Organisms with

Oncogenic
Potential
COMPETENCY COVERED MI 8.3
 CHAPTER PREVIEW

At the end of the session, the students will be able to

understand:

▰ Oncogenic viruses

• Overview of Viral Oncogenesis

• Oncogenic RNA Viruses

• Oncogenic DNA Viruses

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▰ Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
ONCOGENIC
VIRUSES 4
Human oncogenic viruses and
associated malignancies

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Human oncogenic viruses and
associated malignancies (Cont..)

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Human oncogenic viruses and
associated malignancies (Cont..)

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OVERVIEW OF
VIRAL
ONCOGENESIS 8
OVERVIEW OF VIRAL
ONCOGENESIS
▰ Complex and multistep process requiring prolonged time
(years to decades) and occur only in a small percentage of
the infected individuals.

▰ There are multiple oncogenic events that take place -

transform the host cells into cancer cells.

▰ Viruses contribute to only a portion of those oncogenic

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events.
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Oncogenes
▰ Oncogenes - encode certain proteins (onco proteins)
that trigger the transformation of normal cells into cancer
cells.
 V-onc (viral oncogenes): Essential for the
replication of the virus. Viral oncogenes - expressed
only by certain retroviruses (called as acutely
transforming retroviruses)
 C-onc (cellular oncogenes): Cellular counter part of
viral oncogenes present in the cancer cells
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Oncogenes (Cont..)

▰ Proto-oncogenes - cellular counter part of viral

oncogenes present in the normal host cells.

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Genes Regulating Host Cell
Growth
▰ Four categories of genes - regulate the cellular growth &
proliferation.
▰ Defect in any of these regulatory genes - lead to
transformation of the normal host cells into abnormal
tumor cells:
 Proto-oncogenes
 Anti-oncogenes or tumor suppressor genes
 Apoptosis-regulatory genes
 DNA repair genes
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Events that Must Occur Before
Oncogenesis
▰ Establishing persistent infection

▰ Evades host immune response

▰ Immunosuppression

▰ Host cell susceptibility

▰ Retention of viral nucleic acid inside the host cells

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Establishing persistent
infection
▰ Prolonged interaction between the tumor virus and the
host cell is essential for oncogenesis to develop

▰ Possible only when the tumor virus establishes a long-

term persistent infection in host cells.

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Evades host immune
response
▰ Host immune response plays an important role in viral
clearance.

▰ Tumor virus follows various evasion mechanisms to

bypass the host immune response, which are as follows-

 By restricting the expression of viral genes which go

unnoticed by the immune cells (e.g. EBV in B cells)
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Evades host immune
response (Cont..)
 Infecting the sites that are relatively inaccessible to
immune responses (HPV infecting epidermis)

 Undergoing mutation of certain genes that allows the

virus to escape from the host cellular and humoral
responses (HIV).

 Infection and suppression of essential immune cells (CD4

16
T cell by HIV).
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Immunosuppression
▰ Host allows the cancer cells to proliferate and escape the
host immune response

▰ Immunosuppressed organ transplant recipients and HIV-

infected individuals increased risk of EBV and HPV
associated malignancies.

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Host cell susceptibility

▰ Permissive cells support viral growth and replication of

a progeny virus;
non-permissive cells do not.

▰ Non-permissive cells - host cells - do not have surface

receptors for viral attachment ,do not support the viral
replication or release of virus progeny.
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▰ Essentials
Risk ofof oncogenicity
Medical - Smore
Microbiology, 4/e by Apurba when
Sastry © Jaypee a non-permissive
Brothers Medical Publishers cell is
Retention of viral nucleic acid
inside the host cells
▰ Essential to maintain a stable genetic change that occurs
in a tumor cell.

▰ DNA copies of tumor viruses (both DNA & RNA tumor

viruses) are integrated within the host cell chromosome.

▰ RNA of retroviruses get reverse transcribed to DNA

▰ Hepatitis C virus is an exception

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ONCOGENIC
RNA VIRUSES 20
Oncogenic Retroviruses

▰ Acutely-transforming viruses: Possess viral

oncogenes (V.onc) in their RNA - after being integrated
with the host chromosome - inducing oncogenesis

 Highly oncogenic and cause malignancy within weeks

to months

 Examples - animal retroviruses - Rous sarcoma virus.

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Oncogenic Retroviruses (Cont..)

▰ Slow transforming viruses: HIV and HTLV-1

 Possess additional regulatory gene (e.g. tax gene for

HTLV-1and tat gene for HIV) - after inserting into host
chromosome, activates the host cell machineries -
induces oncogenesis

 Low oncogenic potential, long latent period to develop

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malignancy.
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Human T Cell Lymphotropic
Virus (HTLV)
▰ HTLV belongs to the family Retroviridae, under the genus
Deltaretrovirus.

▰ Two important members are HTLV-I and HTLV-II.

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Human T Cell Lymphotropic
Virus-I (HTLV-I)
Associated with several malignancies—

▰ (1) Adult T cell leukemia/ lymphoma,

▰ (2) cutaneous T cell lymphoma, and

▰ (3) tropical spastic paraparesis.

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Human T Cell Lymphotropic
Virus-I (HTLV-I) (Cont..)
▰ Transmission: Occurs through various routes— (1) from
mother to child especially via breast milk (most
common), (2) sexual (men to women),
(3) infected blood

▰ Target cells: Like HIV, HTLV-I - infects CD4 T cells.

GLUT1 (glucose transporter protein-1) on CD4 T cells -
receptor for virus attachment 25
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Human T Cell Lymphotropic
Virus-I (HTLV-I) (Cont..)
Mechanisms of oncogenesis:

▰ HTLV-I expresses a unique gene - Tax gene which has

oncogenic potential .

Distribution:
▰ HTLV-I is endemic in certain parts of Japan (10% prevalence)
and the Caribbean, but also found sporadically elsewhere.
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Human T Cell Lymphotropic
Virus-I (HTLV-I)
(Cont..)
▰ Tax gene is capable of activating the transcription of
several cellular genes involved in T cells proliferation.
These include-

 Genes coding interleukin-2(IL-2), myeloid growth

factor.

 Promote cell growth cycle -Tax protein inactivates

27
the cell cycle inhibitor p16/INK4a - activates cyclin D (a
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Human T Cell Lymphotropic
Virus-I (HTLV-I)
(Cont..)
▰ Tax gene activates nuclear factor κβ (NF-κβ), a
transcription factor - regulates certain host anti-
apoptotic genes.

▰ Tax gene interferes with DNA-repair pathways - leads

to sustained DNA mutation.

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Human T Cell Lymphotropic
Virus-II (HTLV-II)
▰ HTLV-II is endemic in certain native American tribes and in
Africa.

▰ Transmission and replication of HTLV-II is similar to that of

HTLV-1.

▰ Its pathogenic potential is uncertain.

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AIDS Associated
Malignancies
1. AIDS-defining cancers:
▰ Non-Hodgkin’s lymphomas (NHLs):
 Burkitt’s lymphoma (associated with EBV)
 Diffuse large B cell lymphoma– often involving the
CNS
 Primary effusion lymphoma (associated with HHV-8)
▰ Kaposi’s sarcoma—in association with HHV-8
▰ Invasive cervical carcinoma—in association with HPV.
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AIDS Associated
Malignancies (Cont..)
2. Non-AIDS-defining cancers:

▰ Classical Hodgkin’s lymphoma,

▰ Anal cancers

▰ Lung cancers.

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Mechanisms of Oncogenesis
▰ Altered cytokine expression

▰ B cell stimulation

▰ Associated infections - HPV, EBV, HHV-8 Genetic alteration

▰ Tat protein - early nonstructural protein of HIV, necessary

for virus replication - linked to the pathogenesis of
malignancies.
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Hepatitis C Virus Associated
Malignancy
▰ Hepatitis C is the only oncogenic virus that does not get
integrated with host chromosome but its RNA remains in
the host cell.

▰ Strongly linked to the pathogenesis of liver cancer.

▰ The oncogenic mechanisms of HCV are less well defined

than are those of HBV.
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Hepatitis C Virus Associated
Malignancy (Cont..)

▰ Similar to HBV, chronic liver cell injury and compensatory

regeneration - main mechanism.

▰ Components of the HCV genome - HCV core protein -

activate a number of growth-promoting signal
transduction pathways.

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ONCOGENIC
DNA VIRUSES 35
EBV Associated Malignancies
▰ EBV is associated with several malignancies-

 Burkitt's lymphoma (tumor of jaw, mostly seen in African

children)

 Nasopharyngeal Carcinoma

 Hodgkin’s lymphoma (mixed-cellularity type)

 NHL (Non Hodgkin lymphoma) 36

Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Mechanism of Oncogenesis
of EBV
▰ EBV infects B lymphocytes and pharyngeal epithelial cells
- attaching to the complement receptor CD21.

▰ EBV does not actively replicate inside the B cells - does

not cause lysis of B cells.

▰ Latently infected B cells with EBV - immortalized - ability

to grow indefinitely in cell lines.
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Mechanism of Oncogenesis
of EBV (Cont..)
▰ Persistent EBV infection - induce malignant transformation
of infected B cells and epithelial cells by expressing latent
EBV antigens:

 LMP (latent membrane protein)

 EBNA (EBV nuclear antigen).

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Mechanism of Oncogenesis
of EBV (Cont..)
▰ LMP-1 is the most important viral oncogene:

 Coated on the surface of the infected cells and behaves

as active CD40 receptor, a key recipient of helper T-cell
signals - stimulate B-cell growth

 LMP-1 - activates the NF- κβ and JAK/STAT signalling

pathways and promotes B-cell survival and
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proliferation.
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Mechanism of Oncogenesis
of EBV (Cont..)
▰ LMP-1 is the most important viral oncogene (Cont..):

 LMP-1 prevents apoptosis by activating anti-

apoptotic factor BCL2

 LMP-1 induces the expression of pro-angiogenic

factors - VEGF -contribute to the oncogenesis of
nasopharyngeal carcinoma.
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Mechanism of Oncogenesis
of EBV (Cont..)
▰ Viral EBNA-2 - Activates host cell cyclin-D, and the
proto-oncogene src - promotes cell proliferation

▰ VIL-10 (viral interleukin 10) is a viral cytokine secreted -

modulates the transformation of B cells.

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Role of Host Immune Response
and c-MYC
▰ Effective host immune response is crucial for preventing
transformation.

▰ Oncogenicity is kept under control by anti LMP-1

antibodies.

▰ Markedly enhanced in immunosuppressed individuals

who are not able to produce anti LMP-1 antibodies.
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Role of Host Immune Response
and c-MYC
(Cont..)
▰ B cells in immunocompetent individuals can still undergo
malignant transformation in presence of another pre-
existing mutation t(8;14) that in turn activates the
growth promoting MYC oncogene.

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Human Herpesvirus 8 Associated
Malignancies
Epidemiology:
▰ In high prevalence area: HHV-8 is endemic in Africa,
where it is transmitted by oral secretion
▰ In low prevalence areas such as North America, Asia,
northern Europe, it affects adults and it is transmitted by
sexual route (homosexual men)

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Human Herpesvirus 8 Associated
Malignancies
▰ Disease association: In
immunocompromised individuals
(e.g. HIV-infected people), HHV-8 is
associated with:

 Kaposi’s sarcoma Kaposi’s sarcoma of the

hard palate secondary
 Primary effusion lymphoma to AIDS
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(body cavity-based
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Mechanism of Oncogenesis
of HHV-8
▰ HHV8 - infects the endothelial cells and/or hematopoietic
progenitor cells.

▰ Transformation of malignant cells is directly related to the

expression of early lytic genes of HHV-8 such as viral G
protein-coupled receptor K1,
viral interleukin-6 (vIL-6) and K15
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 Mechanism of
Oncogenesis of HHV-8
▰ These genes induce the host cells to secrete the
angiogenic, inflammatory and proliferative factors such
as, vascular endothelial growth factor (VEGF), platelet
derived growth factor-β, angiopoietin 2, IL-6 and IL-8 that
amount to continuous growth and transformation of cells.

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Human Papillomavirus (HPV)
Infections
▰ Human papillomavirus (HPV) has selective tropism for
epithelium of skin and mucous membranes.

▰ Produces an array of infections ranging from benign

warts, to malignant neoplasia of cervix

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Morphology
▰ Non-enveloped

▰ Measure 50–55 nm in size

▰ Icosahedral capsid

▰ Circular dsDNA.

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Clinical Manifestations
▰ Benign warts

▰ Epidermodysplasia verruciformis

▰ Cervical lesions

▰ Head and neck lesions

▰ Pityriasis versicolor like lesions

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Mechanism of Oncogenesis

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Laboratory Diagnosis
▰ Molecular methods: PCR or the hybrid capture assay -
detect HPV DNA and identify specific virus types -
targeting genes coding for E6 and E7 regions

▰ Most lesions are visible to the naked eye.

▰ Solutions of 5% acetic acid - applied to improve visibility

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Laboratory Diagnosis (Cont..)

▰ Cytologic evidence of HPV infection is detected by:

 Papanicolaou smears prepared from cervical or anal

scrapings

 Histopathological staining of biopsies.

▰ Antibody detection is not much useful

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Treatment of HPV
malignancies
▰ Removal of the lesions: Cryosurgery,
electrodesiccation, surgical excision
and laser therapy

▰ Topical preparations of podophyllum, interferon or

imiquimod (interferon inducer) can be used for genital
warts

▰ Essentials
Recurrence is common.
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Prevention (HPV Vaccine)
▰ Recommended to all adolescent boys and girls at ages
11–12 years.

▰ Subunit vaccine consists of virus-like particles composed

of HPV L1
proteins -produced in yeast by DNA recombinant
technology

▰ Essentials
Both ofnine valent and bivalent vaccines are licensed
Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
55
Prevention (HPV Vaccine)
▰ Nine valent vaccine (Gardasil 9, Merck): Seven
common cancer-causing serotypes (16, 18, 31, 33, 45, 52
and 58) and two non-cancer causing serotypes (6 and 11)

▰ Quadrivalent vaccine: Earlier version, which included

type 6, 11, 16 and 18.
It is still in use

▰ Essentials
Bivalent vaccine (Cervarix, GSK) high-risk serotypes 16
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Hepatitis B Virus Associated
Malignancy
▰ Hepatitis B virus with hepatitis C - responsible for 70%
to 85% of HCC worldwide.

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Mechanism of Oncogenesis

▰ HBV genome does not contain any oncogenes, however;

in the target cells,
it gets integrated with the host genome randomly.

▰ Immunologically mediated chronic inflammation -

most dominant mechanism in the pathogenesis of viral-
induced hepatocellular carcinoma.
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Mechanism of Oncogenesis
(Cont..)

▰ Chronic viral infection, hepatocellular injury occurs -

compensated by proliferation of hepatocytes.

▰ During the regenerative process, a plethora of growth

factors, cytokines, chemokines, and other bioactive
substances - produced by activated immune cells which
promote cell survival, tissue remodelling, and
angiogenesis. 59
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Mechanism of Oncogenesis
(Cont..)

▰ The activated immune cells - produce reactive oxygen

species - genotoxic
and mutagenic.

▰ One key molecular step - activation of the NF-κβ

pathway in hepatocytes -blocks apoptosis, allowing the
dividing hepatocytes to incur genotoxic stress and to
accumulate mutations. 60
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Mechanism of Oncogenesis
(Cont..)

▰ Hepatitis B X gene (HBx) - a regulatory gene in HBV

genome, can activate the transcription of cellular and
viral genes.

▰ Deletion of tumor suppressor genes- Integration of

viral DNA with the host genome can cause secondary
rearrangements of chromosomes - multiple deletions.
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NONVIRAL
ONCOGENIC
ORGANISMS
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Malignancies associated with
bacteria,
parasites and fungi.

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HELICOBACTE
R PYLORI 64
HELICOBACTER PYLORI

▰ Gastric colonization with H. pylori - pathogenesis of peptic

ulcer disease

▰ Serves as the most important risk factor for several

malignancies - gastric adenocarcinoma and gastric MALT
(mucosa-associated lymphoid tissue) lymphoma.

▰ Lifelong H. pylori colonization - protection against

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esophageal adenocarcinoma
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HELICOBACTER PYLORI (Cont..)

Mechanisms:

▰ H. pylori colonization induces genetic polymorphisms in

man - enhanced activation of the innate immune
response—polymorphisms in cytokine genes (IL-1) or
genes encoding bacterial recognition proteins - Toll-like
receptors (TLRs)
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HELICOBACTER PYLORI (Cont..)

▰ Risk factors: Environmental cofactors are important in

pathogenesis of gastric cancer; such as smoking and
diets high in salt and preserved foods. In contrast, diets
high in antioxidants and vitamin C are protective
▰ Treatment for H. pylori - useful for patients with low-
grade gastric MALT lymphoma.

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SCHISTOSOMA
HAEMATOBIU
M 68
SCHISTOSOMA
HAEMATOBIUM
▰ Induces metaplastic changes in urinary mucosa -
carcinoma of bladder.

Predisposing factors include:

 Diet containing nitroso-compounds intake - Egyptian
food
(cheese, fava beans, raw salted fish)
 Secondary bacterial infections, causing cystitis
 Genetic factors: activation of H-ras, inactivation of
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SCHISTOSOMA
HAEMATOBIUM (Cont..)

Type:

▰ Squamous cell carcinoma - most common type

▰ Seen with high to moderate worm burden

▰ Transitional cell carcinoma may occur in areas with

lighter worm load.

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CLONORCHIS
AND
OPISTHORCHIS 71
CLONORCHIS AND
OPISTHORCHIS
▰ Clonorchis sinensis and Opisthorchis viverrini cause
chronic irritation of the bile duct for long periods - bile
duct carcinoma (cholangiocarcinoma).

▰ In addition, Opisthorchis is also associated with

carcinoma of liver

▰ Risk factors for the bile duct carcinoma - elderly people

(60–80 years old)
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CLONORCHIS AND
OPISTHORCHIS (Cont..)
▰ Risk factors for the bile duct carcinoma include elderly
people (60–80 years old) and pre-existing primary
sclerosing cholangitis

▰ Inhibition of tumor suppressor genes (p53) and release

of cytokines –
IL-6 and TNF are the underlying mechanism of
oncogenesis postulated.
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73
Questions:

Q1. All of the following are oncogenic RNA viruses except:

a. Hepatitis B virus
b. Hepatitis C virus
c. HIV
d. Varicella-zoster virus

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Questions:
Q2. Highest risk of squamous cell carcinoma cervix is
associated with which of the following HPV serotypes?
a. Serotypes 6 and 11
b. Serotypes 16 and 18
c. Serotypes 2 and 4
d. Serotypes 27 and 57

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