tumour viruses.ppt

8/22/2019 tumour viruses.ppt

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Viruses cause cancer

Download lecture at: flemingtonlab.com


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Why 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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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)

- Kaposis 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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of cancer

Genetic and epigenetic alterations:


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of cancer

Genetic and epigenetic alterations:Mutations

Deletions

Recombinations

Transpositions

Epigenetic alterations (DNA methylation, imprinting)

Acquisition of viral genetic material


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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 - someviruses contribute single hits while others contribute multiple hits.


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InheritedSomatic

- Random

- Transposition

- Exposure to deleterious environmental agents

- Radiation

- carcinogenic chemicals

- Viruses

- Other persistent infections

Source of genetic alterations


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Integrationsthat cause activation or inactivation ofoncogenes or tumor suppressors (e.g. RNA viruses)

Expression of genesthat 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 needsProliferation control

Cell death control

Modulation of immune response

Induction of vascularization

Metastasis (tumor)/cell migration (viruses)

Why do viruses cause cancer?

f f


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If youre infected, does this mean

that you will get cancer?

If i f t d d thi


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NoViruses did not specifically evolve with the need to cause

cancer - they simply have similar (but distinct) needs



If i f t d d thi


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NoViruses 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


- 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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AdenovirusHuman virus but only causes cancer in non-human cells

SV40

Mesothelioma

HPVCervical Cancer

Squamous cell anal carcinomaPenile cancer

Oral cancers



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HPVSV40

Adenovirus

Normally replicate episomally but almost always foundintegrated in associated tumors - why?



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HPVSV40

Adenovirus

Normally replicate episomally but almost always foundintegrated in associated tumors - why?

Replication must be abortive

HPV, viral encoded negative regulatory factor must be deleted


DNA T Vi I


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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-linked

16% of all female cancers linked to HPV



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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 18proteins made in

yeast - Gardasil)


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Papilloma Viruses

The important transforming genes in papillomaviruses are the non-structural regulatory genes,E6and E7

HPV is normally episomal but is alwaysintegrated 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 inabsence of structural genes and virusproduction Can occur by infection of non-permissive host

Can occur by integrations that delete regions of viralgenome required for replication but leave early genesintact.


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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

Utilizes

Host Cell DNA

Replication MachineryNeed cells that are in S-

phase to replicate viral

genome Host enzymes


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Inappropriate activation of cell


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cycle



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cycle

Apoptosis



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cycle

Apoptosis

e.g.

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

-Defense mechanism against rogue proliferating cells?



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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

Encode early genes that


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Encode early genes that

inhibit apoptosis

AdenovirusE1B

HPVE6

SV40T Ag

SV40 d HPV


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SV40 and HPV

Ad i


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Adenovirus

E1B is Bcl2 family member - blocks function of pro-apoptotic Bcl2 family members through dimerization

S


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Summary

Small DNA tumor viruses usually replicate in episomalform but are found integrated in viral associated tumors

Early genes promotecell cycle progression andprevenapoptosis

Adenovirus -E1A (cell cycle) and E1B (apoptosis)

HPV - E7(cell cycle) and E6(apoptosis)

SV40 - T Ag(cell cycle and apoptosis)

H i


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Herpes viruses

Oncogenic members:Epstein Barr virus (EBV)

Kaposis Sarcoma Herpes virus (KSHV)

Oncogenic mechanisms are dis t inct from small

DNA tumor vi ruses

- Dont need to integrate

- Cel l cycle is not d r iven by lyt ic repl icat ion regulatory gen

H i


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Herpes viruses

Hallmark of herpesviruses:

H i


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Herpes viruses

Hallmark of herpesviruses:

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

Herpes viruses


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Herpes viruses

Lytic replication phase for herpesviruses:

Herpes viruses


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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

Herpes viruses


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Herpes viruses

Latency:

- Small subset of viral genes are expressed that are not expressed

during lytic replication.

- Latency is partlya 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 traffickingto specific lymphoid

compartments that are suited to the life cycle

of the virus

Herpes viruses


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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

Epstein Barr virus


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Epstein Barr virusPathologies in immuno-competentindividuals

Infectious mononucleosis

Burkitts Lymphoma

Hodgkins lymphoma

Nasopharyngeal carcinoma

Pathologies in immuno-compromisedindividuals

Post-transplant lymphoproliferative diseases

(PTLD)

Hodgkins lymphomaA variety of non-Hodgkins lymphoblastoid

malignancies

Epstein Barr virus


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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 Redare key regulatory genes involved in B cell activation


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Epstein Barr virus


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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 nave peripheral blood lymhocytes


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Epstein Barr virus


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Epstein Barr virusGreater than 90% of US population are carriers of

EBV

-Only small percentage of carriers develop tumors

- who?

-Imm uno-comprom ised - a llows fu l l set of on congenicgenes to be expressed

-Immuno -com petent who have mult ip le addit ional

genet ic hi ts

EBV does not integrate - exists as an

extrachromosomal episome

Kaposis Sarcoma Herpes


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Virus - HHV-8

Hematologic malignanciesPrimary effusion lymphoma

Multicentric Castleman's disease (MCD)a rare

lymphoproliferative disorder (AIDS)

MCD-related immunoblastic/plasmablastic

lymphoma

Various atypical lymphoproliferative disorders

Kaposis sarcoma

Hepatitis B and C


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Long latency period to development of HCC (Hepatocellular Carcinom

20-30 years

Mechanism is probably due to chronic inflammatory response

Silver lining to viral


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associate cancersOffer 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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