Transcript Viruses-and-Cancer

Viruses and Cancer
Orla Sheils
Department of Histopathology
Carcinogenesis
What Causes Cancer?
Carcinogens
 Age
 genetic make up
 immune system
 diet
 day-to-day environment
 Viruses
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Age
Diet
Factors in Carcinogenesis
Chromosomes/DNA
In addition to chemicals and radiation, a few viruses also can trigger the
development of cancer. In general, viruses are small infectious agents that cannot
reproduce on their own, but instead enter into living cells and cause the infected cell
to produce more copies of the virus. Like cells, viruses store their genetic
instructions in large molecules called nucleic acids. In the case of cancer viruses,
some of the viral genetic information carried in these nucleic acids is inserted into
the chromosomes of the infected cell, and this causes the cell to become malignant.
Viral Oncology –historical perspective
First tumour viruses described at start of
20th Century
 Retroviruses
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Avian leukaemia virus - Ellerman & Bang
 Avian sarcoma virus –Rous
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Ludwig Goss 1950s - retroviruses cause
tumours in mice
 William Jarrett – feline leukaemia virus
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Viruses
Viruses contribute to development of some
cancers. Typically, the virus can cause genetic
changes in cells that make them more likely to
become transformed.
These cancers and viruses are linked
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Cervical cancer and the genital wart virus, HPV
Primary liver cancer and the Hepatitis B virus
T cell leukaemia in adults and the Human T cell
leukaemia virus
HTLV-1
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naturally infects CD4+ T lymphocytes and can be
transmitted between close contacts through blood
transfer or from mother to infant through cells in breast
milk.
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In most cases the infection is harmless. However, as many as
1 in 20 infected individuals eventually develop a type of adult
T cell leukaemia in which every tumour cell carries a clonally
integrated HTLV1 provirus.
HTLV1 differs from the standard 'chronically
oncogenic' and 'acutely oncogenic' retroviruses in its
mechanism of action;
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it appears to drive cell growth through expression of a
particular viral protein, Tax, in latently-infected cells
HTLV retrovirus and adult T-cell leukaemia
Mode of action
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Tax can transactivate expression of a
number of key cellular genes that
enhance cell growth.
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The best examples are the genes encoding
interleukin 2 (a T cell growth factor) and
 the interleukin 2 receptor (a molecule that allows
cells to respond to the growth factor).
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As a consequence, the infected cells not
only make their own growth signals, but also
respond to them
Mode of action
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HTLV1 induces a weak growth transformation of T cells in the
laboratory but, in the body, is probably never sufficiently strong to
induce T cell leukaemia on its own.
BUT, a virally infected cell in which growth controls have even
partly broken down, is more susceptible to further genetic
accidents.
During persistent infection a gradual build-up of HTLV1-positive T
cells which have accumulated additional genetic changes may
occur.
Eventually this can lead to selection and outgrowth of a fully
malignant, HTLV1-positive clone
At this stage malignant cell growth can occur in the absence of
tax gene expression.
Epstein Barr Virus
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Epstein-Barr virus (EBV), also called Human
herpesvirus 4 (HHV-4), is a virus of the herpes family
(which includes Herpes simplex virus and
Cytomegalovirus),
 one of the most common viruses in humans.
 Most people become infected with EBV,
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often asymptomatic
but commonly causes infectious mononucleosis.
It is named after Michael Epstein and Yvonne Barr,
who together with Bert Achong discovered the virus in
1964.
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On infecting the B-lymphocyte, the linear virus
genome circularises and the virus subsequently
persists within the cell as an episome.
The virus can execute several distinct programmes of
virally-encoded gene expression
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broadly categorised as being lytic cycle or latent cycle.
The lytic cycle or productive infection results in staged
expression of a host of viral proteins with the ultimate
objective of producing infectious virions. Formally, this phase
of infection does not inevitably lead to lysis of the host cell as
EBV virions are produced by budding from the infected cell.
The latent cycle programmes are those that do not result in
production of virions.
EBV-associated malignancies
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The strongest evidence linking EBV and
cancer formation is found in Burkitt's
lymphoma and Nasopharyngeal
carcinoma
Burkitts Lymphoma
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a type of Non-Hodgkin's lymphoma
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most common in equatorial Africa
co-existent with the presence of malaria.
Malaria infection causes reduced immune surveillance of EBV
immortalised B cells, so allowing their proliferation. This proliferation
increases the chance of a mutation to occur. Repeated mutations
can lead to the B cells escaping the body's cell-cycle control,
allowing the cells to proliferate unchecked, resulting in the formation
of Burkitt's lymphoma. Burkitt's lymphoma commonly affects the jaw
bone, forming a huge tumour mass. It responds quickly to
chemotherapy treatment, namely cyclophosphamide, but recurrence
is common.
Other B cell lymphomas arise in immunocompromised patients
such as those with AIDS or who have undergone organ
transplantation with associated immunosuppression.
Smooth muscle tumours are also associated with the virus.
Nasopharyngeal carcinoma
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found in the upper respiratory tract, most
commonly in the nasopharynx, and is linked to
the EBV virus.
 It is found predominantly in Southern China
and Africa, due to both genetic and
environmental factors. It is much more
common in people of Chinese ancestry
(genetic), but is also linked to the Chinese diet
of a high amount of smoked fish, which
contain nitrosamines, well known carcinogens
(environmental).
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When EBV infects B-lymphocytes in vitro,
lymphoblastoid cell lines eventually emerge
that are capable of indefinite growth.
 The growth transformation of these cell lines is
the consequence of viral protein expression.
 EBNA-2, EBNA-3C and LMP-1 are essential
for transformation while EBNA-LP and the
EBERs are not.
 The EBNA-1 protein is essential for
maintenance of the virus genome
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EBNA-2 is the main viral transactivator, switching
transcription from the Wp promoters used during initial
infection to the Cp promoter.
Together with EBNA-3C, it also activates the LMP-1
promoter. It is known to bind the host RBP-Jκ protein
that is a key player in the Notch pathway. EBNA-2 is
essential for EBV-mediated growth transformation.
EBNA-3A/EBNA-3B/EBNA-3C also bind the host
RBP-Jκ protein.
EBNA-3C is also a ubiquitin-ligase and has been
shown to target cell cycle regulators like pRb.
Kaposi's sarcoma
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form of skin cancer that can involve
internal organs. It most often is found in
patients with acquired immunodeficiency
syndrome (AIDS), and can be fatal.
K.S.
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Kaposi's sarcoma (KS) was once a very rare form of
cancer, primarily affecting elderly men of
Mediterranean and eastern European background
(tumours on lower legs), until the 1980s, when it
began to appear among AIDS patients.
AIDS-related KS, emerged as one of the first illnesses
observed among those with AIDS. Unlike classic KS,
AIDS-related KS tumours generally appear on the
upper body, including the head, neck, and back. The
tumours also can appear on the soft palate and gum
areas of the mouth, and in more advanced cases, they
can be found in the stomach and intestines, the lymph
nodes, and the lungs.
Kaposi Sarcoma and HHV8
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Studies in 2000 showed that HHV-8 was the culprit
behind KS.
It does not work alone.
In combination with a patient's altered response to
cytokines (regulatory proteins produced by the
immune system) and the HIV-1 transactivating protein
Tat which promotes the growth of endothelial cells,
HHV-8 can then encode interleukin 6 viral proteins,
specific cytokines that stimulate cell growth in the skin.
This becomes KS.
HHV-8
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HHV-8 destroys the immune system further by
directing a cell to remove the major
histocompatibility complex (MHC-1) proteins
that protect it from invasion.
 These proteins are then transferred to the
interior of the cell and are destroyed.
 This leaves the cell unguarded and vulnerable
to invaders which would normally be targeted
for attack by the immune system.
Global burden of cervical cancer
Age standardised incidence rates per 100,000
The natural history of HPV infection and
cervical cancer
Cervical Screening
Genomic Map of HPV
(von Knebel Doberitz/European Journal of Cancer 2002; 38: 2229-2242).
The interactions of E6 and E7
The interacting worlds of HPV and p16
Pathways of Cell Cycle Regulation in Cervical
Cancer
p16(INK4a)
p16(INK4a)
MCM5
p16(INK4a)
Geminin
The Hepatitis B Virus (HBV)
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HBV is a mostly double-stranded DNA virus in the
Hepadnaviridae family.
HBV causes hepatitis in human.
The HBV genome has four genes: pol, env, pre-core
and X that respectively encode the viral DNApolymerase, envelope protein, pre-core protein (which
is processed to viral capsid) and protein X.
The function of protein X is not clear but it may be
involved in the activation of host cell genes and the
development of cancer.
Consequences of HBV Infection
HBV causes acute and chronic hepatitis.
 The chances of becoming chronically
infected depends upon age.
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About 90% of infected neonates and 50% of
infected young children will become
chronically infected.
 In contrast, only about 5% to 10% of
immunocompetent adults infected with HBV
develop chronic hepatitis B.
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Hepatocellular carcinoma
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cancer that arises from hepatocytes, the major
cell type of the liver.
 Hepatocellular carcinoma is one of the major
cancer killers.
 It affects patients with chronic liver disease
who have established cirrhosis,and currently is
the most frequent cause of death in these
patients.
 The main risk factors for its development are
hepatitis B and C virus infection,alcoholism
and aflatoxin intake.
HBV DNA integration
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Should be viewed as a dynamic process.
Longterm chronic inflammation, associated with
increased liver cell proliferation, induces several
rearrangements of the integrated viral sequences
(Hessein et al., 2005).
Deletions of part of the viral genome as well as more
complex rearrangements are frequently observed
(Wang et al., 2004b).
Hepatitis B virus insertion can induce chromosomal
deletions at the HBV integration sites.
Transpositions of the viral sequences, together with
the flanking cellular sequences from one chromosome
toanother, have been recently confirmed
integrated HBV can generate
chromosomal instability
 it has been suggested that viral DNA
sequences encompassing the
encapsidation signal may exhibit intrinsic
recombinogenic activity via binding to a
putative ‘recombinogenic’ cellular protein
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HBV integration
The insertion of HBV genome
in cellular genes frequently
targets genes that regulate
key cellular pathways. The
figure illustrates that HBV
targets a variety of genes
controlling various steps of
cellular signalling, cell
proliferation and viability
HBx
Targets modulated by HBx -
Targets of HBx
Schematic representation of the different targets of HBx. The
figure shows the cytoplasmic, mitochondrial and nuclear
transduction cascades activated by HBx.