Microorganism & Human Cancer

Riyani Wikaningrum
Bag. Mikrobiologi
FK Universitas YARSI
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Viruses and Human Cancer

Virus acts as a cofactor

Viruses act as initiators of neoplastic process various mechanisms

Interaction Tumor Virus - Host

1. Persistent infection
2. Host immune response
3. Mechanisms of action by Human Cancer
Virus
4. Cell susceptibility to viral infection
5. Retention of tumor virus nucleic acid in host
cell
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Genes unrestrained cell growth

genes that are stimulatory for growth and which
cause cancer when hyperactive oncogenes
genes that inhibit cell growth and which cause
cancer when they are turned off antioncogenes or tumor-suppressor genes
Viruses cancers
virus carry a copy of one of these genes
virus alter expression of the these genes

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

Viruses
Epstein-Barr
virus

Cancer

Strength of
association

Viral genome
in cancer cells

Burkitt's
lymphoma

++

Malaria

Nasopharyngeal
carcinoma

++

Nitrosamine
s

++

? cigarettes

Hodgkin's
disease
Human
papillomavirus

Cervical cancer

Cofactor

? HSV2
Skin cancer

? UV light

Hepatitis B
virus

Liver cancer

++

? Aflatoxin

Hepatitis C
virus

Liver cancer

++

?
Hepatocyte
regeneration

HTLV1

T-cell leukemia

++

HSV2

Cervical cancer

Tumor Viruses
For most viruses:
Replication

Genome

Lysis

Progeny virions

all viral proteins

Lytic Life Cycle

Non-structural and structural proteins made
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Tumor Viruses
Virus

Latent Life Cycle

Cell

Integration (often)

Transformation

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 terminate cell must be infected by
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complete virus

Tumor Viruses
Transformation:
Loss of growth control
Reduced adhesion

Motility
Invasion
Ability to form tumors - viral genes interfere with control of
cell replication and other aspects of the cell phenotype

Transformed cells frequently exhibit chromosomal

aberrations
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Tumor Viruses
TRANSFORMATION
VIRAL TRANSFORMATION
The changes in the biological functions of a cell that result from
REGULATION

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

infected cell certain properties characteristic of
NEOPLASIA
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Tumor Viruses
Both DNA and RNA tumor viruses can
transform cells
Integration of viral genome into the host
chromosomes often occurs

Similar mechanisms of transformation by

each type of tumor virus
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Two Major Classes of Tumor Viruses

DNA Tumor Viruses
DNA viral genome
DNA-dependent
DNA polymerase
(Host or viral)

Host RNA
polymerase

Viral mRNA
Similar to host cell!

Viral protein
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RNA Tumor Viruses

Viral RNA genome
Reverse transcriptase (Virus-encoded)

Viral DNA genome (integrated)

DNA-dependent RNA polymerase (Host
RNA pol II)

IMPORTANT

Viral genomic RNA

Splicing (Host splicing enzymes)

messenger RNA

viral protein

Virus

Important: Use HOST

RNA polymerase
to make its genome
An enzyme that
normally
makes mRNA

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DNA Tumor Viruses

DNA genome
Host RNA
polymerase II

mRNA
Host enzymes

protein

virus

OR TRANSFORMATION
In transformation usually only EARLY functions are expressed
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DNA Tumor Viruses In

Human Cancer
Papilloma Viruses

cause natural cancers in animals

cause benign warts
ubiquitous
epitheliotropic - most human tumors are malignancies of epithelial
cells
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DNA Tumor Viruses In

Human Cancer
Papilloma Viruses

Epidermodysplasia verruciformis
wart

malignant
skin squamous cell carcinoma

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DNA Tumor Viruses In

Human Cancer
Epidermodysplasia
verruciformis
Papilloma virus

2008
Dermatology
Online Journal
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DNA Tumor Viruses In

Human Cancer
Papilloma Viruses
urogenital cancer
wart

malignant squamous cell carcinoma

Squamous cell carcinoma:

Larynx
Esophagus
Lung

All histologically similar

10% of human cancers may be HPV-linked

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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)
EPIDEMIOLOGIAL STUDIES BUT:
HPV 16 and HPV 18 do transform human keratinocytes
Effective Vaccine
(quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in
yeast - Gardasil)
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Papilloma Viruses
The important transforming genes in
papilloma viruses are: E6 and E7
Early genes - Not encoding structural
proteins
Oncogenes

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DNA Tumor Viruses In

Human Cancer
Polyoma Viruses
Simian virus 40 - juvenile hamster sarcomas, transformation

Polyoma - mouse leukemia, in vitro transformation

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

Possible association of BK with human prostate cancer

Polyoma virus transforms cells when the genome is incomplete

Early functions are necessary - ONCOGENES

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JC: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

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 antigens
E1B region: 1 T antigen
E1A and E1B = Oncogenes

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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
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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 is
known as a VIRAL ONCOGENE

v-onc
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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

25

DNA Tumor Viruses In

Human Cancer
Epstein-Barr Virus
Burkitts Lymphoma
Nasopharyngeal cancer
Infectious mononucleosis (glandular fever)
Transforms human B-lymphocytes in vitro

Burkitts lymphoma: malarial infested regions

Nasopharyngeal cancer: China, SE Asia diet?
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DNA Tumor Viruses In

Human Cancer
Human herpes virus 8
Kaposis Sarcoma Herpes Virus
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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DNA Tumor Viruses In

Human Cancer
Hepatitis B Virus
DNA genome
RNA polymerase II

Host enzyme

RNA Provirus
Reverse transcriptase

DNA genome

Viral enzyme

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Hepatocellular Carcinoma (HCC)

DNA Tumor Viruses In

Human Cancer
Hepatitis B continued

Vast public health problem

10% of population in underdeveloped countries are chronic carriers

Long latency

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DNA Tumor Viruses In

Human Cancer
Hepatitis B continued

Epidemiology:
Strong correlation between
HBV and hepatocellular
carcinoma
China: 500,000 - 1 million new
cases of hepatocellular carcinoma
per year
Taiwan: Relative risk of getting
HCC is 217 x risk of non-carriers
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DNA Tumor Viruses In

Human Cancer
Summary

These viruses can transform cells or have lytic life cycle

Often integrate into host genome

In transformation often ONLY early genes
(non-structural) are transcribed
These are genes that are also necessary for a
PRODUCTIVE infection

True viral genes

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RNA Tumor Viruses

RNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virus
REVERSE TRANSCRIPTASE
RNA genome
Reverse transcriptase

virus

DNA genome
Integrase

virus

Integrates
Host RNA polymerase II

RNA genome

host
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RNA Tumor
Viruses

34

RNA Tumor Viruses

A normal retrovirus has:
3 genes
GAG : internal proteins
ENV: Envelope glycoproteins
POL: Enzymes
Reverse transcriptase RNase H
Integrase
Protease

35

RNA Tumor Viruses

RNA is:
Diploid

Capped and polyadenylated

Positive sense (same as mRNA)

Viral RNA cannot be read as mRNA

(even though same sense)
New mRNA must be made
Virus must make negative sense DNA before proteins are
made

Therefore virus must carry REVERSE TRANSCRIPTASE

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into the cell

RNA Tumor Viruses

37

RNA Tumor Viruses

Groups of Retroviruses
Oncovirinae

important

Tumor viruses and similar

Lentiviruses

important

Long latent period

Progressive chronic disease
Visna

HIV
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RNA Tumor Viruses

Retroviruses 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)

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RNA Tumor Viruses

Human T cell lymphotropic virus -1 (HTLV-1)
UNITED STATES AND OTHER WESTERN COUNTRIES
IV DRUG USERS

US rate of infection about one tenth of that of HIV

BUT half as prevalent as HIV in IV drug users

Also causes: Tropical spastic paraparesis

(affects the gray and white matter of the spinal
cord - myelopathy)
1-4% of infected people
Immunosuppression

40

RNA Tumor Viruses

Retroviruses known to cause human cancer
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)
Seroprevalence in these populations > 20%
Women over 50: seroprevalence - up to 50% in some populations

HIV ?

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RNA Tumor Viruses

Retrovirus Life Cycle
Bind to
surface receptor

Endocytosis

Fusion of membranes

Release of nucleocapsid to cytoplasm

Nucleus

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RNA Tumor Viruses

Parental RNA
Reverse transcriptase

RNA/DNA Hybrid
Reverse
transcriptase

Linear DNA/DNA duplex

Circular Duplex DNA

Integrase

Host DNA
polymerase

Integration

Replication (DNA genome in cell)

Host RNA pol II

Transcription

Host splicing
enzymes

Viral RNA genome

mRNA

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protein

RNA Tumor Viruses

Drawback to this lifestyle

Genomic RNA

Reverse transcriptase
DNA

Host RNA pol II

Genomic RNA
Pol II is a host enzyme that, in the uninfected cell, makes mRNA
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When making mRNA, pol II does not copy entire gene to RNA

Problem of using RNA pol II to copy a gene

RT
primer

Viral
genomicRNA

Reverse
transcriptase
dsDNA
RNA synthesis
initiation site
promotor

RNA pol II
RNA synthesis termination
site

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

RNA Tumor Viruses

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

Perhaps virus could integrate downstream of a promotor etc so

that the cell provides sequences
OR

Virus provides its own promotors etc

BUT not copied!

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RNA Tumor Viruses

Repeat
region

Clue: Difference in the two forms

Repeat
region

RNA
R

U5

GAG

POL

ENV

U3

DNA

U3

R
LTR

U5

GAG

POL

ENV U3

U5
LTR

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U5

Viral RNA

U3

R
Reverse
transcriptase

U3

U5

U3

U5

Long terminal repeats are formed

promotor
POLII

POLII

RNA initiation site

RNA termination site

48

Retroviruses can have only one

promotor region
Contained in U3

LTR

LTR

POLII

POLII

RNA initiation site

RNA termination site

Therefore only one long RNA can be made

U5

Therefore mRNA requires processing

Explains why RNA has to be positive sense

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Some retroviruses have an

extra gene

typical retrovirus

U5

GAG

POL

ENV

U3

Rous Sarcoma Virus

R

U5

GAG

POL

ENV

SRC

U3

R
50

Some retroviruses have an oncogene

instead of their regular genes
Avian Myeloblastosis
Virus
R

U5

GAG

POL

MYB

U3

Feline Sarcoma Virus (FSV)

R

U5

dGAG

FMS

dENV

U3

Avian Myelocytoma Virus (MC29)

R

U5

dGAG

MYC

dENV

U3

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RNA Tumor Viruses

Viral Oncogene
V-onc

Cellular Proto-oncogene
C-onc
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RNA Tumor Viruses

Proto-oncogene
A cellular (host) gene that is homologous with a
similar gene that is found in a transforming virus

A cellular oncogene can only induce

transformation after
mutation
some other change in the cells genome

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RNA Tumor Viruses

The discovery of the acutely transforming
retroviruses that contain
v-oncs explains how cancers may arise as a result
of infection

These viruses cause rapid cancer in animals in

the laboratory

54

RNA Tumor Viruses

In contrast:
Chronically transforming retroviruses
cause tumors inefficiently after prolonged period of time
Avian Leukosis Virus (causes lymphomas)

U5

GAG

POL

ENV

U3

No oncogene! How does it cause a

tumor?

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RNA Tumor Viruses

ALV can integrate into the host cell genome at
MANY locations
but in tumor it is always at the SAME site (or
restricted number of sites)
Suggests tumor arose from one cell

Something must be important about this site for

transformation
Crucial event must be rare
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RNA Tumor Viruses

What is special about this site?
Myelocytoma tumors from several birds all have
the oncogene close to this site

It is close to
C-myc!
Oncogenesis by promotor insertion
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RNA Tumor Viruses

Could C-oncs be involved in NON-VIRAL cancers?

58

RNA Tumor Viruses

What do oncogenes encode?
Proteins that are involved in growth control and
differentiation

Growth factors
Growth factor receptors
Signal transduction proteins
Transcription factors

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DNA Tumor Viruses

How they tumors depended on
our knowledge of RNA tumor
viruses

60

DNA Tumor Viruses

Herpes

myb

mos
myc

Genes can be
assigned to
sites on
specific
chromosomes

mos and myc :

chromosome 8
fes

fes: chromosome 15
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Cancers often result from gene

translocations
Burkitts Lymphoma
8:14 translocation

Break in chromosome
14 at q32

myc

Acute myelocytic leukemia

7:15
9:18
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11:15:17

Oncogenesis by rearrangement
Tumor

c-onc

Burkitts lymphoma

myc

(8)

new promotor
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
T cell chronic lymphocytic
leukemia

(14 inversion)
myc

T cell receptor (8 to 14)

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Oncogenes
Mutations 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

64

Proto-oncogenes
Heterozygote

Dominant
mutations

Homozygote

Allele 1

Allele 2

Allele 1

Allele 2

Normal

Mutant

Mutant

Mutant

Binds under
special
circumstances

Mutant
always
binds

Always binds

Mutant
always
binds

Mutant
always
binds
Always binds
65

Function gained

Function gained

Anti-Oncogenes
Recessive mutations

Mutation
Rb Gene

Mutant Rb

growth
Mutant Rb

Mutant Rb

Rb
Rb protein

Heterozygote

Rb
Binds and controls cell cycle
Turns off DNA replication

Homozygote
Function lost
No binding - Growth continues
66

Anti-Oncogenes
Retinoblastoma gene has normal
regulatory function in many cells

Involved in

Retinoblastoma
Lung carcinomas
Breast carcinomas

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Anti-Oncogenes
P53
Inactivated by

deletion
point mutation

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DNA Tumor Viruses

Oncogenes
Adenovirus

E1A region 2

SV 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

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Anti-Oncogenes
Retinoblastoma

Adenovirus E1A

Rb Gene

Rb
protein

Rb

105kD
Rb

Rb
Stops replication

Cell cycle continues

70

Anti-Oncogenes
p53
P53 gene

P53 gene
Hepatitis C

P53

P53

P53 gene
Papilloma
P53

Papilloma
proteolysis

P53

DNA

Stops replication

replication

replication

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Bacteria and Human Cancer

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Helicobacter pylori
Associated with:
Gastric and duodenal cancer
Gastric mucosa-associated lymphoid tissue
(MALT) lymphoma
Inflammatory reaction to H. pylori chronic
atropic gastritis (CAG) metaplasia dysplasia
carcinoma
Other factor (?) genetic or environmental
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