Download Small DNA Tumor Viruses

Viruses and Cancer
Tumor Virology
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Cancer
• Cancer is one of the most common diseases in the
developed world:
• 1 in 4 deaths are due to cancer
• 1 in 17 deaths are due to lung cancer
• Lung cancer is the most common cancer in men
• Breast cancer is the most common cancer in
women
• There are over 100 different forms of cancer
Cancer
• The division of normal cells is precisely controlled.
New cells are only formed for growth or to replace
dead ones.
• Cancerous cells divide repeatedly out of control
even though they are not needed, they crowd out
other normal cells and function abnormally. They
can also destroy the correct functioning of major
organs.
What causes cancer?
• Cancer arises from the mutation of a normal gene.
• Mutated genes that cause cancer are called
oncogenes.
• It is thought that several mutations need to occur to
give rise to cancer
• Cells that are old or not functioning properly
normally self destruct and are replaced by new
cells.
• However, cancerous cells do not self destruct and
continue to divide rapidly producing millions of new
cancerous cells.
• A factor which brings about a mutation is called
a mutagen.
• A mutagen is mutagenic.
• Any agent that causes cancer is called a
carcinogen and is described as carcinogenic.
• So some mutagens are carcinogenic.
Carcinogens
• Ionising radiation – X Rays, UV light
• Chemicals – tar from cigarettes
• Virus infection – papilloma virus can be responsible for
cervical cancer.
• Hereditary predisposition – Some families are more
susceptible to getting certain cancers. Remember you
can’t inherit cancer its just that you maybe more
susceptible to getting it.
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)
- Kaposi’s Sarcoma Herpesvirus (KSHV)
Other
- Hepatitis virus B
RNA viruses
Human 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 - some
viruses contribute single hits while others contribute multiple hits.
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Source of genetic alterations
Inherited
Somatic
- Random
- Transposition
- Exposure to deleterious environmental agents
- Radiation
- carcinogenic chemicals
- Viruses
- Other persistent infections
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Viruses and Cancer
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How do Viruses contribute to
cancer?
• Integrations that cause activation or inactivation of
oncogenes or tumor suppressors (e.g. RNA viruses)
• Expression of genes that alter key signal transduction
pathways - this is our focus
• Chronic activation of inflammatory responses
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Why do viruses cause cancer?
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Why do viruses cause cancer?
• Viruses and cancer cells have similar needs
• Proliferation control
• Cell death control
• Modulation of immune response
• Induction of vascularization
• Metastasis (tumor)/cell migration (viruses)
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If you’re infected, does this mean
that you will get cancer?
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If you’re infected, does this mean
that you will get cancer?
• No
• Viruses did not specifically evolve with the need to cause
cancer - they simply have similar (but distinct) needs
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If you’re infected, does this mean
that you will get cancer?
• No
• Viruses 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)
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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)
- Kaposi’s Sarcoma Herpesvirus (KSHV)
Other
- Hepatitis virus B
RNA viruses
Human T-cell Leukemia Virus 1 (HTLV1)
Hepatitis virus C
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Small DNA tumor viruses
• Adenovirus
• Human virus but only causes cancer in non-human cells
• SV40
• Mesothelioma
• HPV
• Cervical Cancer
• Squamous cell anal carcinoma
• Penile cancer
• Oral cancers
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Small DNA tumor viruses
• HPV
• SV40
• Adenovirus
• Normally replicate episomally but almost always found
integrated in associated tumors - why?
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Small DNA tumor viruses
• HPV
• SV40
• Adenovirus
• Normally replicate episomally but almost always found
integrated in associated tumors - why?
• Replication must be abortive
• HPV, viral encoded negative regulatory factor must be deleted
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DNA Tumor Viruses In
Human Cancer
Papilloma Viruses
urogenital cancer
wart
malignant squamous cell carcinoma
Papilloma 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
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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 18 proteins made in
yeast - Gardasil)
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Papilloma Viruses
• The important transforming genes in papilloma
viruses are the non-structural regulatory genes,
E6 and E7
• HPV is normally episomal but is always
integrated 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 in
absence of structural genes and virus
production
– Can occur by infection of non-permissive host
– Can occur by integrations that delete regions of viral
genome required for replication but leave early genes
intact.
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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
Utilizes
Host Cell DNA
Replication Machinery
Need cells that are in Sphase to replicate viral
genome
Host RNA
polymerase
Viral mRNA
Host enzymes
Viral protein
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Inappropriate activation of cell
cycle
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Inappropriate activation of cell
cycle
Apoptosis
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Inappropriate activation of cell
cycle
Apoptosis
e.g.
-Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis
- Defense mechanism against rogue proliferating cells?
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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
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Encode early genes that
inhibit apoptosis
Adenovirus E1B
HPV E6
SV40 T Ag
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SV40 and HPV
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Adenovirus
E1B is Bcl2 family member - blocks function of proapoptotic Bcl2 family members through dimerization
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Summary
Small DNA tumor viruses usually replicate in episomal
form but are found integrated in viral associated tumors
Early genes promote cell cycle progression and prevent
apoptosis
Adenovirus - E1A (cell cycle) and E1B (apoptosis)
HPV - E7 (cell cycle) and E6 (apoptosis)
SV40 - T Ag (cell cycle and apoptosis)
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Herpes viruses
Oncogenic members:
Epstein Barr virus (EBV)
Kaposi’s Sarcoma Herpes virus (KSHV)
• Oncogenic mechanisms are distinct from small
DNA tumor viruses
- Don’t need to integrate
- Cell cycle is not driven by lytic replication regulatory genes
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Herpes viruses
Hallmark of herpesviruses:
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Herpes viruses
Hallmark of herpesviruses:
Existence of latent stage (in addition to lytic/replicative stage)
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Herpes viruses
Lytic replication phase for herpesviruses:
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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 don’t require an S-phase
environment for replication
- Encode early genes that induce cell cycle
arrest
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Herpes viruses
Latency:
- Small subset of viral genes are expressed that are not expressed
during lytic replication.
- Latency is partly a 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 trafficking to specific lymphoid
compartments that are suited to the life cycle
of the virus
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Herpes viruses
Human Herpesviruses and latency function:
Epstein Barr virus (EBV) - multiple functions
Kaposi’s Sarcoma Herpes virus (KSHV) - multiple functions
Cytomegalovirus (CMV) - Stealth mechanism
Herpes Simplex (HSV) - Stealth mechanism
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Epstein Barr virus
Pathologies in immuno-competent individuals
• Infectious mononucleosis
• Burkitt’s Lymphoma
• Hodgkin’s lymphoma
• Nasopharyngeal carcinoma
Pathologies in immuno-compromised individuals
• Post-transplant lymphoproliferative diseases
(PTLD)
• Hodgkin’s lymphoma
• A variety of non-Hodgkin’s lymphoblastoid
malignancies
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Epstein Barr virus
Latency 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 Red are key regulatory genes involved in B cell activation
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Epstein Barr virus
4 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, EBNALP, EBNA3A, 3B, 3C (highly antigenic)
Growth program
-Initial infection (prior to immune response)
- Immuno-compromised individuals
- in vitro infection of naïve peripheral blood lymhocytes
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Epstein Barr virus
Greater than 90% of US population are carriers of
EBV
-Only small percentage of carriers develop tumors
- who?
- Immuno-compromised - allows full set of oncongenic
genes to be expressed
- Immuno-competent who have multiple additional
genetic hits
EBV does not integrate - exists as an
extrachromosomal episome
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Kaposi’s Sarcoma Herpes
Virus - HHV-8
Kaposi’s sarcoma
Hematologic malignancies
• Primary effusion lymphoma
• Multicentric Castleman's disease (MCD) – a rare
lymphoproliferative disorder (AIDS)
• MCD-related immunoblastic/plasmablastic
lymphoma
• Various atypical lymphoproliferative disorders
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Hepatitis B and C
Long latency period to development of HCC (Hepatocellular Carcinoma)
20-30 years
Mechanism is probably due to chronic inflammatory response
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Silver lining to viral
associate cancers
Offer 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
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