Tumor Virus Bacteria6473825744

8/10/2019 Tumor Virus Bacteria6473825744

1/73

Microorganism & Human Cancer

Riyani Wikaningrum

Bag. Mikrobiologi

FK Universitas YARSI

1


2/73

Viruses and Human Cancer

Virus acts as a cofactor

Viruses act as initiators of neoplastic processvarious mechanisms


3/73

Interaction Tumor Virus - Host

1. Persistent infection

2. Host immune response

3. Mechanisms of action by Human CancerVirus

4. Cell susceptibility to viral infection

5. Retention of tumor virus nucleic acid in host

cell

3


4/73

Genesunrestrained cell growth

genes that are stimulatory for growth and whichcause cancer when hyperactiveoncogenes

genes that inhibit cell growth and which cause

cancer when they are turned off

anti-oncogenes or tumor-suppressor genes

Virusescancersvirus carry a copy of one of these genes

virus alter expression of the these genes


5/73

Malignant transformation

Changes Details

Morphology Loss of shape; rounding

Decreased adhesion to surface

Growth, contact Loss of contact inhibition of growth and movement

Increased ability to grow from a single cell

Increased ability to grow in suspension

Capacity for continued growth (immortalization)

Cellular properties DNA synthesis induced

Chromosomal changes

Appearance of new antigens (viral or cellular in

origin)Biochemical properties Loss of fibronectin

Reduced cAMP


6/73

Viruses Cancer Strength of

association

Viral genome

in cancer cells

Cofactor

Epstein-Barr

virus

Burkitt's

lymphoma

++ + Malaria

Nasopharyngealcarcinoma

++ + Nitrosamines

Hodgkin's

disease

- - -

Human

papillomavirus

Cervical cancer ++ + ? cigarettes

? HSV2

Skin cancer + ? UV light

Hepatitis B

virus

Liver cancer ++ + ? Aflatoxin

Hepatitis C

virus

Liver cancer ++ - ?

Hepatocyteregeneration

HTLV1 T-cell leukemia ++ + -

HSV2 Cervical cancer -


7/73

7

Tumor Viruses

Genome all viral proteins

Replication Lysis Progeny virions

Lytic Life Cycle

For most viruses:

Non-structural and structural proteins made


8/73

8

Tumor VirusesVirus

Cell

Integration (often)

Transformation

Latent Life Cycle

Some virus-specific proteins expressed (early functions) - No

mature virus

Viral structural proteins are not expressed

Changes in the properties of host cell - TRANSFORMATION

Sometimes latency may terminatecell must be infected by

complete virus


9/73

9

Tumor VirusesTransformation:

Loss of growth control

Reduced adhesion

Motility

Invasion

Ability to form tumors - viral genes interfere with control o

cell replication and other aspects of the cell phenotype

Transformed cells frequently exhibit chromosomalaberrations


10/73

10

TRANSFORMATION

VIRAL TRANSFORMATION

The changes in the biological functions of a cell that result fromREGULATION

of the cells metabolism by viral genes and that confer on the

infected cell certain properties characteristic of

NEOPLASIA

Tumor Viruses


11/73


12/73

12

Two Major Classes of Tumor Viruses

DNA Tumor VirusesDNA viral genome

Host RNA

polymerase

Viral mRNA

Viral protein

DNA-dependent

DNA polymerase

(Host or viral)

Similar to host cell!


13/73

13

RNA Tumor VirusesViral RNA genome

Reverse transcriptase (Virus-encoded

Viral DNA genome (integrated)

DNA-dependent RNA polymerase (Ho

RNA pol II)

Viral genomic RNA

Splicing (Host splicing enzymes)

messenger RNA

viral protein

Virus

Important: UseHOST

RNA polymerase

to make its genome

An enzyme that

normally

makes mRNA

IMPORTANT


14/73

14

DNA Tumor VirusesDNA genome

mRNA

protein

virus

Host RNA

polymerase II

Host enzymes

OR TRANSFORMATION

In transformation usually only EARLYfunctions are expressed


15/73

15

DNA Tumor Viruses In

Human Cancer

Papilloma Viruses

cause natural cancers in animals

cause benign warts

ubiquitous

epitheliotropic - most human tumors are malignancies of epithelialcells


16/73

16


Human Cancer

Papilloma Viruses

Epidermodysplasia verruciformis

wart malignant

skin squamous cell carcinoma


17/73

17


Human CancerEpidermodysplasiaverruciformis

Papilloma virus

2008

DermatologyOnline Journa

DNA T Vi I


18/73

18


Human Cancer

Papilloma Viruses

urogenital cancer

wart malignant squamous cell carcinoma

Squamous cell carcinoma:

Larynx

Esophagus All histologically similar

Lung

10% of human cancers may be HPV-linked


19/73


20/73

DNA T Vi I


21/73

21


Human Cancer

Polyoma VirusesSimian virus 40 - juvenile hamster sarcomas, transformation

Polyoma - mouse leukemia, in vitro transformation

Human polyomas (JC and BK) - monkey sarcoma, transformatio

Early functions are necessary - ONCOGENES

JC:PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PM

Possible association of BK with human prostate cancer

Polyoma vi rus transforms cells when the genome is incomplete

DNA T Vi I


22/73

22


Human Cancer

Adenoviruses

Highly oncogenic in animals

Only part of virus integrated

Always the same part

Early functions

E1A region: 2 T antigensE1B region: 1 T antigen

E1A and E1B = Oncogenes



23/73

23


Human Cancer

Common pattern

Early functions (non-structural) proteins are involved

in transformation

Papilloma: E6 and E7

Polyoma: Large T and small T antigen

Adenovirus: E1A and E1B



24/73

24


Human Cancer

ONCOGENE

A gene that codes for a protein that potentially can transform

a normal cell into a malignant cell

An oncogene may be transmitted by a virus in which case it

known as a VIRAL ONCOGENE

v-onc



25/73

25


Human Cancer

Herpes Viruses

Considerable evidence for role in human cancer

Some very tumorigenic in animals

Integrated viral DNA found in small proportion of tumor cells:

hit and run



26/73

26


Human Cancer

Burkitts Lymphoma

Nasopharyngeal cancer

Infectious mononucleosis (glandular fever)

Transforms human B-lymphocytes in v i t ro

Burkitts lymphoma: malarial infested regions

Nasopharyngeal cancer: China, SE Asiadiet?

Epstein-Barr Virus



27/73

27


Human Cancer

Human herpes virus8Kaposis Sarcoma Herpes Viru

Hematologic malignancies

Primary effusion lymphomaMulticentric Castleman's disease (MCD)a rare

lymphoproliferative disorder (AIDS)

MCD-related immunoblastic/plasmablasticlymphoma

Various atypical lymphoproliferative disorders

Kaposis sarcoma



28/73

28


Human Cancer

Hepatitis B Virus

DNA genome

RNA polymerase II

RNA Provirus

Reverse transcriptase

DNA genome

Host enzym

Viral enzyme


29/73

Hepatocellular Carcinoma (HCC)



30/73

30


Human CancerHepatitis B continued

Vast public health problem

10% of population in underdeveloped countries are chronic carrie

Long latency



31/73

31


Human CancerHepatitis B continued

Epidemiology:

Strong correlation between

HBV and hepatocellular

carcinoma

China: 500,000 - 1 million newcases of hepatocellular carcinoma

per year

Taiwan: Relative risk of getting

HCC is 217 x risk of non-carriers



32/73

32

DNA Tumor Viruses InHuman Cancer

Summary

These viruses can transform cells or have lytic life cyc

Often integrate into host genome

In transformation often ONLY early genes

(non-structural) are transcribed

These are genes that are also necessaryfor a

PRODUCTIVE infectionTrue viral genes

RNA T Vi


33/73

33

RNA Tumor VirusesRNA Genome - Retroviruses

RNA-dependent DNA Polymerase encoded by virus

REVERSE TRANSCRIPTASE

RNA genome


DNA genome

Integrase

Integrates

Host RNA polymerase II

RNA genome

virus

virus

host


34/73

34

RNA Tumor

Viruses


35/73

35

RNA Tumor Viruses

POL: Enzymes

Reverse transcriptaseRNase HIntegrase

Protease

A normal retrovirus has:

3 genes

GAG: internal proteins

ENV: Envelope glycoproteins

RNA Tumor Viruses


36/73

36

RNA Tumor VirusesRNA is:

Diploid Capped and polyadenylated

Positivesense (same as mRNA)

Viral RNA cannot be read as mRNA

(even though same sense)

New mRNA must be made

Virus must make negative sense DNAbefore proteins ar

madeTherefore virus must carry REVERSE TRANSCRIPTASE

into the cell

RNA T Vi


37/73

37

RNA Tumor Viruses


38/73

38

RNA Tumor Viruses

Groups of RetrovirusesOncovirinae

Tumor viruses and similar

Lentiviruses

Long latent period

Progressive chronic disease

Visna HIV

important

important

RNA T Vi


39/73

39

RNA Tumor VirusesRetroviruses known to cause human cancer

Human T cell lymphotropic virus -1 (HTLV-1)

Adult T cell leukemia, Sezary T-cell leukemia

Africa, Caribbean

S. America (Peru, Bolivia)

Some Japanese Islands

Okinawa, Kiyushu, Shikoku (12 - 16% infection rate)

RNA T Vi


40/73

40

RNA Tumor Viruses

Also causes: Tropical spastic paraparesis

(affects the gray and white matter of the spinal

cord - myelopathy)

1-4% of infected people


UNITED STATES AND OTHER WESTERN COUNTRIESIV DRUG USERS

US rate of infection about one tenth of that of HIV

BUT half as prevalent as HIV in IV drug users

Immunosuppression


41/73

41

RNA Tumor Viruses


Hairy cell leukemia

Americas, particularly in native American populations

New Mexico (Navajo and Pueblo Indians)

Florida (Seminole Indians)

Retroviruses known to cause human cancer

HIV ?

Seroprevalence in these populations > 20%

Women over 50: seroprevalence - up to 50% in some populations

RNA Tumor Viruses


42/73

42

RNA Tumor VirusesRetrovirus Life Cycle

Endocytosis

Fusion of membranes

Release of nucleocapsid to cytoplasm

Nucleus

Bind tosurface receptor

RNA Tumor Viruses


43/73

43

RNA Tumor VirusesParental RNA

RNA/DNA Hybrid

Linear DNA/DNA duplex

Circular Duplex DNA

Integration Replication (DNA genome in c

Transcription Viral RNA genome mRNA protein


Reverse

transcriptase

Integrase

Host RNA pol II

Host DNA

polymerase

Host splicing

enzymes

RNA Tumor Viruses


44/73

44

RNA Tumor Viruses

Drawback to this lifestyle

Genomic RNA

DNA

Genomic RNA

HostRNA pol II


Pol II is a host enzymethat, in the uninfected cell, makes mRNA

When making mRNA, pol II does not copyentire gene to RNA

Problem of using RNA pol II to copy a gene


45/73

45

primer

Viral

genomicRNA

Reversetranscriptase

dsDNA

promotor

RNA synthesis

initiation site

RNA pol IIRNA synthesis termination

site

Result: New copy of viral RNA is shorter - lacks control sequences

RT

RNA Tumor Viruses


46/73

46

?

RNA Tumor Viruses

Perhaps virus could integrate dow nstream of a promotor etc so

that the cel l provides sequences

RNA polymerase II will not copy

Upstream sequences from transcription initiation site

Promotors / Enhancers

Down stream sequences from transcription termination site

Enhancers / Poly A site / termination site

OR

Virus provides i ts own prom otors etc

BUT not copied!


47/73

47

RNA Tumor Viruses

Clue: Difference in the two forms

RNA

R U5 GAG POL ENV U3 R

LTR

Repeat

region

Repeat

region

DNA

U3 R U5 GAG POL ENV U3 R U5

LTR


48/73

48

promotor

Viral RNA

Reversetranscriptase

R U5 U3 R

U3 R U5 U3 R U5

Long terminal repeats are formed

RNA initiation site RNA termination site

POLIIPOLII

Retroviruses can have only one


49/73

49

Retroviruses can have only one

promotor region

LTR LTR

U5

RNA initiation site RNA termination site

Therefore only one long RNA can be made

Therefore mRNA requires processing

Explains why RNA has to be positive sense

POLIIPOLII

Contained in U3

Some retroviruses have an


50/73

50


Rous Sarcoma Virus


extra gene

typical retrovirus

SRC

Some retroviruses have an oncogene


51/73

51

Feline Sarcoma Virus (FSV)

R U5 dGAG FMS dENV U3 R

Avian Myelocytoma Virus (MC29)

R U5 dGAG MYC dENV U3 R

Avian MyeloblastosisVirus

R U5 GAG POL MYB U3 R

g

instead of their regular genes


52/73

52

RNA Tumor Viruses

Viral Oncogene

V-onc

Cellular Proto-oncogene

C-onc


53/73

53

RNA Tumor Viruses

Proto-oncogene

A cellular (host) gene that is homologous with a

similar gene that is found in a transforming virus

A cellularoncogene can only induce

transformation after

mutation

some other change in the cells genome

RNA Tumor Viruses


54/73

54

RNA Tumor Viruses

The discovery of the acutely transforming

retrovirusesthat containv-oncs explains how cancers may arise as a resu

of infection

These viruses cause rapid cancer in animals in

the laboratory


55/73

55

RNA Tumor Viruses

In contrast:Chronically transforming retroviruses

cause tumors inefficiently after prolonged period of tim

No oncogene!How does it cause atumor?


Avian Leukosis Virus (causes lymphomas)

RNA Tumor Viruses


56/73

56

RNA Tumor Viruses

Suggests tumor arose from one cell

Something must be important about this site fo

transformation

Crucial event must be rare

ALV can integrate into the host cell genome at

MANYlocations

but in tumor it is always at the SAMEsite (or

restricted number of sites)

RNA Tumor Viruses


57/73

57

RNA Tumor Viruses

What is special about this site?

Myelocytoma tumors from several birds allhave

the oncogene close to this site

It is close to

C-myc!

Oncogenesis by promotor insertion


58/73

58

RNA Tumor Viruses

Could C-oncs be involved in NON-VIRAL cancers

RNA Tumor Viruses


59/73

59

What do oncogenes encode?

Proteins that are involved in growth control and

differentiation

Growth factors

Growth factor receptors

Signal transduction proteins

Transcription factors


60/73

60

DNA Tumor VirusesHow they tumors depended on

our knowledge of RNA tumorviruses

DNA Tumor Viruses

Herpes


61/73

61

Herpes

Genes can be

assigned to

sites on

specific

chromosomes

mos and myc :

chromosome 8

fes: chromosome 15fes

mosmyc

myb

Cancers often result from genetranslocations

B kitt L h


62/73

62

Burkitts Lymphoma

8:14 translocation

Break in chromosome14 at q32

Acute myelocytic leukemi7:15

9:18

11:15:17

myc

Oncogenesis by rearrangement


63/73

63

Tumor c-onc new promotorBurkitts lymphoma myc (8) Ig heavy (8 to 14)

Ig light (8 to 2)

B-cell chronic lymphocytic bcl-1 Ig heavy (11 to 14)leukemia bcl-2 Ig heavy (18 to 14)

T cell chronic lymphocytic tcl-1 T cell receptor

leukemia (14 inversion)

T cell chronic lymphocytic myc T cell receptor (8 to 14)

leukemia

Oncogenes


64/73

64

gMutations in a proto-oncogene are dominant gain

of function mutations

However other oncogenic genes show recessive

mutations

Anti-Oncogenes

Loss of function mutations

Retinoblastoma

p53

Proto-oncogenes


65/73

65

Heterozygote Homozygote

Allele 1 Allele 2 Allele 1 Allele 2

Normal Mutant Mutant Mutant

Function gained Function gained

Dominant

mutations

Binds under

special

circumstances

Mutant

always

binds

Mutant

always

binds

Mutant

always

binds

Always binds Always binds

Anti-Oncogenes


66/73

66

Rb Gene Mutant Rb Mutant Rb

Rb

Rb

Rb protein

Binds and controls cell cycleTurns off DNA replication

No binding - Growth continues

Mutant Rb

Recessive mutations

Function lost

Mutation growth

Heterozygote Homozygote

Anti Oncogenes


67/73

67

Anti-Oncogenes

Retinoblastoma genehas normalregulatory function in many cells

Involved in

Retinoblastoma

Lung carcinomasBreast carcinomas

Anti Oncogenes


68/73

68

Anti-Oncogenes

P53

Inactivated by

deletion

point mutation

DNA Tumor Viruses

Oncogenes


69/73

69

Oncogenes

Adenovirus E1A region 2SV 40 Large T

Polyoma Large T

BK virus Large T

Lymphotropic virus Large T

Human papilloma Virus-16 E6, E7

All have a sequence in common

Mutations in this region abolish transformation capacity

Anti-Oncogenes


70/73

70

g

Rb Gene

RbRb

protein

Rb

Stops replication

Rb

Adenovirus E1A

Cell cycle continues

Retinoblastoma

105kD

Anti-Oncogenes


71/73

71

p53

P53 gene P53 gene P53 gene

P53

P53 DNA

Stops replication

Hepatitis C

P53

replication replication

Papilloma

proteolysi

P53

Papilloma


72/73

Bacteria and Human Cancer

72

Helicobacter pylori


73/73

Helicobacter pylori

Associated with:

Gastric and duodenal cancer

Gastric mucosa-associated lymphoid tissue

(MALT) lymphoma Inflammatory reaction to H. pylorichronic

atropic gastritis (CAG) metaplasiadysplasia

carcinoma

Other factor (?)genetic or environmental

73

Tumor Virus Bacteria6473825744

Documents

Transcript of Tumor Virus Bacteria6473825744