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Viruses and Cancer

Tumor Virology

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.

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Viruses cause cancerWhy has the study of viruses and cancer been important?

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Viruses 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 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 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 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

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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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Inherited

Somatic- Random- Transposition- Exposure to deleterious environmental agents

- Radiation- carcinogenic chemicals- Viruses- Other persistent infections

Source of genetic alterations

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Viruses and Cancer

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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?

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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?

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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?

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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?

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Major 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 viruses

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• HPV• SV40• Adenovirus

• Normally replicate episomally but almost always found integrated in associated tumors - why?

Small 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 viruses

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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-linked16% 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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AdenovirusesHighly oncogenic in animalsOnly 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

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Inappropriate activation of cell cycle

Apoptosis

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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

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

Adenovirus E1BHPV E6

SV40 T Ag

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SV40 and HPV

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Adenovirus

E1B is Bcl2 family member - blocks function of pro-apoptotic 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 virusesOncogenic 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-phaseenvironment for replication- Encode early genes that induce cell cyclearrest

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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 alsoinduce cell differentiation/activation programsthat facilitate expansion of infected cell populationand induce trafficking to specific lymphoid compartments that are suited to the life cycleof the virus

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Herpes viruses

Human Herpesviruses and latency function:Epstein Barr virus (EBV) - multiple functionsKaposi’s Sarcoma Herpes virus (KSHV) - multiple functionsCytomegalovirus (CMV) - Stealth mechanismHerpes Simplex (HSV) - Stealth mechanism

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Epstein 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 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 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 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

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

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