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Viruses cause cancerViruses cause cancerDownload lecture at: flemingtonlab.com
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Viruses cause cancerViruses cause cancerWhy has the study of viruses and cancer been important?
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Viruses cause cancerViruses cause cancerWhy 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 cancerViruses cause cancerWhy 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 cancerViruses cause cancer30-40% 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 VirusesMajor human Oncogenic VirusesDNA 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 virusesHuman T-cell Leukemia Virus 1 (HTLV1)Hepatitis virus C
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Changes in cell that are at the roots of cancer
Changes in cell that are at the roots of cancer
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Changes in cell that are at the roots of cancer
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
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
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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Inherited
Somatic
- Random
- Transposition
- Exposure to deleterious environmental agents- Radiation
- carcinogenic chemicals
- Viruses
- Other persistent infections
Source of genetic alterationsSource of genetic alterations
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• 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
How do Viruses contribute to cancer?
How do Viruses contribute to cancer?
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Why do viruses cause cancer?Why do viruses cause cancer?
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• Viruses and cancer cells have similar needs• Proliferation control• Cell death control• Modulation of immune response• Induction of vascularization• Metastasis (tumor)/cell migration (viruses)
Why do viruses cause cancer?Why do viruses cause cancer?
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If you’re infected, does this mean that you will get cancer?
If you’re infected, does this mean that you will get cancer?
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• No• Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs
If you’re infected, does this mean that you will get cancer?
If you’re infected, does this mean that you will get cancer?
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• 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)
If you’re infected, does this mean that you will get cancer?
If you’re infected, does this mean that you will get cancer?
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Major human Oncogenic VirusesMajor human Oncogenic VirusesDNA 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 virusesHuman T-cell Leukemia Virus 1 (HTLV1)Hepatitis virus C
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• Adenovirus• Human virus but only causes cancer in non-human cells
• SV40• Mesothelioma
• HPV• Cervical Cancer• Squamous cell anal carcinoma• Penile cancer• Oral cancers
Small DNA tumor virusesSmall DNA tumor viruses
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• HPV• SV40• Adenovirus
• Normally replicate episomally but almost always found integrated in associated tumors - why?
Small DNA tumor virusesSmall DNA tumor viruses
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• 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
Small DNA tumor virusesSmall DNA tumor viruses
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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-linked16% of all female cancers linked to HPV
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DNA Tumor Viruses In Human Cancer
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 partEarly (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
Host RNA polymerase
Viral mRNA
Viral protein
UtilizesHost Cell DNA
Replication Machinery
Need cells that are in S-phase to replicate viral
genome Host enzymes
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Inappropriate activation of cell cycle
Inappropriate activation of cell cycle
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Inappropriate activation of cell cycle
Inappropriate activation of cell cycle
Apoptosis
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Inappropriate activation of cell cycle
Inappropriate activation of cell cycle
Apoptosise.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
Inappropriate activation of cell cycle
Apoptosise.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
Encode early genes that inhibit apoptosis
Adenovirus E1B
HPV E6
SV40 T Ag
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SV40 and HPVSV40 and HPV
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AdenovirusAdenovirus
E1B is Bcl2 family member - blocks function of pro-apoptotic Bcl2 family members through dimerization
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SummarySummary
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 virusesHerpes 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 virusesHerpes viruses
Hallmark of herpesviruses:
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Herpes virusesHerpes viruses
Hallmark of herpesviruses:
Existence of latent stage (in addition to lytic/replicative stage)
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Herpes virusesHerpes viruses
Lytic replication phase for herpesviruses:
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Herpes virusesHerpes 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 virusesHerpes 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 virusesHerpes 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 virusEpstein Barr virusPathologies 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 virusEpstein 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 Red are key regulatory genes involved in B cell activation
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Epstein Barr virusEpstein 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 naïve peripheral blood lymhocytes
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Epstein Barr virusEpstein Barr virusGreater 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 Herpes Virus - HHV-8
Hematologic malignancies • Primary effusion lymphoma
• Multicentric Castleman's disease (MCD) – a rare lymphoproliferative disorder (AIDS)
• MCD-related immunoblastic/plasmablastic lymphoma
• Various atypical lymphoproliferative disorders
Kaposi’s sarcoma
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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
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