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Human oncogenic viruses
Nearly 20% of all cancers worldwide are attributed to viruses
• Oncogenic viruses are viruses that produce
tumors in their hosts (natural or experimental)
and induce malignant transformation of cell
cultures.
• Tumor viruses: the DNA tumor viruses and
the RNA tumor viruses.
• Common aspect of their life cycle:
the ability to integrate their own genome into
that of the host cell.
• Transformation is the introduction of
inheritable changes in a cell causing changes
in the growth phenotype and immortalisation.
• Cancers are the result of a disruption of the
normal control on cell growth and proliferation.
• Properties of cancer cells:
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immortality;
uncontrolled growth;
undifferentiation;
spread into and destroy
surrounding tissues;
– spread to other parts
of the body.
• Transformation by a virus is changes in the
biologic functions of a cell that result from
regulation of the cell by viral genes and that
confer on the infected cell certain properties
characteristic of neoplasia.
• Transformed cell is a cell in which a virus
takes up residence and alters its properties.
Francis Peyton Rous (1879-1970)
• Rous is the first person to show that a virus
could cause cancer in animals.
• He demonstrated that a virus (Rous sarcoma
virus) can cause cancer in chickens (1911).
• For his discovery the Rous sarcoma virus
F.P.Rous won the Nobel Prize in 1966.
Silber L.A. (1894-1966) - author of the viral-genetic
theory of carcinogenesis
• Cellular proto-oncogenes usually encode proteins that
function in DNA replication.
• Normally, they are not expressed in a cell since cells would multiply to
repair damage, for example after a wound or operation .
• They can be transformed in oncogenes only after being
altered such as:
– mutation or
– coming under the control of a highly active promotor.
• Oncogenes are cellular genes that influence cell growth and
differentiation and code for a protein that potentially can
transform a normal cell into a malignant cell.
• Viral oncogenes are cellular oncogenes that become
incorporated into the virus by recombination.
• A virus may cause cancer in two ways:
- it may carry an oncogene into a cell or
- it may activate a cellular proto-oncogene as promotor.
BASIC MECHANISM OF CELL GROWTH TRANSFORMATION BY
DNA VIRUSES
Viral DNA integration into cellular genome occurs only rarely and is not a normal
part of the virus life cycle.
A. Integrated viral DNA carries an oncogene into a cell and permanently expresses
“early” viral genes
B. Viral DNA integration destabilises cellular genome and/or activates adjacent
cellular oncogenes
Discoverers of viral reverse transcriptase.
The Nobel Prize in Physiology or Medicine 1975
• They discovered reverse transcriptase, a DNA-polymerase enzyme that
transcribes RNA into DNA.
• Their discovery showed that the DNA's genetic information, which
ordinarily travels from DNA to RNA, can also travel in the other direction,
allowing viruses to replicate the RNA into the DNA of otherwise healthy
calls, which can cause some forms of cancer.
Howard M. Temin (1934-1994)
David Baltimore (1938)
The reverse transcriptase of retroviruses
catalyses a series of reactions to convert the
single-stranded RNA genome of viruses into
double-stranded DNA for host-cell integration.
BASIC MECHANISM OF CELL GROWTH TRANSFORMATION BY
RETROVIRUSES
Provirus integrates into cellular genome as a normal part of virus life cycle.
A. Integrated provirus activates adjacent cellular oncogene.
B. Provirus carries a “captured” cellular oncogene.
C. Provirus-coded protein activates cellular genes.
The general classes of oncogenes encode:
- growth factors,
- membrane receptors,
- signaling proteins, conveying signals from the outside of
the cell to the interior,
- DNA binding proteins - factors which interact in gene
regulation and replication,
- and other regulatory proteins.
ANTI-ONCOGENES (Tumor suppressor genes)
• They stop the cell multiplying or doubling.
• If one of these genes becomes damaged and
stops working, then the cell may carry on and on
multiplying and becomes immortal.
• Tumour suppressor gene p53 normally
– stops cells with other damaged genes from
reproducing to allow for DNA damage repair
– or causes the cell to undergo apoptosis if the damage
cannot be repaired.
p53 is a tumor suppressor
• It is referred to as The Guardian of the Genome since
it regulates of the DNA damage control system.
• p53 is damaged or missing in most human cancers.
• How does p53 work in a functional cell?
• A few of p53 molecules - in a healthy cell.
• DNA becomes damaged
DNA replication results
The rise in p53
stops DNA replication.
p53 is a transcription factor.
1. p53 binds to a specific site on the chromosomes and switches on
other genes and these, in turn, shut down DNA replication.
2. Hepatitis C virus causes hepatocellular carcinoma by taking the
tumor suppressor out of action by complexing it in an inactive form that cannot
bind to the specific site on DNA.
3. Papilloma viruses bind p53 and direct it to a protease that
destroys it.
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Human oncogenic viruses
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RNA-viruses
Family Retroviridae (HTLV-1, HTLV-2)
Family Flaviviridae (hepatitis virus C)
DNA-viruses
Family Hepadnaviridae (hepatitis virus B)
Family Herpesviridae (HSV 2, Epstain Bar
virus, HV 8)
• Family Papillomaviridae (18 types)
Family Retroviridae. Genus Deltaretrovirus.
Human T lymphotropic viruses
(HTLV-1, HTLV-2)
- HTLV was the first unequivocal
human cancer virus to be identified by
Yorio Hinuma and colleagues in 1981.
- HTLV are characterized by the
proliferation of mainly CD4+ Tlymphocytes and the
development of adult T cell
leukemia
(in some Japanese islands, the
Caribbean, Latin America and Africa).
HTLV is sexually and
parenterally transmitted.
Natural course from the infection of HTLV-I to
onset of aneuploid adult T-cell leukaemia (ATL)
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HTLV-I promotes proliferation of infected cells by actions of Tax
Proliferation of infected cells is controlled by cytotoxic T-cells.
Alternations in the host genome lead to the onset of ATL.
After an asymptomatic period of 20–40 years, ATL-cells ('flower
cells', with flower-shaped nuclei) emerge in approximately 5%
of infected individuals.
Most HTLV-1-infected
individuals remain life-long
asymptomatic carriers.
Family Flaviviridae. Hepatitis virus C
Hepatocellular сarcinoma develops in about 50%
of persons with chronic infection over a period
of 10 to 30 years
Hepatitis B Virus
30-90 % of infected young patients less than five
years and 10-15% of infected patients of five years
and older go on to the chronic infection.
Chronic hepatitis leads to hepatocellular carcinoma
in up to a quarter of patients.
Liver cancer
Possible mechanisms
of hepatitis B virus involvement in oncogenesis:
(1) Integration viral DNA induces synthesis of HBxAg
which binds p53.
(2) Repression of the cell beta-interferon promoter.
(3) Integration within a cell cycle control gene, cyclin.
(4) Integration near a hormone response gene, thus
altering control.
(5) Deletion of the anti-oncogene p53.
However, the strongest association with cancer
occurs with chronic liver disease.
Herpes Simplex Virus
• Prior infection with HSV-2 is associated with
cervical intraepithelial neoplasia and carcinoma
of the uterine cervix.
• Smoking and exposure to a number of genital
infections increases the probability of
developing cervical cancer.
• Epidemiology: HSV-2 is sexually transmitted.
Epstein Barr Virus (EBV)
• Burkitt's lymphoma (African manifestation)
• Nasopharyngeal cancer (common Chinese
& SE Asian manifestation)
• B cell lymphomas in immune suppressed
individuals (organ transplantation or HIV)
• Oral hairy leukoplakia (in HIV-infected
patients)
• Burkitt's lymphoma is a tumor of the jaw and
face found in children.
• There is probably a genetic reason possibly involving an association with
malaria.
• Nasopharyngeal cancer is a tumor of the
epithelium of the upper respiratory tract
• South China, Alaska, Tunisia, east Africa.
– genetic predisposition
– environmental cofactor involved.
• Oral hairy leukoplakia results in lesions in
the mouth (whitish, corrugated or hairy,
adherent plaques, lateral margins of the
tongue)
Kaposi’s Sarcoma (HHV 8)
KS is a systemic disease that can present with cutaneous lesions with or
without internal involvement. KS can involve the oral cavity, lymph
nodes, and viscera of gastrointestinal and respiratory tract.
Morphologies of cutaneous lesions: macular, patch, plaque, nodular.
The AIDS-related KS lesions affect the upper trunk, face, and oral cavity
Transmission: through saliva (by kissing),
organ transplantation,
blood transfusion.
Papillomaviruses (HPV)
• Transmission:
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sexually
fingers-genital contact
direct contact through abrasion
perinatally from mother to child.
• Papillomaviruses are associated with:
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human penile, anal, vaginal, uterine and cervical carcinomas
genital warts that can convert to carcinomas
carcinomas of skin, esophagus, larynx and lung.
condilomas, papilomas, warts
• HPV cause 16% of female cancers worldwide and
10% of all cancers.
• Vulvar, penile and cervical cancers - types 16 and 18.
Harald zur Hausen (born March 11, 1936)
• He has done research on cancer of
the cervix, where he discovered the
role of papilloma viruses.
• He identified HPV16 and HPV18 in
cervical cancers in 1983-4. This
research directly made possible the
development of a vaccine which was
introduced in 2006.
• For this discovery he received the
Nobel Prize in Physiology or
Medicine 2008.
Papillomaviruses
HPV have a circular ds DNA protected
by protein capsid.
170 types are pathogenic for human.
18 types are involved in cancer.
270000 women die from cervical
cancer every year
Cervical cancer
• Cervical cancer does not have symptoms until it is quite
advanced.
• For this reason, it is important for women to get routine Pap
tests regularly for cervical cancer.
Genital warts
• Warts may appear within weeks or
months after sexual contact with an
infected person.
• They usually appear as small bumps
or groups of bumps, usually in the
genital area. They can be raised or
flat, single or multiple, small or large,
and sometimes cauliflower shaped.
• They can appear on the vulva, in or
around the vagina or anus, on the
cervix, and on the penis, scrotum,
groin, or thigh.
• If left untreated, genital warts may go
away, remain unchanged, or increase
in size or number.
Papillomaviruses
Oral papillomas
Infectious warts
Cancer
of the tounge
Condilomas
Papillomas
Laryngeal papillomatosis
• Symptoms:
• Adults
– hoarseness, or a strained or breathy voice.
– Size and placement of the tumors dictate the change in the
person's voice.
– Breathing difficulties may occur but more commonly are
found in children.
• Children
– trouble swallowing, noisy breathing, and chronic cough.
– Noisy breathing may be a stridor, which can sound like a
whistle or a snore, and is a sign that the laryngeal or
tracheal parts of the airway are narrowing.
• Oral HPV infection is associated with
oropharyngeal cancer.
Human papilloma virus vaccines
1. Gardasil, marketed by Merck (L protein of 6, 11, 16 and 18 types).
2. Cervarix, marketed by GlaxoSmithKline (L protein of 16 and 18 types).
Types 16 and 18 cause 99,7% cervix cancer cases.
Types 6 and 11 cause 90% of genital warts.
Both are delivered in three shots over six months (0-1-6 months).
Cervarix efficacy is proven for 7.4 years while Gardasil - for 5 years.
Principal cellular and soluble antitumoral components
of innate immune system
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Dendritic cells
Neutrophils
Macrophages
NK cells
T cells
B cells
• Complement
• Transforming growth
factor beta (TGFß)
• Cytokines (IL-10, IL-12)
• γ-Interferon
Dendritic cell and T cells
are attacking cancer cell
Mechanisms
responsible for death
of tumor cells
macrophage
• T cells, which recognize tumor
antigens, became activated and
produce interferon IFNγ and
lymphotoxin, which activate
natural killer (NK) and
macrophages.
• NK cells release perforin- and
granzyme-containing granules,
which causes apoptosis.
• Macrophages release tumor
necrosis factor TNFγ and other
cytokines as well as reactive
oxygen intermediates.
• Antibodies (Abs) to tumorspecific antigens (TSAs) induce
arrest of tumor growth or mediate
antibody-dependent cellular
toxicity (ADCC) by arming
effector cells (NK cells or
macrophages).
Coordinated tumor immunity
Immune-mediated rejection of established Her-2 positive breast tumors
requires CD4+ and CD8+ T cells, NK T cells, neutrophils, macrophages,
antibodies (Ab’s), Fc receptors, IFN-γ, and perforin.
Two outcomes of
interactions between
tumor cells and immune
cells in the tumor
microenvironment
Cytokines secreted by
tumor and immune
cells can either
promote tumor
development and
tumor cell survival or
exert antitumor effects
IL-10, through
antiinflammatory
effects, and IL-12,
through activation of
CTLs and NK cells
and expression of
cytotoxic mediators,
can lead to tumor
suppression.
The three Es of cancer immunoediting: host protective versus tumor sculpting
actions of immunity. Following cellular transformation and the failure of intrinsic
tumor suppressor mechanisms, a developing tumor is detected by the immune
system and its ultimate fate is determined by whether or not it is eliminated by the
host protective actions of immunity (Elimination phase), maintained in a dormant or
equilibrium state (Equilibrium phase) or escapes the extrinsic tumor suppressor
actions of immunity by either becoming non-immunogenic or through the elaboration
of immunosuppressive molecules and cells (Escape phase
Preparation of Tumor-infiltrating lymphocytes