Viruses cause cancer

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Viruses cause cancer

Why has the study of viruses and cancer been important?

Viruses cause cancer

Why has the study of viruses and cancer been important? - We learn about the basic mechanisms of specific types
of tumors.

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

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

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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Changes in cell that are at the roots of cancer

Changes in cell that are at the roots of cancer

Genetic and epigenetic alterations:

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

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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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 youre infected, does this mean that you will get cancer?

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If youre 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 youre 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) - Kaposis 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) 23

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 Host RNA polymerase

Need cells that are in Sphase to replicate viral genome

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)
Kaposis Sarcoma Herpes virus (KSHV) Oncogenic mechanisms are distinct from small DNA tumor viruses

- Dont 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 dont 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 Kaposis 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 Burkitts Lymphoma Hodgkins lymphoma Nasopharyngeal carcinoma Pathologies in immuno-compromised individuals Post-transplant lymphoproliferative diseases (PTLD) Hodgkins lymphoma A variety of non-Hodgkins 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 nave 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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Kaposis Sarcoma Herpes Virus - HHV-8

Kaposis 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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