Transcript Oncogenic Viruses

Viruses and Cancer
Cancers of viral aetiology
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Hepatocellular carcinoma (HBV and HCV)
Burkitt’s lymphoma (EBV)
nasopharyngeal carcinoma (EBV)
Hodgkins disease (EBV)
cervical carcinoma (HPV)
Kaposi’s sarcoma (HHV-8)
adult T cell leukaemia/lymphoma (HTLV-1)
Criteria
epidemiology
 virus in tumour tissue
 viral genes and oncogenesis
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Mechanisms of Oncogenesis
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2.
3.
modulation of cell cycle control (The virus may alter
the regulatory mechanisms controlling the progress
of the cell cycle and cell division)
modulation of apoptosis (the virus must prevent the
host cell from undergoing apoptosis, a normal
cellular response to viral-induced injury, which would
otherwise abort the further development of
uncontrolled cell proliferation)
ROS (Reactive oxygen species) mediated damage
Cell Cycle Control
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pRB ( a tumor suppressor protein that is
dysfunctional in several major cancers. One function
of pRb is to prevent excessive cell growth by
inhibiting cell cycle progression until a cell is ready to
divide)
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cyclin D1 (cell cycle control)
Modulation of Apoptosis
P53 (transcription factor activated by
DNA damage that can induce growth
arrest and apoptosis)
 Bcl-2 (supress apoptosis)
 FLICE inhibitory proteins (FLIPs) (inhibit
apoptosis signalling)
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ROS Damage
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inflammatory responses generate radicals,
including OH. and NO.
free radicals target
DNA (mutation)
protein (nitration, nitrosation)
RNA
lipids (lipid peroxidation)
ROS Damage
Free radicals may promote cancer by
 mutating cancer related genes
 activating signal transduction pathways
 promoting angiogenesis
 exerting selective pressure (p53 and NO.)
Hepatocellular Carcinoma
Hepatocellular Carcinoma
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HCC is one of the most prevalent malignant
diseases in the world
chronic infection with HBV or HCV accounts
for more than 80% of HCC cases
other risk factors include aflatoxin B1, heavy
alcohol consumption and smoking
HCC and HBV
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insertional activation
HBx
transactivation of proinflammatory genes
interaction with p53
generation of ROS
HCC and HCV
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HCV sequences are present in HCC tissue
HCV antigen expression in HCC (or other
tissue) cannot be assessed
HCV contains genes with potential oncogenic
function
HCV genes
HCV core protein has been shown to
 cause HCC in transgenic mice
 modulate apoptosis
 drive cells to proliferation
 generate ROS
HCC and hepatitis viruses
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mass vaccination against HBV will radically
reduce the incidence of HCC in SE Asia
elimination of HCV or HBV reduces the risk of
developing HCC
Human Herpesvirus 8 and
Kaposi’s Sarcoma
Kaposi’s Sarcoma
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Kaposi’s sarcoma (KS) is a mesenchymal
tumour involving blood and lymphatic vessels
KS occurs in three forms:
classical
endemic
epidemic
Pathology of KS
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Multicentric lesions composed of interweaving
bands of spindle cells that form irregular
vascular channels
Spindle cells express markers of endothelial
cells (CD34 and Factor VIII)
KS and HIV
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The incidence of KS in HIV positive gay men
is 20,000 fold that of the general population
KS is 20 times more common in homosexual
men with AIDS than other risk groups
the risk of KS in HIV positive men increases
with the frequency and risk of sexual activity
Herpesviruses and KS
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In 1994 RDA isolated viral sequences from KS
tissue
these sequences were identified as a new
herpesvirus, designated HHV-8
HHV-8 has now been found in almost 100%
of tissues from all forms of KS
Epidemiology
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HHV-8 seropositivity in various populations is
correlated with the population risk of KS
Longtitudinal surveys have shown infection
with HHV-8 precedes the onset of KS
Virus and Tumour Tissue
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In individuals with KS, HHV-8 sequences are
found in tumour but not in adjacent tissue
within KS lesions, HHV-8 DNA and antigen
expression is localised to spindle cells
Genes and oncogenesis
HHV-8 encodes homologues of human proteins
(examples):
 cyclin D1
 G-protein coupled receptor
 bcl-2
 FLICE inhibitory protein
 And others
v-cyclin D1
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HHV-8 v-cyclin is expressed in KS lesions and
interacts with CDK6
v-cyclin in complex with CDK6 is not inhibited
by p16 INK4a or p27Kip1
HHV-8 (G protein-coupled
receptor) GPCR
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HHV-8 encodes a viral G protein-coupled
receptor (vGPCR).
v-GPCR is homologous to the IL-8 receptor
v-GPCR has been shown to transform cells
and tumour formation.
HHV-8 bcl-2
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the viral protein has both sequence and
structural homology to bcl-2 family proteins
v-bcl-2 is functional
the role of v-bcl-2 in the viral life cycle is not
yet clear
v-FLIP
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v-FLIPs inhibit apoptosis signalling through
death receptors
HHV-8 v-FLIP physically interacts with procaspase-8 and prevents recruitment to DISC
Non-homologous Viral Genes
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Latency -associated nuclear antigen (LANA) is
essential to the maintenance of HHV-8
LANA interacts with p53 and suppresses its
transcriptional activity