VIRUS and

CANCER
Oncogenic virus

Distinguishing
Characteristics of Viruses
Obligate
intracellular
parasites
Contain DNA or
RNA
Replication
involves
disassembly and
reassembly
2

Viruses enter the body of

the host
in a variety of ways, for
example...

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Routes of entry:
Inhalation
ingestion

inoculation

sexual

Blood
organ t/plant

Congenital / vertical

WHO Estimates
Worldwide, the WHO International
Agency for Research on Cancer
estimated that in 2002, 20% of
human cancers were caused by
infection, of which 1015% are
caused by one of seven different
viruses. The importance of this is that
some of these cancers might be
easily prevented through vaccination
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What is Cancer
Cancer results from alterations in
critical regulatory genes that control
cell proliferation, differentiation, and
survival. Studies of tumor viruses
revealed that specific genes (called
oncogenes) are capable of inducing
cell transformation, thereby providing
the first insights into the molecular
basis of cancer.
6

How virus causes

Cancers:
The viral agents causing cancer in
eukaryotic animals by integrating in
host genome
*A virus associated with malignancies in
natural host, experimental animals or
cell cultures.
*viruses which modified protooncogene, obligatory host specific, with
the ability immortalization, possess
genes which stimulate growth and
cause cancer.
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Early History
The theory that cancer could be caused
by a virus began with the experiments
of Oluf Bang and Vilhelm Ellerman in
1908 who first show that avian
erythroblastosis (a form of chicken
leukemia) could be transmitted by cellfree extracts. This was subsequently
confirmed for solid tumors in chickens in
1910-1911 by Peyton Rous.
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Research History

In 1908, Ellerman
& Bang first
discovered virus,
producing leukemia
in chicken.
In 1911 Peyton
Rous 1st shows the
presence of
filterable sarcoma
material that induce
the CANCER.

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Relationship of
viruses with
malignancy
Ellerman & Bang (1908)
leukemia in fowls
Rous (1911) fowl sarcoma
Shope isolated Rabbit fibroma virus
(1932), papilloma virus (1933)
Bittner (1936) Breast Ca in mice
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Oncovirus
An oncovirus is a virus that can
cause cancer. This term originated
from studies of acutely-transforming
retroviruses in the 195060s, often
called oncornaviruses to denote their
RNA virus origin. It now refers to any
virus with a DNA or RNA genome
causing cancer and is synonymous
with "tumor virus" or "cancer virus".
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by transforming cells
cancer
When a virus infects a cell, it
expresses proteins that cause the
cell to proliferate and/or block
apoptosis
Cancer is multi-factorial: Oncogenic
viruses are very common, only a small
% of people infected actually get
cancer

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Major viral cancers

Viruses are involved in about 15% of human cancers:
cancers

Cancer of the cervix

Cancer of the liver
Certain leukemia's & lymphomas
Kaposis sarcoma
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Copyright John Valentine DMD

13 1999

Classification

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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 viruses
Human T-cell Leukemia Virus 1 (HTLV1)
Hepatitis virus C
15

Oncogenic viruses may be

RNA or DNA
20% of human
cancers believed to
be of viral origin
These include:
Cervical cancer
Burkitts
lymphoma
Hepatocarcinoma
Kaposis sarcoma
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Viruses Associated With

The Development Of
Human Neoplasia
VIRUSES

NEOPLASMS

DNA VIRUSES

Human papilloma virus

Cervical Ca, warts,
anogenital carcinoma
Herpes simplex virus II
Cervical carcinoma
Epstein-Barr virus
NPCa, African Burkitts
Human Herpes virus 8 Kaposis sarcoma
Hepatitis B virus Hepatocellular Ca
Herpes simplex virus 6
Certain B cell
Human B-lymphotropic
virus (HBLV)
lymphomas
17

Viruses Associated With

The Development Of
Human Neoplasia

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RNA viruses
Some RNA
viruses have also
been associated
such as the
hepatitis virus
as well as human
T-lymphotropic
virus (HTLV-1).
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Oncogenic viruses

Oncogenesis is the result

of genetic changes that
alter the expression or
function of proteins that
play critical roles in the
control of cell growth and
division
Oncogenic viruses cause
cancer by inducing
changes that affect cell
growth and division
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Oncogenic
Retroviruses

More than 40 different highly oncogenic

retroviruses have been isolated from a
variety of animals, including chickens,
turkeys, mice, rats, cats, and monkeys.
All of these viruses, like RSV, contain at
least one oncogene In some cases,
different viruses contain the same
oncogenes, but more than two dozen
distinct oncogenes have been identified
among this group of viruses
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Changes in cell that are at the

roots of cancer
Genetic and epigenetic alterations:
Mutations
Deletions
Recombination's
Transpositions
Epigenetic alterations (DNA methylation,
imprinting)
Acquisition of viral genetic material
22

Changes in cell that are at the roots of

cancer
Genetic and epigenetic alterations:
Mutations
Deletions
Recombination's
Transpositions
Epigenetic alterations (DNA methylation, imprinting)
Acquisition of viral genetic material

Various combinations of these lead to the development of

cancers - some viruses contribute single hits while others
contribute multiple hits.
23

How do Viruses contribute to

cancer?
Integrations that cause
activation or inactivation of
oncogenes or tumor suppressors (e.g.
RNA viruses)
Expression of genes that alter
key signal transduction pathways this is our focus
Chronic activation of

24

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25

Viruses causing human

malignancies
Hepatitis B & C viruses:
Hepatocellular Cancer.
E-B virus: Nasopharyngeal Ca,
Burkitts lymphoma
HPV 16 & 18: Ca Cx
HTLV: Adult T cell leukemia
HHV 8: Kaposis sarcoma
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Retroviruses:
1.Avian leukosis
viruses
2.Murine leukosis
viruses
3.Murine
mammary tumor
virus
4.Leukosissarcoma viruses
5.Human T cell
leukemia virus
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Retroviridae
Any virus capable of
inducing tumors. The
RNA tumor viruses
(family Retroviridae),
which are well
defined and rather
homogeneous, or the
DNA viruses, which
contain a number of
viruses capable of
inducing
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Cancer
Cancer arises from
a combination of
dominant gain of
function mutations
in proto- oncogenes
and recessive loss
of function
mutations in tumor
suppressor genes
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Understanding Cancer
CANCER
Cancer is an overgrowth of cells bearing cumulative
genetic injuries that confer growth advantage over the
normal cells [Nowells Law]
Cancer cells can be characterized as antisocial,
fairly autonomous units that appear to be indifferent
to the constraints and regulatory signals imposed on
normal cells [Robbins]
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CANCER CELLS AND NORMAL

CELLS
CANCER CELLS

NORMAL CELLS

Frequent
mitoses
Normal
cell
Nucleus
Few
mitoses

Blood vessel

Abnormal
heterogeneous cells

Loss of contact inhibition

Oncogene expression is rare

Increase in growth factor secretion

Intermittent or co-ordinated
growth factor secretion

Increase in oncogene expression

Loss of tumor suppressor genes
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Presence of tumor suppressor

genes
32

CHARACTERISTICS OF
CANCER
Clonality

Cancer is a genetic disease at the

cellular level.
Genetic mutations play a critical role
in pathogenesis of cancer.
Consequences of genetic instability:
Phenotypic heterogeneity
Tumor progression

Proto-oncogenes and oncogenes

Dominant and recessive mutations
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Cancer Genetics
Tumors arise as clones from a
single cell. At the cellular level,
cancer is a genetic disease.
The development of the malignant
clone is due to mutations in DNA
due to:
Random replication errors
Exposure to carcinogens
Faulty DNA repair process
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Cancer Genes
Proto-oncogenes normally promote
normal cell growth; mutations convert
them to oncogenes.
Tumor suppressor genes normally
restrain cell growth; loss of function results
in unregulated growth.
Mutator or DNA repair genes when
faulty, result in an accumulated rate of
mutations.
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ONCOGENE FAMILY

Mouse fibroblast cell line NIH 3T3 can take up foreign

D
+ oncogenes
Mouse fibroblast cell line NIH 3T3 can take up foreign DNA,
incorporate them into their genome and express them
DNA extracted from human tumour cells can transform NIH
Oncogenes
3T3
promote cell proliferation
Such transforming genes have been shown to be identical
with cellular oncogenes
dominant & highly conserved
14NA, incorporate them into their genome and express
them viral oncogenes [v-oncs]
types:
DNA extracted from human tumour cells can transform NIH
3T3
cellular oncogenes [c-oncs]
Such transforming genes have been shown to be identical
with cellular oncogenes
Proto-oncogene Mutation Oncogene
14
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Viral
Carcinogenesis
Viral carcinogens are classified
into RNA and DNA viruses.
Most RNA oncogenic viruses
belong to the family of
retroviruses that contain

reverse transcriptase

mediates transfer of viral RNA

into virus specific DNA.
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Statistical Prevalence in
Different Worlds

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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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Two Major Classes of Tumor

Viruses
DNA Tumor Viruses
DNA viral genome

DNA-dependent
DNA polymerase
(Host or viral)

Host RNA
polymerase
Viral mRNA

Viral protein
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RNA Tumor Viruses

Viral RNA genome
Reverse transcriptase
(Virus-encoded)

Viral DNA genome (integrated)

IMPORTANT
polymerase (Host

DNA-dependent RNA
RNA pol II)

Viral genomic RNA

enzymes)

messenger RNA

Splicing (Host splicing

Important: Use HOST
RNA polymerase
to make its genome

viral protein
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Virus

An enzyme that
normally
makes mRNA
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Small DNA tumor viruses

Adenovirus

Human virus but only causes cancer in

non-human cells

SV40

Mesothelioma

HPV

Cervical Cancer
Squamous cell anal carcinoma
Penile cancer
Oral cancers

42

DNA Tumor Viruses In

Human Cancer
Papilloma Viruses
urogenital cancer
wart

malignant squamous cell

carcinoma
Papilloma viruses are found in 91% of women with cervical cancer

Squamous cell carcinoma:

Larynx
Esophagus
Lung

All histologically similar

10% of human cancers may be HPV-linked

43

DNA Tumor Viruses In

Human Cancer
Herpes Viruses
Considerable evidence for role in human
cancer
Some very tumorigenic in animals
Viral DNA found in small proportion of tumor cells: hit and run
Epstein-Barr Virus
Burkitts Lymphoma
Nasopharyngeal cancer
Infectious mononucleosis
Transforms human B-lymphocytes in vitro
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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
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getting HCC is 217
x MD

45

DNA Tumor Viruses In

Human Cancer
Papilloma Viruses

51 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)
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Human Papillomavirus
(HPV)
Human Papillomavirus
(HPV) is a doublestranded DNA virus of
the family
Papovaviridae. It infects
only epithelial cells in
humans such as skin
and mucus membranes.
It can affect the lower
genital tract including
the vulva, vagina,
urethra, penis, anal
canal and perianal skin
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DNA viruses
Human Papilloma virus
(HPV), a DNA virus, causes transformation in

cells through interfering with tumor

suppressor proteins such as p53. Interfering
with the action of p53 allows a cell infected
with the virus to move into a different stage
of the cell cycle, enabling the virus genome
to be replicated. Forcing the cell into the S
phase of the cell cycle could cause the cell
to become transformed types of HPV
increase the risk of, e.g., cervical cancer.
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Epstein Barr virus

Pathologies in immuno-competent individuals
Infectious mononucleosis
Burkitts Lymphoma
Hodgkins lymphoma
Nasopharyngeal carcinoma
Pathologies in immuno-compromised individuals
Post-transplant lymphoproliferative diseases (PTLD)
Hodgkins lymphoma
A variety of non-Hodgkins lymphoblastic malignancies
50

Epstein-Barr virus
(Human herpes virus 4)
EBV is the herpes
virus that is most
strongly associated
with cancer. It infects
primarily lymphocytes
and epithelial cells. In
lymphocytes, the
infection is usually
non-productive, while
virus is shed
(productive infection)
from infected
epithelial cells.
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Burkitt's
lymphoma

Burkitt's lymphoma in the tropics, where it is more

common in malaria-endemic regions
Nasopharyngeal cancer, particularly in China and
SE Asia, where certain diets may act as cocarcinogens
B cell lymphomas in immune suppressed
individuals (such as in organ transplantation or HIV)
Hodgkin's lymphoma in which it has been detected
in a high percentage of cases (about 40% of
affected patients)
X-linked lymphoproliferative Disease (Duncan's
syndrome)
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Infectious
mononucleosis

EBV also causes infectious

mononucleosis, otherwise known as
glandular fever. This is a self-resolving
infection of B-lymphocytes which
proliferate benignly. Often infection goes
unnoticed (it is sub-clinical) and about
half of the population in western countries
has been infected by the time they reach
20 years of age. Why this virus causes a
benign disease in some populations but
malignant disease in others is unknown
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Kaposis Sarcoma
Herpes Virus - HHV-8
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
54

Human Herpes Virus 8

(HHV-8, Kaposi's Sarcoma
Herpes Virus)

HHV-8 infects lymphocytes and

epithelial/endothelial cells and is the
causative agent of Kaposi's sarcoma. It has
also been associated with hematologic
malignancies, including primary effusion
lymphoma, Multicentric Castleman's (also
Castelman's) disease (MCD), MCD-related
immunoblastic/plasmablastic lymphoma
and various atypical lymphoproliferative
disorders
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Kaposi's sarcomaassociated herpesvirus

Kaposi's sarcoma-associated
herpesvirus (KSHV or HHV-8) is
associated with Kaposis sarcoma, a
type of skin cancer. Epstein-Barr virus
(EBV or HHV-4) is associated with four
types of cancers Merkel cell
polyomavirus a polyoma virus is
associated with the development of
Merkel cell cancer
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RNA oncogenic
viruses

Retroviridae

Human T cell leukemia viruses

(HTLV-1 and HTLV-2)
Causes
Adult T cell leukemia
Lymphoma

Feline leukemia virus (FeLV)

Contagious
Causes leukemia and lymphoma in cats

Related to presence of reverse transcriptase

Some contain promoters that turn on other
oncogenes
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RNA Tumor Viruses

Groups of Retroviruses
Oncovirinae

important

Tumor viruses and similar

Lentiviruses

important

Long latent period

Progressive chronic disease
Visna

HIV

Spumavirinae

58

VIRAL AGENTS: DNA viruses

Human Papillomavirus [HPV types 16, 18, 31, 33 & 35]

Interruption of the E1/E2 ORF

E2 is not expressed

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Over-expression
Dr.T.V.Rao of
MDE6 & E7

59

VIRAL AGENTS: DNA

viruses
Epstein-Barr Virus [EBV]

in Burkitts, B-cell & Hodgkins lymphomas + NP ca

tropism: CD21+ cells [e.g., B cells, epithelial cells]

mechanism: viral entry episomal existence latency

(+) LMP-1, EBNA-1, EBNA-2 immortalization

Hepatitis B virus [HBV]

induction of chronic hepatocyte injury (+) HBx

HBx activates protein kinase c for transformation

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Hepatitis B
DNA virus with RNA
intermediate
In tumors virus is
integrated with little
gene expression
Believed to be from
chronic liver
damage/loss and
replacement causing
increased mutations
(similar to SOS
response?)
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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

62

HEPADNAVIRIDAE
HEPATITIS B VIRUS
Hepatitis B virus is very different from the
other DNA tumor viruses. Indeed, even
though it is a DNA virus, it is much more
similar to the oncornaviruses (RNA tumor
viruses) in its mode of replication. The DNA
is transcribed into RNA not only for the
manufacture of viral proteins but for
genome replication. Genomic RNA is
transcribed back into genomic DNA. This is
called reverse transcription. The latter is not
typical of most DNA tumor viruses but
reverse transcription is a very important
factor in the life cycles of RNA-tumor viruses
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HCC is one of the most

common tumors
worldwide

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Hepatocellular
carcinoma

Hepatocellular carcinoma (HCC, also

called malignant hepatoma) is a primary
malignancy (cancer) of the liver. Most cases
of HCC are secondary to either a viral
hepatitide infection (hepatitis B or C) or
cirrhosis (alcoholism being the most common
cause of hepatic cirrhosis).In countries where
hepatitis is not endemic, most malignant
cancers in the liver are not primary HCC but
metastasis (spread) of cancer from elsewhere
in the body, e.g., the colon.
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RNA Tumor
Viruses
Retroviruses known to cause human c

Human T cell lymphotropic virus -1 (HTLV-

Adult T cell leukemia, Sezary T-cell leuk

Africa, Caribbean, Some Japanese

Human T cell lymphotropic virus -2 (HTLV2)

Hairy cell leukemia

HIV?
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Proto-oncogenes
Heterozygote

Dominant
mutationsHomozygote

Allele 1

Allele 2

Allele 1

Normal

Mutant

Mutant

Binds
Muta
under
nt
special
alway
circumstan
s
Always
binds
ces
binds
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Function

gained

Muta
nt
alway
s
binds

Dr.T.V.Rao MD Function

Allele 2
Mutant

Muta
nt
alway
s
Always
binds binds
gained

67

Anti-Oncogenes
Recessive mutations
Mutation
Rb Gene

growth
Mutant Rb

Mutant Rb

Mutant Rb

Rb

Rb
protein

Heterozygote

Rb

Binds and controls cell

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cycle

Homozygote

Function lost

No binding - Growth
Dr.T.V.Rao MD
continues

68

Anti-Oncogenes
Retinoblastoma gene has normal
regulatory function in many cells
Involved in
Retinoblastoma
Lung carcinomas
Breast carcinomas
69

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

70

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

Retinoblastoma
Lung carcinomas
Breast carcinomas
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Anti-Oncogenes
Retinoblastoma

Adenovirus E1A

Rb Gene

Rb
protein

Rb

105kD

Rb

Rb
Stops
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replication

Dr.T.V.Rao MDCell

cycle continues

72

Anti-Oncogenes
P53
Inactivated by
deletion
point mutation
In a series of colorectal cancers all showed:
Allele 1: partial or complete deletion
Allele 2: Point mutation
73

Anti-Oncogenes
p53
P53 gene

P53 gene
Hepatitis C

P53

P53

P53 gene
Papilloma

P53

Papilloma
proteolysis
P53

DNA

Stops
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replication
Dr.T.V.Rao MD

replication

74