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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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- We learn about the basic mechanisms of specific types

of tumors.

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- 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


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Genetic and epigenetic alterations:

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Genetic and epigenetic alterations:• Mutations

• Deletions

• Recombinations

• Transpositions

• Epigenetic alterations (DNA methylation, imprinting)

• Acquisition of viral genetic material

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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?


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• No• Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs



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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)



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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?


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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


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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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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


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Apoptosis

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Apoptosise.g.

-Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis

- Defense mechanism against rogue proliferating cells?

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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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Hallmark of herpesviruses:

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Hallmark of herpesviruses:

Existence of latent stage (in addition to lytic/replicative stage)

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Lytic replication phase for herpesviruses:

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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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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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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

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