-ras that can cause Costellos syndrome (high
birth weight, cardiomyopathy and predisposition to cancers).
Oncogenes can be activated in three ways to cause cancers
(Figure 2).
Tumour suppressor genes (TSG) are normal cellular genes
whose function involves inhibition of cell proliferation and
survival. They are frequently involved in controlling cell cycle
progression and apoptosis. TSG are phenotypically recessive e the
function of both copies must be lost in order to promote cancer e
and are responsible for inherited cancer syndromes (see Genetic
predisposition to cancer in Medicine 2012; 40(1)).

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.

Keywords angiogenesis; apoptosis; cancer; enabling characteristics;


hallmarks; metastasis; mutation; oncogene; tumour suppressor gene

The structure of DNA


DNA consists of a double helix composed of a deoxyribose sugarphosphate backbone and four bases (adenine, guanine, thymine
and cytosine). The four bases form hydrogen bonds with specific
bases on the opposite strand. A binds with T and C binds with G.
deoxyR, deoxyribose; p, phosphate; a, adenine; t, thymine;
c, cytosine; g, guanine.

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

Cancer is driven by two classes of genes (oncogenes and tumour


suppressor genes), each of which provides an essential function
in normal cells.

deoxyR

deoxyR

P
A

MEDICINE 39:12

deoxyR

Kevin J Harrington PhD FRCP FRCR is a Reader in Biological Cancer


Therapies at The Institute of Cancer Research, Targeted Therapy
Laboratory, Division of Cancer Biology, London, UK and a Consultant
Clinical Oncologist at The Royal Marsden Hospital, London. His
research interests include gene and virotherapy of cancer and targeted
radiation sensitisation of cancer.

3
Figure 1

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CANCER BIOLOGY AND IMAGING

Oncogenic activation via three pathways

Growth factor independence

Normal gene expression leads to formation of normal mRNA and


expression of a normal protein in normal amounts. a Specific
mutations in the sequence of the DNA code lead to alterations in
the amino acid sequence of the protein, giving it enhanced activity.
b Increased numbers of normal copies of the gene (amplification)
result in the formation of increased am ounts of normal protein.
c Translocation of part of the DNA from one chromosomal location
to another can result in the generation of a fusion protein with
enhanced biological activity.

Growth factor independence can lead to sustained signalling in


pathways that control essential biological functions, such as
growth, apoptosis, angiogenesis, invasion and DNA damage repair.
EGF binds to
extracellular
domain

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

Proliferation DNA repair

mRNA
Figure 3

Protein
Mutant protein Amplified normal protein

Fusion protein

Growth factor independence


A general scheme for the function of growth factor receptors and their
ligands in promoting cell growth (and other effects) is shown in
Figure 3. In this case, binding of epidermal growth factor (the cognate
ligand) to its specific ligand-binding domain on the extracellular
component of the epidermal growth factor receptor (EGFR) leads to
a signal being passed from the membrane to the nucleus via a cascade
of intermediary messengers, such that ligand binding on the cell
surface alters the behaviour of the cell. Under normal circumstances,
activation of growth factor receptors is very tightly controlled e as is
the synthesis and release of the ligands that stimulate them. Cancer
cells frequently usurp normal growth factor signalling pathways and
use them to promote unrestrained cell division.3
Cancer cells exploit three main strategies for achieving selfsufficiency in growth factors: they manufacture and release
growth factors which stimulate their own receptors (autocrine
signalling) and those of their immediate neighbours (paracrine
signalling); they alter the number, structure or function of the
growth factor receptors on their surface, such that they are more
likely to send a growth signal to the nucleus (even in the absence of
the cognate ligand); and they deregulate the signalling pathway
downstream of the growth factor receptor so that it is permanently
turned on (constitutively active).

Figure 2

Hallmarks of cancer and enabling characteristics


In 2000, Hanahan and Weinberg described six key changes that
occur in cancer (growth factor independence, evading growth
suppressors, avoiding apoptosis, maintaining replicative potential, angiogenesis and invasion/metastasis); these can be seen as
largely responsible for driving malignant behaviour.1 Recently,
they have updated their description to include two additional
emerging hallmarks (re-programming energy metabolism and
evading immune destruction) and two enabling characteristics
(genomic instability and inflammation) (Table 1).2 The role
played by each of these processes will be reviewed briefly below.

Hallmarks of cancer and enabling characteristics


Hallmarks of cancer
C
Growth factor independence or self-sufficiency
C
Insensitivity to anti-growth signals
C
Avoidance of programmed cell death (apoptosis)
C
Ability to recruit a dedicated blood supply
C
Immortalization by reactivation of telomerase
C
Ability to invade adjacent normal tissues and
metastasize to distant sites
C
Reprogrammed energy metabolism
C
Evading immune destruction

Insensitivity to anti-growth signals


Several normal anti-growth signals counteract the positively
acting growth signals described above. Anti-growth signals work
either by forcing cells into quiescence (G0 stage of the cell cycle)
or by inducing their terminal differentiation such that they are
permanently unable to re-enter the cell cycle. Anti-growth signalling is mediated by ligands (e.g. transforming growth factor
beta, TGF-b) that act on cellular receptors (e.g. TGF-b receptor)
and send signals to the nucleus via second messengers. These
pathways are mainly involved in controlling the cell cycle clock
and mediate their effects through proteins that include

Enabling characteristics of cancer


Genomic instability
C
Inflammation
C

Table 1

MEDICINE 39:12

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2011 Elsevier Ltd. All rights reserved.

CANCER BIOLOGY AND IMAGING

retinoblastoma protein (Rb), cyclins, cyclin-dependent kinases


(CDK) and their inhibitors (CDKi). Abnormalities in anti-growth
signalling pathways are extremely common in cancer and play
a role in helping cancer cells to progress through the cell cycle.
Therefore, loss of Rb and members of the CDKi family, and
overexpression of certain cyclins and CDK have been shown to
occur in a large number of tumour types.

have switched off their apoptotic pathway are more likely to be


intrinsically resistant to anti-cancer treatments. In fact, the use of
these treatments may promote the accumulation of other mutations
that may have a negative influence on the biology of the disease.
Sustained angiogenesis
In normal tissues, the growth of new blood vessels (angiogenesis) is
held very tightly in check by a balance between positive (proangiogenic) and negative (anti-angiogenic) signals (see Table 2).
The growth of cancer deposits is intimately related to their ability
to secure a blood supply. A small cluster of cancer cells can grow to
60e100 mm by deriving a supply of oxygen and nutrients by direct
diffusion, but beyond this size the fledgling tumour must acquire its
own dedicated blood supply. Cancers acquire the ability to grow
a new blood supply by subverting the balance between pro- and
anti-angiogenic factors. Essentially, cancers switch to an angiogenic phenotype by upregulating production of pro-angiogenic
proteins, such as vascular endothelial growth factor (VEGF), and/
or by downregulating production of anti-angiogenic proteins, such
as thrombospondin-1.

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

Normal apoptotic signalling pathways


Cells can undergo programmed cell death in response to activation
of either the intrinsic or extrinsic apoptotic pathway. Cancers
frequently subvert these pathways to allow them to survive signals
that would lead to the death of normal cells.
EXTRINSIC PATHWAY
Death ligand

Death receptor

Extrinsic
pathway
signalling
molecule
(caspase 8)

Mitochondrion

Intrinsic pathway
signalling
molecule
(cytochrome C)

Caspase 3

Cell
membrane

Pro- and anti-angiogenic factors


Pro-angiogenic
C
Vascular endothelial growth factor (VEGF)
C
Basic fibroblast growth factor (bFGF)
C
Acidic fibroblast growth factor (aFGF)
C
Transforming growth factors a and b (TGF-a, TGF-b)
C
Platelet-derived growth factor (PDGF)
C
Tumour necrosis factor a (TNF-a)

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

Common final pathway


to cell death

Table 2

Figure 4

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CANCER BIOLOGY AND IMAGING

Reprogrammed energy metabolism


In their updated review, Hanahan and Weinberg have designated
reprogrammed energy metabolism as an emerging hallmark
of cancer. This hallmark recognizes the fact that the chronic,
uncontrolled cell proliferation in cancer requires a reconfiguration
of the way in which cancer cells metabolize glucose. Normal cells
process glucose initially in the cytoplasm by glycolysis, to yield
pyruvate, and then in the mitochondria by oxidative phosphorylation, to generate carbon dioxide and water. In contrast, even under
oxygenated conditions, cancer cells tend to switch their metabolism
to preferential use of glycolysis with generation of lactate (the
so-called Warburg effect). As yet, the reasons for this change are not
clear, but the fact that it is driven by mutations in key oncogenes
and tumour suppressor genes suggest that it is an important
underlying principle of cancer biology.

Invasion and metastasis of cancer cells


Invasion and metas tasis of cancer cells results from upregulated
expression of molecules that allow cells to digest the extracellular
matrix around them, migrate and intravasate into blood vessels
and then take up residence in distant organs. The sites of distant
metastasis can be determined by the expression of specific
chemokine receptors by cancer cells that allow them to home in
on suitable sites to establish secondary deposits.
Patient with
breast cancer
Tumour cell expressing
specific chemokine
receptor
Lymph
node

Tumour cell invasion,


migration and
intravasation

Evading immune destruction


An unresolved issue regarding tumour formation and maintenance is the role of the immune system. According to the theory of
immune surveillance, the immune system mounts a constant vigil
against the emergence of pre-malignant and frankly malignant
cells. The most often cited evidence for this effect comes from the
observation that chronic immune suppression is associated with
a marked increase in specific cancers, especially those of viral
origin. There is also evidence that the immune system presents
a significant barrier to non-virally induced cancers in immunocompetent patients. Thus, the occurrence of tumours can be
perceived as a failure of the immune system to recognize, reject
and destroy tumour cells that express altered self antigens. As part
of this process, it is thought that selection of less immunogenic
cancer cells (through immuno-editing) and active recruitment of
immunosuppressive components of the immune system [e.g.
regulatory T cells (Treg) and myeloid-derived suppressor cells
(MDSCs)] to some cancers allows tumours to develop and spread
without becoming targets for immune clearance.

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

MEDICINE 39:12

Enabling characteristics of cancer


As part of the biology underpinning cancer development, two
key enabling characteristics have recently been defined: genomic
instability and inflammation. The first relates to the state in
which cancer cells lose control of the integrity of their genetic
material and acquire an increasing repertoire of mutational
changes that progressively alter their biology and promote the
hallmarks of cancer. The second enabling characteristic describes
the common situation in which pre-malignant and frankly
malignant lesions excite an inflammatory state, through the
recruitment and activation of components of the immune system
that promote and support tumour growth and spread.
A

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.

692

2011 Elsevier Ltd. All rights reserved.

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