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Viruses cause cancer
Download lecture at: flemingtonlab.com
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Viruses cause cancer
Why has the study of viruses and cancer been important?
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Viruses cause cancer
Why has the study of viruses and cancer been important?
- We learn about the basic mechanisms of specific types
of tumors.
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Viruses cause cancer
Why has the study of viruses and cancer been important?
- We learn about the basic mechanisms of specific types
of tumors.
- We identify fundamental pathways important for oncogenesis
- viruses are lower complexity
- We can identify potential unique therapeutic targets for viral
associated tumors
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Viruses cause cancer
30-40% of cancers are known to have viral etiology
-But as more research is done,
this percentage is likely to be found to be higher
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Major human Oncogenic Viruses
DNA Viruses
Small DNA tumor viruses
- Adenovirus
- SV40
- Human Papilloma virus (HPV)
Herpesviruses (large)
- Epstein Barr virus (EBV)
- Kaposis Sarcoma Herpesvirus (KSHV)
Other
- Hepatitis virus B
RNA virusesHuman T-cell Leukemia Virus 1 (HTLV1)
Hepatitis virus C
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Changes in cell that are at the roots
of cancer
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Changes in cell that are at the roots
of cancer
Genetic and epigenetic alterations:
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Changes in cell that are at the roots
of cancer
Genetic and epigenetic alterations:Mutations
Deletions
Recombinations
Transpositions
Epigenetic alterations (DNA methylation, imprinting)
Acquisition of viral genetic material
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Changes in cell that are at the roots
of cancer
Genetic and epigenetic alterations:Mutations
Deletions
Recombinations
Transpositions
Epigenetic alterations (DNA methylation, imprinting)
Acquisition of viral genetic material
Various combinations of these lead to the development of cancers - someviruses contribute single hits while others contribute multiple hits.
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InheritedSomatic
- Random
- Transposition
- Exposure to deleterious environmental agents
- Radiation
- carcinogenic chemicals
- Viruses
- Other persistent infections
Source of genetic alterations
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Integrationsthat cause activation or inactivation ofoncogenes or tumor suppressors (e.g. RNA viruses)
Expression of genesthat alter key signal transduction
pathways - this is our focus
Chronic activation of inflammatory responses
How do Viruses contribute to
cancer?
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Why do viruses cause cancer?
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Viruses and cancer cells have similar needsProliferation control
Cell death control
Modulation of immune response
Induction of vascularization
Metastasis (tumor)/cell migration (viruses)
Why do viruses cause cancer?
f f
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If youre infected, does this mean
that you will get cancer?
If i f t d d thi
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NoViruses did not specifically evolve with the need to cause
cancer - they simply have similar (but distinct) needs
If youre infected, does this mean
that you will get cancer?
If i f t d d thi
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NoViruses did not specifically evolve with the need to cause
cancer - they simply have similar (but distinct) needs
Development of tumors almost always requires:Additional genetic alterations and/or
Compromised host (e.g. immuno-suppression)
If youre infected, does this mean
that you will get cancer?
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Major human Oncogenic Viruses
DNA Viruses
Small DNA tumor viruses
- Adenovirus- SV40
- Human Papilloma virus (HPV)
Herpesviruses (large)
- Epstein Barr virus (EBV)
- Kaposis Sarcoma Herpesvirus (KSHV)
Other
- Hepatitis virus B
RNA viruses
Human T-cell Leukemia Virus 1 (HTLV1)
Hepatitis virus C
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AdenovirusHuman virus but only causes cancer in non-human cells
SV40
Mesothelioma
HPVCervical Cancer
Squamous cell anal carcinomaPenile cancer
Oral cancers
Small DNA tumor viruses
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HPVSV40
Adenovirus
Normally replicate episomally but almost always foundintegrated in associated tumors - why?
Small DNA tumor viruses
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HPVSV40
Adenovirus
Normally replicate episomally but almost always foundintegrated in associated tumors - why?
Replication must be abortive
HPV, viral encoded negative regulatory factor must be deleted
Small DNA tumor viruses
DNA T Vi I
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DNA Tumor Viruses In
Human Cancer
Papilloma Viruses
urogenital cancer
wart malignant squamous cell carcinomaPapilloma viruses are found in 91% of women with cervical cancer
10% of human cancers may be HPV-linked
16% of all female cancers linked to HPV
DNA Tumor Viruses In
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DNA Tumor Viruses In
Human Cancer
Papilloma Viruses >100 types identified - most common are types 6 and 11
Most cervical, vulvar and penile cancers are ASSOCIATED with
types 16 and 18 (70% of penile cancers)
Effective Vaccine(quadrivalent recombinant HPV 6, 11, 16 and 18proteins made in
yeast - Gardasil)
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Papilloma Viruses
The important transforming genes in papillomaviruses are the non-structural regulatory genes,E6and E7
HPV is normally episomal but is alwaysintegrated in tumors
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Adenoviruses
Highly oncogenic in animals
Only part of virus integrated
Always the same part
Early (regulatory) genes
E1A and E1B = Oncogenes
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SV40
The important transforming gene is T Ag
- provides similar functions as E1A +E1B (Adenovirus) and E6 and E7 (HPV)
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Abortive replication is key to oncogenesis
by these small viruses
Expression of early (regulatory) genes inabsence of structural genes and virusproduction Can occur by infection of non-permissive host
Can occur by integrations that delete regions of viralgenome required for replication but leave early genesintact.
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Small DNA Tumor Viruses
What are the needs of small DNA tumor
viruses that make them oncogenic and
What are the key mechanisms through which
they attain their needs?
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Small DNA Tumor Viruses
DNA viral genome
Host RNA
polymerase
Viral mRNA
Viral protein
Utilizes
Host Cell DNA
Replication MachineryNeed cells that are in S-
phase to replicate viral
genome Host enzymes
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Inappropriate activation of cell
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Inappropriate activation of cell
cycle
Inappropriate activation of cell
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Inappropriate activation of cell
cycle
Apoptosis
Inappropriate activation of cell
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Inappropriate activation of cell
cycle
Apoptosis
e.g.
-Overexpression of E2F1 or c-Myc induces cell cycle and apoptos
-Defense mechanism against rogue proliferating cells?
Inappropriate activation of cell
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Inappropriate activation of cell
cycle
Apoptosis
e.g.
- Overexpression of E2F1 or c-Myc induces cell cycle and
apoptosis
- Same is true for over-expression of Adenovirus E1A or HPV E7
Encode early genes that
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Encode early genes that
inhibit apoptosis
AdenovirusE1B
HPVE6
SV40T Ag
SV40 d HPV
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SV40 and HPV
Ad i
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Adenovirus
E1B is Bcl2 family member - blocks function of pro-apoptotic Bcl2 family members through dimerization
S
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Summary
Small DNA tumor viruses usually replicate in episomalform but are found integrated in viral associated tumors
Early genes promotecell cycle progression andprevenapoptosis
Adenovirus -E1A (cell cycle) and E1B (apoptosis)
HPV - E7(cell cycle) and E6(apoptosis)
SV40 - T Ag(cell cycle and apoptosis)
H i
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Herpes viruses
Oncogenic members:Epstein Barr virus (EBV)
Kaposis Sarcoma Herpes virus (KSHV)
Oncogenic mechanisms are dis t inct from small
DNA tumor vi ruses
- Dont need to integrate
- Cel l cycle is not d r iven by lyt ic repl icat ion regulatory gen
H i
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Herpes viruses
Hallmark of herpesviruses:
H i
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Herpes viruses
Hallmark of herpesviruses:
Existence of latent stage (in addition to lytic/replicative stage)
Herpes viruses
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Herpes viruses
Lytic replication phase for herpesviruses:
Herpes viruses
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Herpes viruses
Lytic replication phase for herpesviruses:
- Herpesviruses are large and encode 80-100 lytic
associated genes
- Encode their own DNA polymerase and replication
accessory enzymes
- Therefore, they dont require an S-phase
environment for replication
- Encode early genes that induce cell cycle
arrest
Herpes viruses
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Herpes viruses
Latency:
- Small subset of viral genes are expressed that are not expressed
during lytic replication.
- Latency is partlya way for virus to hide from immune system
- In cases of EBV and KSHV, latency genes can also
induce cell differentiation/activation programs
that facilitate expansion of infected cell population
and induce traffickingto specific lymphoid
compartments that are suited to the life cycle
of the virus
Herpes viruses
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Herpes viruses
Human Herpesviruses and latency function:
Epstein Barr virus (EBV) - multiple functions
Kaposis Sarcoma Herpes virus (KSHV) - multiple functions
Cytomegalovirus (CMV) - Stealth mechanism
Herpes Simplex (HSV) - Stealth mechanism
Epstein Barr virus
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Epstein Barr virusPathologies in immuno-competentindividuals
Infectious mononucleosis
Burkitts Lymphoma
Hodgkins lymphoma
Nasopharyngeal carcinoma
Pathologies in immuno-compromisedindividuals
Post-transplant lymphoproliferative diseases
(PTLD)
Hodgkins lymphomaA variety of non-Hodgkins lymphoblastoid
malignancies
Epstein Barr virus
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Epstein Barr virusLatency genes
Non-antigenic
- EBNA1 (Epstein Barr Nuclear Antigen 1) -
episomal replication and segregation function
Antigenic
- EBNA2
- EBNA3A, 3B, 3C
- EBNA-LP
- LMP1(Latent Membrane Protein 1)
- LMP2A
Those in Redare key regulatory genes involved in B cell activation
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Epstein Barr virus
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Epstein Barr virus4 different types of latency
True Latency - no viral gene expression
EBNA1 only- EBNA1 (non-antigenic)
Default- EBNA1, LMP1, and LMP2 (moderately
antigenic)
Growth- EBNA1, LMP1, LMP2, EBNA2, EBNA-
LP, EBNA3A, 3B, 3C (highly antigenic)
Growth program
-Initial infection (prior to immune response)- Immuno-compromised individuals
- in vitro infection of nave peripheral blood lymhocytes
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Epstein Barr virus
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Epstein Barr virusGreater than 90% of US population are carriers of
EBV
-Only small percentage of carriers develop tumors
- who?
-Imm uno-comprom ised - a llows fu l l set of on congenicgenes to be expressed
-Immuno -com petent who have mult ip le addit ional
genet ic hi ts
EBV does not integrate - exists as an
extrachromosomal episome
Kaposis Sarcoma Herpes
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Virus - HHV-8
Hematologic malignanciesPrimary effusion lymphoma
Multicentric Castleman's disease (MCD)a rare
lymphoproliferative disorder (AIDS)
MCD-related immunoblastic/plasmablastic
lymphoma
Various atypical lymphoproliferative disorders
Kaposis sarcoma
Hepatitis B and C
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Long latency period to development of HCC (Hepatocellular Carcinom
20-30 years
Mechanism is probably due to chronic inflammatory response
Silver lining to viral
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associate cancersOffer unique targets not common to normal
uninfected cells
Examples:
HPV
- Gardasil
EBV
- In vitro production of EBV specific CTLs for PTLD
- Treatment with agents that induce lytic cycle
(butyrate plus Gancyclovir)
KSHV
- Anti-retroviral therapy