tumor virus bacteria6473825744
Post on 02-Jun-2018
220 Views
Preview:
TRANSCRIPT
-
8/10/2019 Tumor Virus Bacteria6473825744
1/73
Microorganism & Human Cancer
Riyani Wikaningrum
Bag. Mikrobiologi
FK Universitas YARSI
1
-
8/10/2019 Tumor Virus Bacteria6473825744
2/73
Viruses and Human Cancer
Virus acts as a cofactor
Viruses act as initiators of neoplastic processvarious mechanisms
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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 -
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
11/73
-
8/10/2019 Tumor Virus Bacteria6473825744
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!
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
16/73
16
DNA Tumor Viruses In
Human Cancer
Papilloma Viruses
Epidermodysplasia verruciformis
wart malignant
skin squamous cell carcinoma
-
8/10/2019 Tumor Virus Bacteria6473825744
17/73
17
DNA Tumor Viruses In
Human CancerEpidermodysplasiaverruciformis
Papilloma virus
2008
DermatologyOnline Journa
DNA T Vi I
-
8/10/2019 Tumor Virus Bacteria6473825744
18/73
18
DNA Tumor Viruses In
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
-
8/10/2019 Tumor Virus Bacteria6473825744
19/73
-
8/10/2019 Tumor Virus Bacteria6473825744
20/73
DNA T Vi I
-
8/10/2019 Tumor Virus Bacteria6473825744
21/73
21
DNA Tumor Viruses In
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
-
8/10/2019 Tumor Virus Bacteria6473825744
22/73
22
DNA Tumor Viruses In
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
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
23/73
23
DNA Tumor Viruses In
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
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
24/73
24
DNA Tumor Viruses In
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
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
25/73
25
DNA Tumor Viruses In
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
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
26/73
26
DNA Tumor Viruses In
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
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
27/73
27
DNA Tumor Viruses In
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
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
28/73
28
DNA Tumor Viruses In
Human Cancer
Hepatitis B Virus
DNA genome
RNA polymerase II
RNA Provirus
Reverse transcriptase
DNA genome
Host enzym
Viral enzyme
-
8/10/2019 Tumor Virus Bacteria6473825744
29/73
Hepatocellular Carcinoma (HCC)
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
30/73
30
DNA Tumor Viruses In
Human CancerHepatitis B continued
Vast public health problem
10% of population in underdeveloped countries are chronic carrie
Long latency
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
31/73
31
DNA Tumor Viruses In
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
DNA Tumor Viruses In
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
33/73
33
RNA Tumor VirusesRNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virus
REVERSE TRANSCRIPTASE
RNA genome
Reverse transcriptase
DNA genome
Integrase
Integrates
Host RNA polymerase II
RNA genome
virus
virus
host
-
8/10/2019 Tumor Virus Bacteria6473825744
34/73
34
RNA Tumor
Viruses
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
37/73
37
RNA Tumor Viruses
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
Human T cell lymphotropic virus -1 (HTLV-1)
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
-
8/10/2019 Tumor Virus Bacteria6473825744
41/73
41
RNA Tumor Viruses
Human T cell lymphotropic virus -2 (HTLV-2)
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
-
8/10/2019 Tumor Virus Bacteria6473825744
42/73
42
RNA Tumor VirusesRetrovirus Life Cycle
Endocytosis
Fusion of membranes
Release of nucleocapsid to cytoplasm
Nucleus
Bind tosurface receptor
RNA Tumor Viruses
-
8/10/2019 Tumor Virus Bacteria6473825744
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
Reverse
transcriptase
Integrase
Host RNA pol II
Host DNA
polymerase
Host splicing
enzymes
RNA Tumor Viruses
-
8/10/2019 Tumor Virus Bacteria6473825744
44/73
44
RNA Tumor Viruses
Drawback to this lifestyle
Genomic RNA
DNA
Genomic RNA
HostRNA pol II
Reverse transcriptase
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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!
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
50/73
50
R U5 GAG POL ENV U3 R
Rous Sarcoma Virus
R U5 GAG POL ENV U3 R
extra gene
typical retrovirus
SRC
Some retroviruses have an oncogene
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
52/73
52
RNA Tumor Viruses
Viral Oncogene
V-onc
Cellular Proto-oncogene
C-onc
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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?
R U5 GAG POL ENV U3 R
Avian Leukosis Virus (causes lymphomas)
RNA Tumor Viruses
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
58/73
58
RNA Tumor Viruses
Could C-oncs be involved in NON-VIRAL cancers
RNA Tumor Viruses
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
60/73
60
DNA Tumor VirusesHow they tumors depended on
our knowledge of RNA tumorviruses
DNA Tumor Viruses
Herpes
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
67/73
67
Anti-Oncogenes
Retinoblastoma genehas normalregulatory function in many cells
Involved in
Retinoblastoma
Lung carcinomasBreast carcinomas
Anti Oncogenes
-
8/10/2019 Tumor Virus Bacteria6473825744
68/73
68
Anti-Oncogenes
P53
Inactivated by
deletion
point mutation
DNA Tumor Viruses
Oncogenes
-
8/10/2019 Tumor Virus Bacteria6473825744
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
-
8/10/2019 Tumor Virus Bacteria6473825744
70/73
70
g
Rb Gene
RbRb
protein
Rb
Stops replication
Rb
Adenovirus E1A
Cell cycle continues
Retinoblastoma
105kD
Anti-Oncogenes
-
8/10/2019 Tumor Virus Bacteria6473825744
71/73
71
p53
P53 gene P53 gene P53 gene
P53
P53 DNA
Stops replication
Hepatitis C
P53
replication replication
Papilloma
proteolysi
P53
Papilloma
-
8/10/2019 Tumor Virus Bacteria6473825744
72/73
Bacteria and Human Cancer
72
Helicobacter pylori
-
8/10/2019 Tumor Virus Bacteria6473825744
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
top related