Human Cancer Viruses

ONCOgenic VIRUSESONCOgenic VIRUSES

Done By:Morhaf Jalab

Jamil Mourad

Supervised by:

Pr. Fawza Monem

WHAT IS CANCER?WHAT IS CANCER?

Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to deregulated balance of cell proliferation and cell

death ultimately evolving into a population of cells that can

invade tissues metastasize to distant sites, causing significant morbidity and, if untreated, death of the

host.

When a cell proceeds from regulated to unregulated growth, the cell is said to have been trasformed

Oncogenes are usually dominant ar the cellular level

Only a single copy of a mutated oncogene is required to contribute to the multistep process of tumor progression

Tumor suppressor genesTumor suppressor genesThese genes suppress tumor formation by

controlling cell growth Tumour suppressor genes (TSGs) encode

proteins whose◦absence, ◦repression, ◦expression inactivation◦ mutation

Promotes oncogenesisCan do so even if a cell contains one normal

vergin of the gene

In other words , Cells in the body are programmed to ◦develop, ◦grow , ◦differentiate, ◦and die ◦in a response to a complex system of biochemical

signals

Cancer result from the emergence of a clone of cells◦ freed of these developmental programming

constraints◦ capable of inappropriate proliferation

The cell undergoes changes known as transformation

mutation

activation of

Oncogenes as Ras

inactivation of tumor

suppressors Genes as p53

What are the◦Proto-oncogenes◦Oncogenes◦Tumor suppressor genes

Proto-oncogeneProto-oncogene

Proto-oncogene Mutation Oncogene

Are genes involved in the four basic regulators of normal cell growth Growth factors Growth factor reseptors Signal transduction molecules Nuclear transcription factors

OncogenesOncogenes

When a mutation occurs in a proto-oncogene , It can become an oncogene.

Or virus can contain oncogene in its genome.

A gene whose constantly active product can lead to unregulated cell growth and differentiation.

When a cell proceeds from regulated to unregulated growth, the cell is said to have been trasformed.

Oncogenes are usually dominant at the cellular level.

Only a single copy of a mutated oncogene is required to contribute to the multistep process of tumor progression.

Tumor suppressor genesTumor suppressor genes These genes suppress tumor formation by

controlling cell growth. Tumour suppressor genes (TSGs) encode

proteins whoseabsence, repression, expression inactivationmutationPromotes oncogenesis.

Can do so even if a cell contains one normal vergin of the gene.

Such as p53

Mutation

Defect DNA

P53

Failure Success

Apoptosis Normal

In 1908 Ellerman and Bangerman described a form of infectious leukaemia in chickens.

1911 Rous showed that a virus could induce sarcomas (Rous sarcoma virus, RSV).

HistoryHistory

1913, Dane Johannes Grib Figiber reported that stomach cancers in rats could be traced to spirochete worms that they harbored. Thus, he received Nobel Prize, direct validation of the idea that cancer was an infectious disease.

But Metastatic stomach epithelia in those rats were present in the normal stomach with Vitamin deficient.

Since then, Peyton Rous report had been disregarded for two decades.

In 1930, Shope demonstrated that papillomas (warts) could be caused in cottontail rabbits by a virus (the Shope papilloma virus) and that these warts had a propensity to become malignant.

In 1934, Lucke´ observed that kidney carcinomas commonly found in frogs in New England lakes could be transmitted by lyophilized cell-free extracts.

In 1936 Bittner discovered the transmission of a virus (mouse mammary tumour virus, MMTV) that could cause mammary cancer in mice.

in 1951, Gross reported the first mouse leukaemia virus.

This was followed rapidly in 1953 by his discovery of polyoma virus, which causes many types of tumour in mice.

1958 (Dennis Burkitt): Burkitt’s lymphoma.

1964 (Epstein, Achong, and Barr of Bristol): Herpesvirus-like particles/EM.

1970s~1980s : HBV and HCC; HPV and cervical cancer;HTLV-1 and ATL (adult T-cell

leukemia/lymphoma)Anti-HBV vaccine against HCC: 1984/1985; Anti-HPV vaccine against CC: 2005/2006

These discoveries provided experimental systems in which the mechanism of cell transformation to the malignant state became understood.

They also determine mechanisms that are important in human cancer.

A virus that is able to cause cancer is known as an oncogenic virus.

Evidence that a virus is oncogenic includes the regular presence in the tumour cells of virus DNA◦All of the viral genome.◦Part of the virus genome.

In some types of tumour the virus DNA is integrated into a cell chromosome.

other types it is present as multiple copies of covalently closed circular DNA (cccDNA).

For some types of cancer there is evidence for involvement of a virus in most, if not all, cases of the cancer.

For other types virus DNA and/or proteins ◦Are detectable in only a minority of cases◦ It is possible that the virus is just one of a

number of carcinogenic factors that can give rise to these cancers.

Some human adenoviruses are oncogenic◦They can transform cells in culture.◦Can cause tumours when inoculated into animals.◦Though there is no evidence that adenoviruses

cause cancer in humans.

Studies with these viruses have contributed to understanding of oncogenic mechanisms.

The relative incidences of the main virus-associated cancers

Ecotropic viruses infect and replicate only in cells from animals of the original host species.

Amphotropic viruses-exhibit a broad host range (able to infect cells not only of the natural host but of heterologous species as well) because they recognize a receptor that is widely distrib uted.

Xenotropic viruses can replicate in some heterologous (foreign) cells but not in cells of the natural host. Many endogenous viruses have xenotropic host ranges.

Taxonomy of Tumor VirusesTaxonomy of Tumor Viruses

DNA viruses: papovaviruses hepadnaviruses

herpesviruses adenoviruses poxviruses

RNA viruses: retroviruses retrovirusesflavivirusesflaviviruses

32

HPV SV-40 BK, JCHBV

EBV KSHV

HTLV-1Hepatitis C virus

Human Viruses and Associated MalignanciesHuman Viruses and Associated Malignancies

HPV 16, 18, 31, 33, 45HPV 16, 18, 31, 33, 45 Cervical CarcinomaCervical Carcinoma

Hepatitis B&C virusesHepatitis B&C viruses Hepatocellular CarcinomaHepatocellular Carcinoma

HTLV1HTLV1 Adult T cell LeukemiaAdult T cell Leukemia

Epstein-Barr virus (HHV-4)Epstein-Barr virus (HHV-4) Burkitt’s LymphomaBurkitt’s LymphomaHodgkin’s DiseaseHodgkin’s Disease

Nasopharyngeal Nasopharyngeal CarcinomaCarcinoma

Gastric Carcinoma?Gastric Carcinoma?

Kaposi sarcoma-associated Kaposi sarcoma-associated Kaposi’s SarcomaKaposi’s Sarcomaherpesvirus (KSHV, HHV-8)herpesvirus (KSHV, HHV-8)

33

GeneralizationGeneralization

RNA viruses RNA viruses activateactivate oncogenes (expept oncogenes (expept HCV)HCV)

DNA viruses DNA viruses negate tumor suppressorstumor suppressors

34

AdenovirusAdenovirus

From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Fig. 53-1.

TaxonomyTaxonomy Family: AdenoviridaeFamily: Adenoviridae Genus: MastadenovirusGenus: Mastadenovirus Morphology . . . . . . . . . icosahedral Envelope . . . . . . . . . . . no Diameter [nm] . . . . . . . . 80 Structural components. . . core, capsid Additional information. . . antenna-

like 10-50 nm long fibers (polypeptide IV) protrude from the 12 vertices.

GenomeGenome

Nucleic acid . . . . . . . . . DNA Strandedness . . . . . . . . double-stranded Configuration . . . . . . . . linear Segments. . . . . . . . . . . 1 Size [kb]. . . . . . . . . . . . 36 G+C content [%]. . . . . . . 48-61 Transcription units . . . . . 40-45

Additional information: genome is linear, four early regions and two structural regions with one major late promotor and contains one or two VARNA genes.

Genus MembersGenus Members

From Medical Microbiology, 23 ed, Brooks G.F.

(From Fields Virology, 5thed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig. 67-5.)

Adenovirus replication cycle

STAGES OF ADENO REPLICATION IISTAGES OF ADENO REPLICATION II

After translation the proteins accumulate in the nucleus and together with newly made (nascent) viral DNA assembly into virions.

After 2-3 days of accumulation the cells lyse and release several hundred adenovirus particles in a burst.

Adenovirus ReplicationAdenovirus Replication

Endosome

Late mRNAs

Early mRNAs

EarlyproteinsLate

proteins

Virion

IntegrinsCAR

Virion DNAModulate Cell Cycle

Shut down host mRNA transport

Progeny DNA

Cell Lysis

Block CTL Response

ProgenyVirus

Nuclearpore

Nucleus

Cytoplasm

Types of infectionTypes of infection

Lytic

Latent/occult

Oncogenic Transformation

Types of infectionTypes of infection

Lytic

Results in cell death; seen in mucoepithelical cells.

Latent/occult

Virus remains in host cell; seen in lymphoid tissue, Groups

B and C. Oncogenic Transformation

Uncontrolled cell growth and replication occur; seen with

Group A viruses in hamsters .

Several serotypes, especially types 12, 18, and 31, are able to induce tumors when inoculated into newborn hamsters.

All adenoviruses can morphologically transform cells in culture regardless of their oncogenic potential in vivo.

Only a small part (< 20%) of the aden ovirus genome is present in most transformed cells.

The transforming genes of human adenoviruses are located in the early region (ElA and E1B) at the left-hand end of the viral genome.

An exception is type 9; the E4 gene is required for mammary tumorigenesis in rats.

The highly oncogenic nature of adenovirus type 12 may be related to the observation that one effect of its early region is to turn off the synthesis of class I major histocompatibility antigens (H2 or HLA) in some infected and transformed cells, thereby preventing destruction by CTLs.

Adenoviruses are not thought to be important in human cancer.

Studies of adenovirus transforming genes have revealed cellular growth control mechanisms that are altered in many types of cancer cells.

Applications Applications As oncolytic virusVaccinationGene therapy

PolyomavirusPolyomavirus

From: The Springer Index of Viruses, Tidona C. A. and Darai G., Springer 2002

From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24rded, 2007

Polyomaviruses:Polyomaviruses:◦Human polyomaviruses

BK Virus Common, causes disease only in immunosuppressed

Cysttis Nephropathy Severe ranial allograft disfunction

BK Virus Found in immunosuppressed

Progressive multifocal leukoencephalopathy (PML) Wildly distributed in in human populations

Presence of specific antibody in 70-80% of adult sera

These human viruses can transform rodent cells and induce tumors in newborn hamesters

JC virus has been associated with human brain tumors

Polyomaviruses:Polyomaviruses:◦Simian Virus 40 (SV40)

Infects monkeys and humans Discovered as a contaminant of cell lines (Monkey cells) used

to grow virus for the polio vaccine. Detected in selected types of human tumors

Brain tumors Mesotheliomas Bone tumors Lymphomas

Role of SV40 in human cancer still debated (under investigation)

Causes tumors when injected into rodents

◦Polyomavirus Infects mice

GenomeGenome

From: Principles and Practice of Clinical Virology, 5thed, 2006, fig 24.2

GenomeGenome

From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24 rd, 2007 , Fig. 43-7

pRb, p107, p130

Hsc70

p53

DNABinding ATP binding/ATPase HR

Zn finger

Large T

Small t

HPDKGG

pp2A

CBP, p300, p400

p193

Large T antigen

Large T antigen stimulates cell proliferation and blocks p53-dependent apoptosis.

pRb

S phase

p53

apoptosis

PapillomavirusPapillomavirus

From: Virology : principles and applications,Carter J. and Saunders V., John Wiley & Sons Ltd 2007

From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24rded, 2007

From: Virology : principles and applications,Carter J. and Saunders V., John Wiley & Sons Ltd 2007, fig 22.3

Genome Genome

From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24rded, Brooks G.F. Butel G.F. and Morse S.A, McGraw Hill 2007, fig 43-8

Human Papilloma virus Type

Clinical LesionSuspected Oncogenic Potential

1,4Plantar wartsBenign

2,4,26,27, 29Common wartsBenign

3,10,28,41Flat wartsRarely malignant

5,8Epidermodysplasia verruciformis in patients with cell-mediated immune deficiency

30% progress to malignancy

6,11Anogenital condylomas;laryngeal papillomas; dysplasias and intra epithelial neoplasias

Low

7Hand warts of meat and animal handlersBenign

9,12,14,15,17, 19-25, 36,46,47

Epidermodysplasia verruciformisSome progress to carcinomas (eg, HPV-17,HPV-20)

13,32Oral focal epithelial hyperplasiaPossible progression to carcinoma

16,18,30, 31,33, 35,39, 45,51, 52,56

High-grade dysplasias and carcinomas of genital mucosa; laryngeal and esophageal carcinomas

High correlation with genital and oral carcinomas, especially cervical cancer

34,40,42-44,53-55, 58,59,61, 62,64,66-69

Intraepithelial neoplasias (genital,other mucosal sites)

Some progress to carcinomas

75,77Common warts in organ transplant patients

37KeratoacanthomaBenign

Prevention Prevention Trials in women with vaccines designed

to prevent infection with the most common high-risk HPVs have produced promising results

HPV vaccines will soon be in widespread use, with the aim of protecting against◦cervical◦other cancers associated with these viruses

Herpesviruses Herpesviruses


From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24rded, 2007,

Oncogenic herpes virusesOncogenic herpes virusesEpstein-Barr (EB) virus causes

◦Burkitt’s lymphoma

◦Nasopharyngeal carcinoma (NPC)

◦Post-transplant lymphoma

◦Hodgkin’s disease

Human herpesvirus 8 (KSHV/HHV8) causes

◦Kaposi’s sarcoma

From: Principles and Practice of Clinical Virology, 5thed, 2006,

Epstein-Barr (EB) virusEpstein-Barr (EB) virus


Epstein-Barr (EB) virusEpstein-Barr (EB) virus

From: Principles and Practice of Clinical Virology, 5thed, 2006, fig 2D.3

Antibody titerAntibody titer


TreatmentTreatmentBurkett lymphoma is very sensitive to

chemotherapy

one dose of cyclphosphamide often being enough to cause complete regression of the tumour mass

Treatment Treatment


Human herpesvirus 8 Human herpesvirus 8 (KSHV/HHV8)(KSHV/HHV8)In 1994 it was discovered that the tumour cells

contain the DNA of a new herpesvirusThe virus was subsequently isolated and was

named Kaposi’ssarcoma- associated herpesvirus (KSHV)

The virus can be found in most parts of the world, Serological studies have shown that it is more

common in certain regions

◦such as central Africa

◦it is more common in homosexual men

Human herpesvirus 8 Human herpesvirus 8 (KSHV/HHV8)(KSHV/HHV8)There is also good evidence linking

KSHV with two other human cancers:

◦Primary effusion lymphomas

◦Multicentric Castleman’s disease

Both are tumours derived from B cells

Human herpesvirus 8 (KSHV/HHV8)Human herpesvirus 8 (KSHV/HHV8)

From: Principles and Practice of Clinical Virology, 5thed, 2006, fig 2F.3

HepaDNA virusesHepaDNA viruses


From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24rded, 2007,


From: Virology : principles and applications,Carter J. and Saunders V., John Wiley & Sons Ltd 2007, fig 18.10, 18.11

From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24rded, 2007, fig35-4

Transformation strategyTransformation strategyThe persistence of HBV infection

established in early life carry the highest risk of hepatocellular carcinoma in later life

The mechanism of oncogenesis is obscure

In most of the tumours, HBV DNA is integrated into the cell genome◦In most cases the virus DNA has undergone

rearrangements, including deletions◦The P and C ORFs have generally been

destroyed◦The S and X ORFs are often intact◦The only viral gene product that is consistently

present in the tumor cells is the X protein◦X protein is the potential oncoprotein

RNA OncovirusesRNA Oncoviruses

From: Virology : principles and applications,Carter J. and Saunders V., John Wiley & Sons Ltd 2007,

From: Virology : principles and applications,Carter J. and Saunders V., 2007, fig 16.11

From Jawetz, Melnick, and Adelberg’s Medical Microbiology, 24rded, 2007, fig 43-2

T-lymphotropic viruses Human T-lymphotropic virus type 1 (HTLV-1) 1980 Human T-lymphotropic virus type 2 (HTLV-2) 1982

Cell-to cell transmission

Expansion of infected CD4+ cells

Suppression of Tax by Rex, p30 and HBZ

Suppression of Tax by CTL

Alterations of genome

ATLHTLV-1 infected cells

On the other hand, loss of Tax expression is frequently observed in leukemic cells. Three mechanisms have been identified for inactivation of Tax expression: 1) genetic changes of the tax gene (nonsense mutations, deletions or insertions) 2) DNA methylation of the 5'-LTR and 3) deletion of the 5'-LTR Loss of Tax expression gives ATL cells advantage for their survival since they can escape from CTLs.

The proliferation of infected cells is promoted by Tax expression

CTLs attack the Tax-expressing cells since Tax is their major target Rex, p30 and HBZ suppress Tax expression.

Tax expression

HTLV-1 and 2 subtypesHTLV-1 and 2 subtypes

HTLV-2 isolates: prevalent in Southeastern Europe

HTLV-2a subtypes: prevalent in Northern European IDUs, such as in UK, Ireland and Sweden

HTLV-2b subtypes: isolated in Florida, Panama, Colombia, Argentina, Paraguay, Chile

tax

CREB, NF-KB, AP-1

Promotes viral transcription

Up-regulation of several cytokines, cytokine receptor, and induction of gene expression (such as c-jun, API-1, c-Fra, BCL-2)

p53 repression

Cellular proliferation

TGF-inhibition

Critical factors for cancerogenesis

inhibition of tumor suppressor proteins

HCVHCVMember of the flaviviridae familyContains a genome of single standard

RNA 9.4 kb sizeMajor infections are persistent even in

sdultsChronic infection is considered to cause

HCCMost probably that it causes liver cancer

indirectly

HCVHCV

References References Books Brooks G. F., Butel J. S., & Morse S. B Hepatitis Viruses ; Jawetz, Melnick, & Adelberg’s Medical

Microbiology 25thed; Brooks G. F., Butel J. S., & Morse S. B.; Mc Graw Hill; 2007; 245:267 Brooks G. F., Butel J. S., & Morse S. B Human Cancer Viruses; Jawetz, Melnick, & Adelberg’s

Medical Microbiology 25thed; Brooks G. F., Butel J. S., & Morse S. B.; Mc Graw Hill; 2007; 587:604 Carey J. & White B Cancer Genetics; Medical Genetics 3rd ed; Carey J. & White B.; Mosby

Elsevier;2006; 228:247 Crawford D. H.;Epstein–Barr Virus Principles and Practice of Clinical Virology 5th ; Zuckerman

A. J., Banatvala J. E, & Pattison J. R.; pub John Wiley & Sons; 2006 ; 117:141 Dorries K.;Human Polyomaviruses Principles and Practice of Clinical Virology 5th ; Zuckerman A.

J., Banatvala J. E, & Pattison J. R.; pub John Wiley & Sons; 2006; 619:645 John B. Carter and Venetia A. Saunders ;Viruses and Cancer; Virology: Principles and Applications,

John B. Carter and Venetia A. Saunders; pub John Wiley & Sons; 2007; 285:296 McCanc D.J.;Papillomaviruses Principles and Practice of Clinical Virology 5th ; Zuckerman A. J.,

Banatvala J. E, & Pattison J. R.; pub John Wiley & Sons; 2006; 607:618 Schulz T. F.;Kaposi’s Sarcoma-associated Herpesvirus (Human herpesvirus 8); Principles and

Practice of Clinical Virology 5th ; Zuckerman A. J., Banatvala J. E, & Pattison J. R.; pub John Wiley & Sons; 2006.; 167:186

Wadell .; Adenoviruses; Principles and Practice of Clinical Virology 5th ; Zuckerman A. J., Banatvala J. E, & Pattison J. R.; pub John Wiley & Sons; 2006; 307:328

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