world cancer report - iarc

infected cells, whilst oncoproteins E6 and
E7 interfere with the functions of negative
cellular regulators, including p53 and pRb
(Oncogenes and tumour suppressor
genes, p96). Integration of the viral
genome, deregulation of oncogene expression
and other cofactors may all contribute
to malignant progression (Fig. 2.43).
A few other viruses are directly linked to
human cancer, including EBV, HTLV-1 and
HHV-8. EBV infects B lymphocytes and
expression of viral protein is believed to
induce what would otherwise be antigendriven
lymphocyte activation. The immortalization-associated
viral proteins regulate
the maintenance of the episomal viral
DNA and the expression of viral genes, as
Fig. 2.47 The burden of cancer caused by infectious agents in women.
Fig. 2.48 The burden of cancer caused by infectious agents in men.
well as driving cellular proliferation and
blocking apoptosis. It is believed that a
crucial role in the transformation and
immortalization of infected cells is played
by the EBNA-2 protein. Malarial infection
may be a cofactor in the progression of
Burkitt lymphoma. HTLV-1 is able to
immortalize human T lymphocytes in vitro.
Central to this property is the HTLV-1 Tax
protein which, via interference with several
classes of transcription factors, activates
the expression of some cellular
genes involved in the control of cellular
proliferation. HHV-8 is the most recentlyidentified
tumour-causing virus and its
role in pathogenesis is still poorly understood
[7, 13].
Carrier
_
Immune response
Chronic hepatitis
Mitogenesis Mutagenesis
Cellular DNA
damage, chromosomal
abnormalities,
genetic mutations
HBV Infection
Secondary events
Loss of cellular growth control
Hepatocellular
carcinoma
Fig. 2.49 Hepatitis B virus and the chronic injury
hypothesis. A vigorous immune response to hepatitis
B virus (+++) leads to viral clearance while
an absent immune response (-) leads to the
“healthy” carrier state and an intermediate
response (+) produces chronic hepatitis which, via
a multistep process, may eventually lead to hepatocellular
carcinoma.
The second, or indirect, mechanism is the
mode of action for some viruses (HBV, HCV,
HIV), bacteria (H. pylori) and parasites.
These agents provoke cancer by causing
chronic inflammation and/or production of
mutagenic compounds. The hepatitis viruses,
for example, are unable to immortalize
human cells in vitro, but infection may lead
to cancer via induction of chronic liver injury
and hepatitis (Fig. 2.49). Chronic hepatitis
caused by an intermediate immune
response to HBV infection is characterized
by chronic liver cell necrosis which stimulates
a sustained regenerative response. The
inflammatory component includes activated
macrophages which are a rich source of free
radicals. The collaboration of these mitogenic
and mutagenic stimuli has the potential
to cause cellular and viral DNA damage,
chromosomal abnormalities and genetic
mutations that deregulate cellular growth
control in a multistep process that eventually
leads to hepatocellular carcinoma.
A prolonged process, lasting decades,
precedes emergence of most gastric cancers.
H. pylori is the most frequent cause
of chronic gastritis. Gastritis and atrophy
+
+++
Clearance
Viral DNA damage
integration into host
genome,
X gene activation
Chronic infections 59