Transcript BTY328: Viruses

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Viruses and Cancer
BTY328: Virology [email protected]
Some viruses cause cancer
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Viruses are one of the main factors that cause
normal cells to proliferate and to become
malignant: up to 15% of all human cancers are
associated with single or multiple virus
infections
Viruses have evolved many strategies to
prevent infected cells from becoming apoptotic
and to evade the innate and adaptive immune
responses of their hosts.
Changes in critical cellular funtions such as cell
cycle control, cellular signalling, DNA repair,
apoptosis or tumour supression lead to
cancer
Viruses associated with cancers
Viruses associated with cancers
How do viruses cause cancer?
1. Transducing viruses
Oncogenes of retroviruses arose by
transduction of cellular genes by
recombination events.
Originally recognized from studies of the
oncogene (v-src) of Rous sarcoma virus
(RSV) and its cellular progenitor (c-src).
Transducing virus oncogenes
EGF receptor and transducing
virus version
The ErbB protein family or
epidermal growth factor receptor
(EGFR) family is a family of four
structurally related receptor
tyrosine kinases.
Excessive ErbB signaling is
associated with the development of
a wide variety of types of solid
tumor.
Non- transducing viruses and
cancer
2. Non transducing viruses:
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Retroviruses integrate into host genomes and can
disrupt coding regions of host genes (deletions
truncations, rearrangements)
Integration into the host genome alters host genome
expression (eg. LTR can act as enhancers or
repressors of host gene expression). Cis acting viral
sequences.
Produce changes in cell metabolism through the
action of viral proteins acting as trans-acting
factors (protein-protein and protein-DNA interactions
Insertional activation of cellular
oncogene (c-onc)
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Insertional activation
can be by action of
promoter or enhancer
c-onc can be a host
protein critical for cell
cycle control/cellular
signalling/apoptosis
Eg. Ras ., myc
activation
Human papillomavirus E5 protein
Human papillomavirus E5 protein
increases the EGF cell surface
receptor concentration of infected
cells
Inhibits the endosomal H+ ATPase
thus slowing degradation of EGF
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p53- a master tumour supresor
Inactivation of the p53 protein by
adeno- and papo- viral proteins
Viral proteins
inactivate or remove
p53
(tumour repressor)
thereby causing
oncogenesisis
Normal response to remove
infected cells….
EBV
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Epstein-Barr virus (EBV), is a herpesvirus family and
very common. The virus occurs worldwide, and most
people become infected with EBV sometime during
their lives. > 95% of adults between 35 and 40 years
of age have been infected.
Many children become infected with EBV, usually
cause no symptoms or are indistinguishable from
the other mild, brief illnesses of childhood. When
infection with EBV occurs during adolescence or
young adulthood, it causes infectious mononucleosis
35% to 50% of the time.
Also called glandular fever or the “kissing disease”
Diseases Driven by Epstein-Barr Virus
(EBV)
Infectious mononucleosis
Chronic Active EBV
X-linked lymphoproliferative disease
Lymphoproliferative disease
Oral hairy leukoplakia
Hodgkin disease
Nasopharyngeal carcinoma
T cell lymphoma
Proliferation
Burkitt lymphoma
EBV
Gene
Expression
EBV-Driven
Cell
EBV Viral Load is Increased in Patients
with Lymphoproliferative Disease
Riddler, Blood 1994
Viral Load Used to Monitor Transplant
Patients:
Increased EBV load at
onset of LPD
Used to initiate preemptive
therapy
Burkitt Lymphoma
EBV+: 90% of cases in developing countries –
jaw tumors
20% cases in US – children with
abdominal tumors
AIDS patients – tumors in lymph nodes
Dysregulation of c-myc oncogene
Only EBV EBNA-1 expressed
EBV-Associated Smooth Muscle Tumors
Occur in transplant
recipients, AIDS patients,
congenitial
immunodeficiency
Pathology:
leiomyosarcomas and
leiomyomas in various
organs and lymph nodes
EBV Lymphoproliferative Disease
Occurs with immunodeficiency
(AIDS, congenital) or after
transplantation, RA and MTX
Symptoms:
Infectious Mononucleosis
Mass lesions in organs
(less often lymph nodes)
Cohen NEJM 2000
LMP-1 is the EBV Oncogene
LMP-1 mediates signaling through the Tumor
necrosis factor-alpha/CD40 pathway.
 LMP-1 Expression in transgenic mice leads to B
cell lymphoma; expression in fibroblasts leads
to tumors in nude mice
 B Cell Proliferation :
Upregulates adhesion molecules, CD23, CD40,
IL-6, IL-10, etc. Activates NF- B
 Inhibition of apoptosis:
Upregulates Bcl-2, A20, Mcl-1
Signalling pathway of TNF
TNF stimulates
the inflammatory
response and
causes apoptotic
cell death…
Summary
Viruses can cause cancer (uncontrolled cell growth).
Either through the recombination and capture of host
oncogenes (transducing viruses) or by several
mechanisms to alter cellular growth, differentiation and/or
signalling (non-transducing viruses) including:
 Retroviruses integrate into host genomes and can disrupt
coding regions of host genes (deletions truncations,
rearrangements)
 Integration into the host genome alters host genome
expression (eg. Cis acting viral sequences act as
repressors of host gene expression).
 Produce changes in cell metabolism through the action
of viral proteins acting as trans-acting factors (proteinprotein and protein-DNA interactions
The associations beweeen viruses and cancers are
becoming clearer with better epidemiology and methods to
isolate and study viruses.