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124 P RIN C IP L ES O F I NFE C TI O US D IS E ASE
Other anti-inuenza agents
Amantidine and rimantadine inhibit viral M2 protein ion channel function,
which is required for uncoating (see Fig. 6.2). Resistance is widespread,
and these are only used to treat oseltamivir-resistant inuenza A in
patients unable to take zanamivir (e.g. ventilated patients) and when the
strain is susceptible to these agents. Baloxavir marboxil inhibits a component of viral RNA synthesis. It is licensed for uncomplicated inuenza
but is likely to be reserved for neuraminidase-resistant strains. Faviparvir
is an oral or intravenous RNA-dependent RNA polymerase that may
also play a role against resistant strains of inuenza but also other RNA
viruses and has been studied against SARS-CoV-2.
Other agents used to treat viruses
Antiviral agents used to treat hepatitis B and C virus are discussed on pages
886 and 889, and those used against HIV-1 are described on page 366.
Remdesivir
Remdesivir is an intravenous RNA-dependent RNA polymerase inhibitor
that has a broad antiviral spectrum in vitro and has decreased the time to
recovery following SARS-Cov-2 infection. So far it has not demonstrated
efcacy against other viruses clinically. Initial studies have not shown signicant effects on SARS-CoV-2 viral replication, suggesting it may need to be
used early in the course of infection before peak viral replication. The main
side-effects include abnormal liver function tests and infusion reactions.
Ribavirin
Ribavirin is a guanosine analogue that inhibits nucleic acid synthesis in
a variety of viruses. It is used in particular in the treatment of hepatitis C
virus but also against certain viral haemorrhagic fevers, e.g. Lassa fever,
although it has not been useful against Ebola virus.
Antiparasitic agents
Antimalarial agents
Artemisinin (qinghaosu) derivatives
Artemisinin originates from a herb (sweet wormwood, Artemisia annua),
which was used in Chinese medicine to treat fever. Its derivatives,
artemether and artesunate, were developed for use in malaria in the
1970s. Their mechanism of action is unknown. They are used in the
treatment, but not prophylaxis, of malaria, usually in combination with
other antimalarials, and are effective against strains of Plasmodium spp.
that are resistant to other antimalarials. Artemether is lipid-soluble and
may be administered via the intramuscular and oral routes. Artesunate is
water-soluble and is administered intravenously or orally. Serious adverse
effects are uncommon. Current advice for malaria in pregnancy is that
the artemisinin derivatives should be used to treat uncomplicated fal-
ciparum malaria in the second and third trimesters, but should not be
prescribed in the rst trimester until more information becomes available.
Atovaquone
Atovaquone inhibits mitochondrial function. It is an oral agent, used for
treatment and prophylaxis of malaria, in combination with proguanil (see
below), without which it is ineffective. It is also employed in the treatment
of mild cases of Pneumocystis jirovecii pneumonia, or as prophylaxis,
where there is intolerance to co-trimoxazole. Signicant adverse effects
are uncommon.
Folate synthesis inhibitors (proguanil,
pyrimethamine–sulfadoxine)
Proguanil inhibits dihydrofolate reductase and is used for malaria prophylaxis. Pyrimethamine–sulfadoxine may be used in the treatment of malaria.
Quinoline-containing compounds
Chloroquine and quinine are believed to act by intraparasitic inhibition
of haem polymerisation, resulting in toxic build-up of intracellular haem.
The mechanisms of action of other agents in this group (quinidine,
amodiaquine, meoquine, primaquine, etc.) may differ. They are employed
in the treatment and prophylaxis of malaria. Primaquine is used for
radical cure of malaria due to Plasmodium vivax and P. ovale (destruction
of liver hypnozoites). Chloroquine may also be given for extraintestinal
amoebiasis.
Chloroquine can cause signicant pruritus. If used in long-term, highdose regimens, it causes an irreversible retinopathy. Overdosage leads
to life-threatening cardiotoxicity. The side-effect prole of meoquine
includes neuropsychiatric effects ranging from mood change, nightmares
and agitation to hallucinations and psychosis. Quinine may cause hypoglycaemia and cardiotoxicity, especially when administered parenterally.
Primaquine causes haemolysis in people with glucose-6-phosphate
dehydrogenase deciency, which should be excluded before therapy.
Chloroquine is considered safe in pregnancy but meoquine should be
avoided in the rst trimester.
Chloroquine (and its metabolite hydroxychloroquine) exhibits in vitro
activity against the virus SARS-CoV-2 but has not demonstrated clinical
efcacy.
Lumefantrine
Lumefantrine is used in combination with artemether to treat uncomplicated falciparum malaria, including chloroquine-resistant strains.
Its mechanism of action is unknown. Signicant adverse effects are
uncommon.
Drugs used in trypanosomiasis
The antiparasitic agents used to treat human African trypanosomiasis
(HAT) and American trypanosomiasis (Chagas’ disease) (benznidazole,
eornithine, fexinidazole, melarsoprol, nifurtimox, pentamidine and
suramin) are discussed in detail on pages 324 and 325.
In addition to its use in HAT, pentamidine is used in leishmaniasis
(p. 327) and in severe Pneumocystis jirovecii pneumonia, if co-trimox azole
cannot be tolerated or is ineffective. It is administered via intravenous or
intramuscular routes. It is a relatively toxic drug, commonly causing rash,
renal impairment, profound hypotension (especially on rapid infusion),
electrolyte disturbances, blood dyscrasias and hypoglycaemia.
Other antiprotozoal agents
Pentavalent antimonials
Sodium stibogluconate and meglumine antimoniate inhibit protozoal
glycolysis by phosphofructokinase inhibition. They are used parenterally (intravenous or intramuscular) to treat leishmaniasis. Adverse effects
include arthralgia, myalgias, raised hepatic transaminases, pancreatitis
and electrocardiogram changes. Severe cardiotoxicity leading to death
is not uncommon.
Diloxanide furoate
This oral agent is used to eliminate luminal cysts following treatment
of intestinal amoebiasis, or in asymptomatic cyst excreters. The drug
is absorbed slowly (enabling luminal persistence) and has no effect in
hepatic amoebiasis. It is a relatively non-toxic drug, the most signicant
adverse effect being atulence.
Iodoquinol (di-iodohydroxyquinoline)
Iodoquinol is a quinoline derivative with activity against Entamoeba histolytica cysts and trophozoites. It is used orally to treat asymptomatic
cyst excreters or, in association with another amoebicide (e.g. metronidazole), to treat extraintestinal amoebiasis. Long-term use of this drug is
not recommended, as neurological adverse effects include optic neuritis
and peripheral neuropathy.
Nitazoxanide
Nitazoxanide is an inhibitor of pyruvate–ferredoxin oxidoreductasedependent anaerobic energy metabolism in protozoa. It is a broad-spectrum agent, active against various nematodes, tapeworms, ukes and
Fu rt he r i nf o rm at ion 125
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intestinal protozoa. Nitazoxanide also has activity against some anaerobic bacteria and viruses. It is administered orally in giardiasis and cryptosporidiosis. Adverse effects are usually mild and involve the gastrointestinal
tract (e.g. nausea, diarrhoea and abdominal pain).
Paromomycin
Paromomycin is an aminoglycoside that is used to treat visceral leishmaniasis and intestinal amoebiasis. It is not signicantly absorbed when
administered orally, and is therefore given orally for intestinal amoebiasis
and by intramuscular injection for leishmaniasis. It showed early promise in the treatment of HIV-associated cryptosporidiosis but subsequent
trials have demonstrated that this effect is marginal at best.
Drugs used against helminths
Benzimidazoles (albendazole, mebendazole)
These agents act by inhibiting both helminth glucose uptake, causing
depletion of glycogen stores, and fumarate reductase. Albendazole
is used for hookworm, ascariasis, threadworm, Strongyloides infection, trichinellosis, Taenia solium (cysticercosis) and hydatid disease.
Mebendazole is used for hookworm, ascariasis, threadworm and whipworm. The drugs are administered orally. Absorption is relatively poor but
is increased by a fatty meal. Signicant adverse effects are uncommon.
Bithionol
Bithionol is used to treat uke infections with Fasciola hepatica. It is well
absorbed orally. Adverse effects are mild (e.g. nausea, vomiting, diarrhoea, rashes) but relatively common (approximately 30%).
Diethylcarbamazine
Diethylcarbamazine (DEC) is an oral agent used to treat lariasis and loiasis. Treatment of lariasis is often followed by fever, headache, nausea,
vomiting, arthralgia and prostration. This is caused by the host response
to dying microlariae, rather than the drug, and may be reduced by
pre-treatment with glucocorticoids.
Ivermectin
Ivermectin binds to helminth nerve and muscle cell ion channels,
causing increased membrane permeability. It is an oral agent, used in
Strongyloides infection, lariasis and onchocerciasis. Signicant sideeffects are uncommon.
Niclosamide
Niclosamide inhibits oxidative phosphorylation, causing paralysis of
helminths. It is an oral agent, used in Taenia saginata and intestinal
T. solium infection. Systemic absorption is minimal and it has few signicant side-effects.
Piperazine
Piperazine inhibits neurotransmitter function, causing helminth mus-
cle paralysis. It is an oral agent, used in ascariasis and threadworm
(Enterobius vermicularis) infection. Signicant adverse effects are uncom-
mon but include neuropsychological reactions such as vertigo, delirium
and convulsions.
Praziquantel
Praziquantel increases membrane permeability to Ca2+, causing violent
contraction of worm muscle. It is the drug of choice for schistosomi-
asis and is also used in T. saginata, T. solium (cysticercosis) and uke
infections (Clonorchis, Paragonimus) and in echinococcosis. It is admin-
istered orally and is well absorbed. Adverse effects are usually mild and
transient, and include nausea and abdominal pain.
Pyrantel pamoate
This agent causes spastic paralysis of helminth muscle through a
suxa methonium-like action. It is used orally in ascariasis and thread-
worm infection. Systemic absorption is poor and adverse effects are
uncommon.
Thiabendazole
Thiabendazole inhibits fumarate reductase, which is required for energy
production in helminths. It is used orally in Strongyloides infection and
topically to treat cutaneous larva migrans. Signicant adverse effects are
uncommon.
Further information
Websites
cdc.gov. Centers for Disease Control and Prevention, Atlanta, USA. Provides
information on all aspects of communicable disease, including prophylaxis
against malaria.
gov.uk/government/collections/immunisation-against-infectious-disease-the-
green-book. UK Department of Health recommendations for immunisation .
ecdc.europa.eu. European Centre for Disease Prevention and Control. Includes
data on prevalence of antibiotic resistance in Europe .
gov.uk/government/organisations/public-health-england. Public Health England.
Provides information on infectious diseases relating mainly to England,
including community infection control.
idsociety.org. Infectious Diseases Society of America. Publishes up-to-date,
evidence-based guidelines.
who.int. World Health Organization. Provides up-to-date information on global
aspects of infectious disease, including outbreak updates. Also has information
on the ‘World Antibiotic Awareness Week’ campaign.
6
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Multiple Choice Questions
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6.1. A 19-year-old student who had not received any childhood
vaccines through parental choice attends a music festival. Nine
days later she develops an illness consisting of conjunctivitis and
malaise with some intraoral lesions, followed by a generalised
maculopapular rash. With respect to the most likely causative
organism, which of the following statements is false?
A. The basic reproduction number (R
the highest encountered for an infectious disease
B. R
gives an estimate of how many infections are likely to
0
arise from an infected individual and is dependent on vaccine
uptake and previous infections
C. R
for this infection is higher than that for SARS-CoV-2 and
0
Ebola
D. Since R
for this infection is high the proportion of the
0
population who need to be immunised to prevent spread of
infection is high
E. R
gives an estimate of how many infections are likely to arise
e
from an infected individual taking into account vaccine uptake
in the population
) for this pathogen is one of
0
patient has tolerated cephalosporins previously with no problems, it is
reasonable to treat her with an anti-pseudomonal cephalosporin despite
her history of rash with another beta-lactam antibiotic (piperacillintazobactam). Ceftazidime is the only anti-pseudomonal cephalosporin
on this list. The only other third-generation cephalosporin that has good
Gram-negative coverage on the list is ceftriaxone, but it lacks activity
against P. aeruginosa
6.3. A 58-year-old man with diabetes mellitus is hospitalised with
an acute myocardial infarction. He develops cardiac failure and
acute kidney injury (AKI) and spends a period of time in the
cardiac intensive care unit. He subsequently develops a fever and
his blood cultures are positive for a yeast, which is identied as
Candida krusei. An antifungal agent is selected on the basis of
likely susceptibility and patient comorbidities. The mechanism of
action of this antifungal is:
A. Accumulation of toxic 14α-methylated sterols
B. DNA topoisomerase inhibition
C. Ergosterol synthesis inhibition in the cell membrane
D. Impairment of DNA synthesis due to inhibition of thymidylate
synthase
E. Inhibition of β-1,3-glucan synthesis in the cell wall
Answer: B.
The case describes a measles infection. R
ber of cases that can be expected to be acquired from a single primary
is an estimate of the num-
0
case when all individuals in the population are susceptible to infection,
and is high for measles (usually cited as 12–18). R
inherent transmissibility of the organism and assumes susceptibility of
the population. R
population at the time it is calculated, and therefore the R
is affected by the social habits and interactions of a
0
transmitted by close contact will be higher if calculated in a densely pop-
is dependent on the
0
for a disease
o
ulated area than a sparsely populated area. Because measles has a high
R
the number of people in the population who need to be vaccinated
0
to control measles is high. Re gives a more accurate assessment of the
number of infections that can be expected to arise within a population
than R
because it takes into account the number of susceptible indi-
0
viduals within the population (i.e. vaccinated individuals and those who
have acquired immunity through natural infection) as well as changes
in behaviour (e.g. the introduction of social distancing, use of personal
protective equipment etc.). R
behaviour.
therefore varies with time and population
e
6.2. A 23-year-old woman with cystic brosis and a history of multiple
infectious exacerbations is admitted to hospital with increasing
breathlessness. A chest X-ray reveals patchy inltrates throughout
the right lower lung on a background of bronchial dilatation in both
lungs. Sputum culture yields profuse growth of an oxidase-positive
Gram-negative bacillus. The patient has a history of rash with
piperacillin-tazobactam but has tolerated cephalosporins without
previous problems. Which of the following would be a suitable
agent to treat the most likely causative organism?
A. Cefaclor
B. Cefazolin
C. Ceftriaxone
D. Ceftazidime
E. Cephalexin
Answer: E.
The candidaemia is likely to be related to a central venous catheter
infection and Candida krusei is resistant to antifungal azoles. The best
initial therapy is therefore an echinocandin such as caspofungin, which
acts by inhibiting fungal β-1,3-glucan synthase. It would not be appropriate to treat this patient with an amphotericin B preparation because
of his AKI and the potential for nephrotoxicity. Antifungal azoles act by
inhibiting ergosterol synthesis resulting in toxic accumulation of 14α-
methylated sterols. Flucytosine (5-uorocytosine) inhibits DNA synthesis
by its actions on thymidylate synthase. Inhibition of bacterial DNA topoisomerases is the mechanism of action of uoroquinolones, but not of
any antifungals.
6.4. A 26-year-old man who grew up on a farm in rural Argentina
is investigated for chronic abdominal pain and weight loss. He
is found on investigation to have infection with Taenia saginata
and treatment is recommended. Guidelines suggest you should
prescribe praziquantel but your pharmacy is not able to obtain any
supplies of this drug. What would be a suitable alternative agent to
use to treat this infection?
A. Bithionol
B. Diethycarbazamine
C. Niclosamide
D. Piperazine
E. Thiabendazole
Answer: C.
Infections with intestinal tapeworms such as T. saginata are often
asymptomatic but can occasionally give rise to symptoms, as in this
case. The preferred treatment for Taenia infections is praziquantel but
niclosamide or nitazoxanide are alternatives. The other agents listed are
used for other helminth infections.
Answer: D.
The patient has a history of cystic brosis with multiple infectious exacerbations. Although an oxidase-positive Gram-negative bacillus could
describe several organisms, the most likely one in a setting of cystic
brosis with multiple infective exacerbations is P. aeruginosa. As the
S Clive
M Stares
7
Oncology
Clinical examination of the cancer patient 128
Clinical examination of the patient on cancer treatment 129
The 10 hallmarks of cancer 130
1. Genome instability and mutation 130
2. Resisting cell death 130
3. Sustaining proliferative signalling 131
4. Evading growth suppressors 131
5. Enabling replicative immortality 131
6. Inducing angiogenesis 132
7. Activating invasion and metastasis 132
8. Deregulating cellular energetics 133
9. Tumour-promoting inammation 133
10. Evading immune destruction 133
Environmental and genetic determinants of cancer 133
Investigations 133
Determining the extent of disease (staging) 133
Establishing the type of cancer 135
Assessing tness 137
Multidisciplinary teams 138
Acute oncology 138
Acute presentation of new cancer 138
Oncological emergencies 139
Other acute presentations in oncology 142
Symptoms from locally advanced cancer or metastatic sites 143
Treatment-related toxicities 145
Therapeutics in oncology 145
Surgical treatment 145
Radiotherapy 145
Systemic anti-cancer therapy 146
Evaluation of treatment 148
Late toxicity of therapy 148
Cancer clinical trials 148
Specic cancers 149
Breast cancer 149
Ovarian cancer 150
Endometrial cancer 150
Cervical cancer 150
Head and neck tumours 151
Survivorship 151
128 O ncO l Og y
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Clinical examination of the cancer patient
Face
6 7
Conjunctival pallor
Icterus
Horner syndrome
Cushingoid features
5
Lymph nodes (see p. 923)
Cervical
Supraclavicular
Axillary
Inguinal
Respiratory
4
Stridor
Consolidation
Pleural effusion (see p. 481)
Breast asymmetry, lump
3
5
4
6
7
8
3
Skin tethering above the
nipple
Hands
2
Clubbing
Signs of smoking
Pallor
2
9
Cardiovascular
Superior vena cava obstruction
(SVCO) (see Box 7.15)
Atrial fibrillation
Pericardial effusion (see Ch. 16)
Hypo-/hypertension
SVCO in a patient with a
mediastinal mass
Abdomen (see p. 783)
8
Surgical scars
Umbilical nodule
Mass in epigastrium
Visible peristalsis
Abdominal distension
Ascites
Hepatomegaly
Splenomegaly
Renal mass
Pelvic or adnexal mass
Ascites (ovarian carcinoma)
Finger clubbing in
lung cancer
Periphery
1
Calf tenderness, venous
thrombosis
Rash, skin changes (see also p. 1065)
Neurological
9
Focal neurological signs
Sensory deficit
Spinal cord compression
Memory deficit
1
10
Observation
Cachexia
Dehydration
Asymmetry/lumps
Personality change
Skeletal survey
10
Focal bone tenderness
(pelvis, spine, long bones)
Wrist tenderness
(hypertrophic pulmonary
osteoarthropathy)
ci i a ex amia tio of th e pat ie t o a er trea tmet 129
Clinical examination of the patient on cancer treatment
Hair
Alopecia – cytotoxic
Trichomegaly – EGFR inhibitors
Loss of pigmentation – pazopanib
Eye
Uveitis – immunotherapy, BRAF inhibitors,
cytarabine, erlotinib
Cataracts – anti-oestrogen
Lens – steroids
Lungs
Pneumonitis – immunotherapy, taxanes,
bleomycin, gemcitabine, TKIs, radiotherapy
Fibrosis – bleomycin, gemcitabine,
methotrexate, cyclophosphamide,
radiotherapy
Non-cardiogenic pulmonary oedema –
gemcitabine, methotrexate
Liver
Hepatitis – cisplatin, vinblastine, rituximab,
immunotherapy
Pseudocirrhosis – gemcitabine
Sinusoidal obstructive syndrome –
cyclophosphamide, oxaliplatin, vincristine
Steatosis – oxaliplatin, irinotecan,tamoxifen
Skin
Dry skin – all
Maculopapular rashes – TKIs
Mouth
6 7 8
Dysgeusia – all treatment
Xerostomia – all treatment
Stomatitis – 5-FU, methotrexate,
cyclophosphamide, radiotherapy
5
Osteonecrosis of jaw – VEGF inhibitors,
bisphosphonates
4
3
2
Nervous system
Peripheral neuropathy – cisplatin,
oxaliplatin, taxanes, gemcitabine,
brentuximab, immunotherapy
Encephalopathy – ifosfamide, cisplatin,
immunotherapy
Hearing loss – cisplatin
Posterior reversible encephalopathy
syndrome (PRES) – VEGF inhibitors,
rituximab, immunotherapy
Heart
9
Cardiomyopathy – HER2 inhibitors,
anthracyclines, radiotherapy
Myocarditis – immunotherapy, cisplatin
Myocardial ischaemia – 5-FU/ capecitabine,
bevacizumab, radiotherapy
Arrhythmia/QTc prolongation – cytotoxic,
TKIs
Kidneys
10
Nephritis – immunotherapy
Nephrotic syndrome – VEGF inhibitors
Haemorrhagic cystitis – ifosfamide
Nephrotoxicity – cisplatin
GI tract
11
Nausea and vomiting – all treatment
Diarrhoea – all treatment
7
Colitis – ipilimumab, 5-FU/capecitabine,
taxanes, radiotherapy
Paralytic ileus – vinca alkaloids
Bowel perforation – bevacizumab
Strictures – radiotherapy
Vascular
Acneiform rashes – EGFR inhibitors
DRESS syndrome – immunotherapy
Telangiectasia – radiotherapy
Tattoo point marks – radiotherapy
Hands and feet
Palmar plantar erythrodysesthesia –
5-FU, capecitabine, VEGF inhibitors
Paronychia – EGFR inhibitors
Finger tip cracks – EGFR inhibitors
Colour key
Cytotoxic chemotherapy Hormone therapy Targeted therapy Immunotherapy Radiotherapy Supportive
1
Constitutional all
Fatigue – all treatment
Fever – all treatment
Haematological
15
Neutropenia – cytotoxics,
CDK4/6 inhibitors, PARP inhibitors
Bleeding – cytotoxics, VEGF inhibitors
Anaemia – cytotoxics, radiotherapy
12
Venous/arterial thrombo-embolism –
platinum agents, taxanes, TKIs
Phlebitis – fluorouracil, epirubicin, cisplatin,
gemcitabine
Endocrine
13
Hypothyroidism – VEGF inhibitors,
immunotherapy, radio-iodine
Hypophysitis – immunotherapy
Diabetes – immunotherapy, steroids
Adrenalitis – immunotherapy
Addison’s – steroids (withdrawal)
Rheumatological
14
Arthralgia – taxanes, anti-oestrogens,
mTOR inhibitors
Myalgia – taxanes, anti-oestrogens
Bone pain – G–CSF
(CDK = cyclin-dependent kinase; EGFR = epidermal growth factor receptor; G–CSF = granulocyte–colony stimulating factor; PARP = poly-ADP ribose polymerase; TKI =
tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor) (Acneiform rashes) From Potthoff K, Hofheinz R, Hassel JC, et al. Interdisciplinary management of EGFR-
inhibitor-induced skin reactions: a German expert opinion. Ann Oncol 2011; 22(3):524–535. (Colitis) From Som A, Mandaliya R, Alsaadi D, et al. Immune checkpoint inhibitorinduced colitis: A comprehensive review. World J Clin Cases 2019; 7(4):405–418.
130 O ncO l Og y
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Cancer represents a signicant global health, social and economic
burden. In 2018 there were 17 million new cases of cancer worldwide
and 9.6 million cancer deaths, making it the second leading cause of
death. By 2030, it is projected that there will be 26 million new cancer
cases and 17 million cancer deaths per year. The developing world is
disproportionately affected by cancer and in 2018 approximately 70%
of cancer deaths occurred in low- and middle-income countries. These
deaths happen in countries with limited or no access to investigations or
treatment and with low per capita expenditure on health care.
The most common solid organ malignancies arise in the lung, breast
and gastrointestinal tract (Fig. 7.1), but the most common form worldwide is skin cancer. Cigarette smoking accounts for more than 20% of
all global cancer deaths, 80% of lung cancer cases in men and 50%
of lung cancer cases in women worldwide, which could be prevented
by smoking cessation. Diet and alcohol contribute to a further 30% of
cancers, including those of the stomach, colon, oesophagus, breast
and liver. Lifestyle modication could reduce these if steps were taken
to avoid animal fat and red meat, reduce alcohol, increase bre, fresh
fruit and vegetable intake, avoid obesity and increase physical activity.
Infections account for a further 15% of cancers (25% of cancers in lowand middle-income countries), including those of the cervix, stomach,
liver, nasopharynx, anus and bladder, and some of these could be prevented by infection control and vaccination.
The 10 hallmarks of cancer
The formation and growth of cancer is a multistep process, during which
normal cells are transformed into malignant cells. Ten key characteristics
that underlie these steps, collectively referred to as the ‘Hallmarks of
Cancer’, have been described.
60
55
50
45
40
35
30
25
20
15
Number of new cases (thousands)
10
5
0
Lung
Breast
Bowel
Prostate
NHL
Kidney
Melanoma
Head and neck
CNS
Pancreas
Uterus
Bladder
Leukaemia
Male
Female
Ovary
Stomach
Oesophagus
Liver
Thyroid
Myeloma
Other
1. Genome instability and mutation
Random genomic aberrations occur continuously throughout all cells of
the body. This may include somatic point mutations, insertions, deletions
and chromosome structural changes (i.e. copy number changes, chromosomal translocations). Epigenomic aberrations, such as DNA methylation and histone modication, may also occur. Rarely, aberrations will
confer a selective survival advantage on single cells, ‘driving’ overgrowth
and dominance in local tissue environments. Multistep carcinogenesis
results from successive clonal expansions of pre-malignant cells, each
expansion being triggered by acquisition of a random driver aberration.
Under normal circumstances, genome maintenance systems and
DNA repair mechanisms are so effective that almost all spontaneous
genomic aberrations are repaired, or damaged cells are forced into
senescence or apoptosis. In cancer cells, though, the accumulation
of mutations can be accelerated by compromising these maintenance
mechanisms. In turn, this leads to the accumulation of driver genomic
aberrations which lead to cancer growth and progression. Genomic
sequencing technology demonstrates that the pattern of aberrations
vary dramatically between cancer types. However, defects in genome
maintenance mechanisms leading to genome instability are common
ndings across all cancers. This enabling characteristic may lead to the
acquisition of other hallmarks.
2. Resisting cell death
There are three principal mechanisms through which cell death occurs in
healthy tissues: apoptosis, autophagy and necrosis.
Apoptosis
This is programmed cell death. It is frequently found at markedly reduced
rates in cancers, particularly those of high grade or those resistant to
treatment. The cellular apoptotic system has regulatory elements that
sense intrinsic and extrinsic pro-apoptotic signals. This initiates a cascade of proteolysis and cell disassembly with nuclear fragmentation,
chromosomal condensation and shrinking of the cell with loss of intercellular contact, followed by cellular fragmentation and the formation of
apoptotic bodies that are phagocytosed by neighbouring cells. The most
important regulator of apoptosis is the TP53 tumour suppressor gene,
often described as the ‘guardian of the genome’ as it is able to induce
apoptosis in response to sufcient levels of genomic damage. The largest initiator of apoptosis via TP53 is cellular injury, particularly that due
to DNA damage from cytotoxic chemotherapy, oxidative damage and
ultraviolet (UV) radiation. Disruption of p53 protein function as a result of
mutations in the TP53 gene are found in over half of cancers.
Autophagy
This is a catabolic process during which cellular constituents are
degraded by lysosomal machinery within the cell. It is an important physiological mechanism; it usually occurs at low levels in cells but can be
induced in response to environmental stresses, particularly radiotherapy
and cytotoxic chemotherapy, which induce elevated levels of autophagy
that are cytoprotective for malignant cells, thus impeding rather than perpetuating the killing actions of these stress situations. Severely stressed
cancer cells have been shown to shrink via autophagy to a state of
reversible dormancy.
Necrosis
Cancer of unknown primary
Fig. 7.1 The most commonly diagnosed cancers in the UK.
(CNS = central nervous system; NHL = non-Hodgkin lymphoma) Statistics
from Cancer Research UK website (http://info.cancerresearchuk.org)
This is the premature death of cells and is characterised by the release of
cellular contents into the local tissue microenvironment, in marked contrast to apoptosis, where cells are disassembled in a step-by-step fashion and the resulting cellular fragments are phagocytosed. Necrotic cell
Th e 10 ha m ar ks of a er 131
death results in the recruitment of inammatory immune cells, promotion
of angiogenesis and release of stimulatory factors that increase cellular
proliferation and tissue invasion, thereby enhancing rather than inhibiting
carcinogenesis.
3. Sustaining proliferative signalling
The ‘cell cycle’ is tightly controlled at different stages. Normal cells grow
and divide in response to external signals, typically growth factors. These
are able to bind to cell surface-bound receptors that activate an intracellular tyrosine kinase-mediated signalling cascade, ultimately leading to
changes in gene expression that promote cellular proliferation and growth.
The cell cycle
The cell cycle is composed of four ordered, strictly regulated phases
referred to as G1 (gap 1), S (DNA synthesis), G2 (gap 2) and M (mitosis)
(Fig. 7.2). Normal cells grown in culture will stop proliferating and enter
a quiescent state called G0 once they become conuent or are deprived
of serum or growth factors. The rst gap phase (G1) prior to the initiation
of DNA synthesis represents the period of commitment that separates
M and S phases as cells prepare for DNA duplication. Cells in G0 and
G1 are receptive to growth signals, but once they have passed a restriction point, they are committed to enter DNA synthesis (S phase). Cells
demonstrate arrest at different points in G1 in response to different inhibitory growth signals. Mitogenic signals promote progression through G
to S phase, utilising phosphorylation of the retinoblastoma gene product
(pRB, p. 40). Following DNA synthesis, there is a second gap phase (G2)
prior to mitosis (M), allowing cells to repair errors that have occurred
during DNA replication and thus preventing propagation of these errors
to daughter cells. Although the duration of individual phases may vary,
depending on cell and tissue type, most adult cells are in a G0 state at
any one time.
Stimulation of the cell cycle
Many cancer cells produce growth factors, which drive their own proliferation by a positive feedback mechanism known as autocrine stimulation.
Examples include transforming growth factor-alpha (TGF-α) and platelet-
derived growth factor (PDGF). Other cancer cells express growth factor
receptors at increased levels due to gene amplication or express abnor-
mal receptors that are permanently activated. This results in abnormal cell
growth in response to physiological growth factor stimulation or even in
the absence of growth factor stimulation (ligand-independent signalling).
The epidermal growth factor receptor (EGFR) is often over-expressed in
lung and gastrointestinal tumours and the human epidermal growth fac-
tor receptor 2 (HER2)/neu receptor is frequently over-expressed in breast
cancer. Both receptors activate the Ras–Raf–mitogen activated protein
(MAP) kinase pathway, causing cell proliferation.
4. Evading growth suppressors
The cell cycle is orchestrated by a number of molecular mechanisms,
most importantly by cyclins and cyclin-dependent kinases (CDKs).
Cyclins bind to CDKs and are regulated by both activating and inacti-
vating phosphorylation, with two main checkpoints at G1/S and G2/M
transition. The genes that inhibit progression play an important part in
tumour prevention and are referred to as tumour suppressor genes (e.g.
TP53, TP21, TP16 genes). The products of these genes deactivate the
cyclin–CDK complexes and are thus able to halt the cell cycle. The com-
plexity of cell cycle control is susceptible to dysregulation, and mutations
within inhibitory proteins are common in cancer.
5. Enabling replicative immortality
1
Normal cells have a limited number of divisions before they are unable
to divide further (senescence) or before they die (crisis). These limits
are controlled by telomeric DNA sequences, which protect and stabilise
chromosomal ends. During replication, telomeres shorten progressively
as small fragments of telomeric DNA are lost with successive cycles of
replication. This shortening process represents a mitotic clock and even-
tually prevents the cell from dividing further. Telomerase, a specialised
polymerase enzyme, adds nucleotides to telomeres, allowing continued
cell division and thus preventing premature arrest of cellular replication.
The telomerase enzyme is almost absent in normal cells but is expressed
at signicant levels in the majority of human cancers.
7
Quiescent
G
0
Cell
G
1
growth
Cell growth
Cyclin D
CDK4, 6
Cyclin E
CDK2
Terminal
differentiation
Apoptosis
Prophase telophase
Nuclear and cellular division
Terminal differentiation
The cell cycle and sites of action of chemotherapeutic agents. (CDK = cyclin-dependent kinase; RB = retinoblastoma gene)
Fig. 7.2
Mitosis
Apoptosis
M
checkpoint for:
G
2
DNA damage
DNA replication
incomplete
Cyclin B
CDK
1
G
Cyclin A
CDK2
2
Further growth
or DNA repair
DNA replication
S
Restriction point
(regulated by growth
factors)
checkpoint for:
G
1
Damaged DNA
RB blocks
TP53 CDKs blocked
132 O ncO l Og y
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First mutation
Inherited or acquired
gain of oncogene
Loss of tumour
suppressor gene
Lymphatic
spread
Blood spread
Breakdown of connective tissue
via tumour production of
e.g. collagenase
tissue metalloproteinases
Loss of cell adhesion molecules
e.g. E-cadherin
First mutation
Normal
epithelium
Basal lamina
Blood vessel
Connective
tissue
Lymphatic
Further mutation
invasion or metastasis
Initial proliferation Clonal expansion Further mutation
Further mutation; subset
selected for rapid growth
Ectopic
growth factor
production and
autostimulation
Localised
Failed apoptosis
(e.g. TP53 mutation)
Local invasion
through basal
lamina
Angiogenesis
to support
tumour growth
(see Fig. 7.4)
Oncogenesis. The multistep origin of cancer, showing events implicated in cancer initiation, progression, invasion and metastasis.
Fig. 7.3
6. Inducing angiogenesis
All cells and body tissues require sustenance in the form of nutrients
Viable tumour cell
Apoptotic
tumour cell
and oxygen, as well as an ability to evacuate metabolic waste products
and carbon dioxide. Tumours require a functional vascular network to
ensure continued growth and are unable to grow beyond 1 mm
3
without
Inhibition
stimulating the development of a vascular supply through angiogenesis
(Figs. 7.3 and 7.4).
Angiogenesis is dependent on the production of angiogenic growth
factors, of which vascular endothelial growth factor (VEGF) and plate-
A
let-derived growth factor (PDGF) are the best characterised. During
tumour progression, an angiogenic switch is activated and remains on,
causing normally quiescent vasculature to develop new vessels continually to help sustain expanding tumour growth. Angiogenesis is governed
by a balance of pro-angiogenic stimuli and angiogenesis inhibitors, such
as thrombospondin (TSP)-1, which binds to transmembrane receptors
on endothelial cells and evokes suppressive signals. A number of cells
can contribute to the maintenance of a functional tumour vasculature
Loss of
inhibition
Angiogenic
and therefore sustain angiogenesis. These include pericytes and a variety
of bone marrow-derived cells such as macrophages, neutrophils, mast
cells and myeloid progenitors.
7. Activating invasion and metastasis
B C
Angiogenesis, invasion and metastasis.
The ability to invade neighbouring tissue determines whether a tumour
is benign or malignant. Clinically, the presence of metastases often
determines whether a cancer can be cured. The invasion-metastatic
cascade is a complex multistep process. The initiation of this process
is enabled by epithelial-mesenchymal transition (EMT). Cancer cells in a
tumour lose normal cell–cell adhesion through the down-regulation or,
occasionally, mutational inactivation of E-cadherin, a calcium-dependent
cell–cell adhesion glycoprotein. After breaking through the basement
membrane, cancer cells enter the blood stream (intravasation). These circulating tumour cells (CTCs) then exit the blood stream into distant tissues
(extravasation) to form small nodules of cancer cells (micrometastases).
Fig. 7.4
beyond 1 mm
the release of angiogenic factors by the tumour cells and loss of inhibition of the
matrix allow cells to extravasate into the blood stream and metastasise to distant
sites. (VEGF = vascular endothelial growth factor)
Following mesenchymal–epithelial transition these micrometastatic lesions
develop into macroscopic tumours (colonisation) (see Fig. 7.3).
Cross-talk between cancer cells and cells of the surrounding stromal tissue is involved in the acquired capability for invasive growth and
metastasis. Mesenchymal stem cells in tumour stroma have been found
3
factors
VEGF
receptor
VEGF
α
integrin
vβ3
Urokinase
receptor
Coagulation factor
Tissue
factor
Urokinase
Plasminogen
Coagulation
Fibrinogen
Fibrin
Cell adhesion
Proteolysis
Plasmin
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