Viral Oncogenesis
A significant portion of tumors is caused by viruses via a process called viral ongogenesis, where viruses interfere
with normal regulation of proto- and anti-ongogenes or introduce viral oncogenes into the host genome. Both DNA
and RNA virus families contain oncogenic viruses, which act through mechanisms of DNA damage, chronic
inflammatory response “lapsing” into cancer, and immunosuppression.
Proto-oncogenes
- Normal genes that drive cell growth and proliferation
- Common protein products
 Growth factors (e.g. EGF, HCF, PDGF)
 Growth factor receptors, other transmembrane proteins (e.g. receptors for EGF, M-CSF, insulin)
 Membrane-bound GTP proteins (e.g. ras-proteins, p21-proteins)
o Related to G-protein family, which transduce signals from growth factor receptors to IP3
 Nuclear proteins (e.g. c-fos, c-myc, p53)
Immediately upstream from proto-oncogenes are regulatory genes that “turn on” and “turn off” transcription of
proto-oncogenes during normal cell division and differentiation. The regulatory genes that “turn off” protooncogene transcription are considered growth-suppressor genes (“anti-oncogenes”, “tumor suppressor genes”)
Tumor suppressor genes
- Normal cellular genes that encode for proteins involved in down regulation or cessation of transcription and
translation of proto-oncogenes
 p53
o Acts in late G1 phase of cell cycle to prevent cell from entering S phase
o Causes apoptosis if there is DNA damage
 Rb
o Prevents cell cycle to enter S phase by sequestering E2F protein (required to activate S phase
proteins, including tyrosin kinase, DNA polymerase)
Oncogenes (cellular)
- Mutated forms of proto-oncogenes
- No longer controlled by cell’s normal regulatory genes and, therefore, stimulate unregulated cell proliferation
- Two classes
 Growth factors – regulatory genes involved in the control of cell multiplication
 Protein kinases – activate target proteins via phosphorylation, important in signal transduction
Oncogenes (viral)
- Variant forms of proto-oncogenes acquired by viruses from host cells during viral evolution
- Insertion of viral oncogenes into host genes causes unregulated cell growth and disruption of proto-ongogenes,
a process called insertional mutagenesis
Oncoproteins
- Protein products of cellular ongogenes
- Viral oncogene products with homology to cellular proto-oncogene products
- Viral constitutive gene products with no homology to cellular proto-oncogene products
How does a proto-oncogene become an oncogene?
Changes in overall structure and function must occur
- Mutation of proto-oncogene that results in over production of protein
 Gene amplification (50-100 copies)
 Chromosomal rearrangement that changes the regulatory sequence
- Mutation of proto-oncogene that results in production of a defective, hyperactive protein
 Mutation is often a point-mutation or translocation
Of the ~17 distinct families of viruses, 7 consist of DNA-containing viruses and 11 consist of RNA-containing
viruses. Of these, there are 5 DNA-containing and 1 RNA-containing families that contain viruses capable of
producing neoplasms (either naturally or under experimental conditions, or both). It’s important to note that not
every virus within these families act as oncogenic agents.
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Families of oncogenic DNA-viruses
 Poxviridae
 Herpetoviridae
 Adenoviridae
 Hepadnaviridae
 Papovaviridae
Family of oncogenic RNA-viruses
 Retroviridae
Common features of oncogenic DNA viruses
- Genomes insert into host genome and become stable
- Utilize cellular enzymes to replicate
- Can establish lifelong latency (e.g. herpesviruses) because they interrupt genes needed for replication and are
then unable to complete replicative cycles
- Induce cancer by various mechanisms
 Blocking DNA repair
 Blocking tumor suppressor genes products
 Activating cellular proliferation genes
- Viral gene products stimulate cells to proliferate unrestrained
- Oncogenic genes are divided into two categories
 Those that code for “transforming” proteins
 Those that down-regulate tumor suppressor genes and DNA repair genes
How do oncogenic viruses cause neoplasms?
- Interfere with normal regulation and expression of cellular proto-oncogenes and/or tumor suppressor genes
- Introduce virally-encoded homologue genes, which become continuously expressed in an unregulated manner
Poxvirus
- Very complex viruses consisting of a single, large molecule of double-stranded DNA
- Transmission is typically via insect vectors or direct contact
- Viral replication occurs in the cytoplasm, resulting in the formation of unique viral particles
 Eosinophilic intracytoplasmic inclusion bodies
- Typical infection produces cutaneous or mucosal lesions characterized by extensive epithelial cell
hypertrophy, hyperplasia, and necrosis
- Variably oncogenic – lesions may be extremely proliferative and tumor-like but not true neoplasms
 Produce benign neoplasms of epithelial and mesenchymal tissues
- Tumors generally undergo spontaneous regression weeks or months after their induction
- Some poxviruses produce protein products with extensive homology to two normal proto-oncogene products
 EGF (Epidermal Growth Factor)
 TGF-β (Transforming Growth Factor β)
The continuous expression of EGF in infected cells probably accounts for the proliferation of epidermal cells that
characterizes the tumor-like lesions associated with poxvirus infection
Epidermal proliferative lesion
Epidermal proliferative lesion
Examples of oncogenic poxviruses
- Myxomatosis Virus of rabbits
 Sometimes regarded as a malignant neoplasm because it becomes disseminated
Myxoid material interspersed b/w hair follicles,
intracytoplasmic eosinophilic inclusion bodies within
follicular epithelial cells
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Shope Rabbit Fibroma Virus
Microscopic section collected
from a Shope fibroma on the
foreleg of a cottontail rabbit.
Note the eosinophilc
intracytoplasmic inclusion
bodies of the epidermis.
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Molluscum Contagiosum Viruses
(humans, chimpanzees, horses, dogs, kangaroos)
 Rare, proliferative disease of horses
 Papular dermatitis
 Intracytoplasmic molluscum bodies
 Lesions may remain for months to years
 Some lesions may regress
 No treatment
Hare Fibroma Virus
Squirrel Fibroma Virus
Genital Papillomas of Swine
Yaba Virus of Monkeys
Polyomavirus
- Genome is a single, circular molecule of double-stranded DNA
- Multiplication occurs in the nucleus and the viral genome is integrated into the host cell genome
- Not all species are oncogenic
- Early genes encode regulatory proteins called T (tumor) antigens, which bind to and inactivate tumor
suppressor proteins (p53, pRb)
 Large T antigen – binds to p53 protein and up-regulates DNA synthesis
 Middle T antigen – binds with Rb protein
- Late genes encode structural capsid proteins
- Contains three primary groups of viruses
 Papilloma viruses
 Polyoma viruses
 Vacuolating agent (simian virus-40)
o Not oncogenic in normal host (macaques), but causes encephalitis, nephritis, and pneumonia
o Oncogenic in non-host species (e.g. hamster)
Papillomavirus
- Generally speaking, papillomaviruses are extremely species-specific
- Transmitted by direct contact, which is facilitated by cutaneous abrasions
- Not all papillomas are caused by viral infection
- Lesions are usually benign and regress spontaneously, but can undergo malignant transformation
- Benign and pre-neoplastic tumors occur when papillomavirus is episomal (non-integrated into host genome)
- Malignant tumors occur following integration of viral genome into host
- Target basal layer of epithelial cells
 Papillomas are benign epithelial proliferations
 Fibropapillomas are benign dermal/epithelial proliferations
- Encode for numerous proteins during productive infection
 E1 – DNA binding protein required for initiation and elongation of viral DNA synthesis
 E2 – DNA binding protein that regulates viral gene expression through early promotors
 E6, E7 – regulate cell proliferation; activate cellular DNA synthesis required for viral replication
 L1, L2 – late proteins that form the viral capsid
Examples of oncogenic papillomaviruses
- Shope Rabbit Papillomavirus
- Canine Papillomaviruses
- Feline Papillomavirus
- Equine Papillomaviruses
- Goat and Sheep Papillomaviruses
- Simian Papillomaviruses
- Deer Fibroma Virus
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Bovine Papillomaviruses (BPV-3,6 – cutaneous, BPV-1,2, 5 – fibropapillomas, BPV-4 – esophageal, bladder)
 Often occur in the teat and interdigital space
 Cutaneous lesions in young cattle (<2 yrs) typically regress spontaneously
 The transforming protein E5 binds to and activates the PDGF receptor
 Down-regulation of MHC-I expression
 Causes equine sarcoids (persistant, sarcoma-like fibroproliferative cutaneous lesions)
 BPV-1 causes feline cutaneous fibropapillomas
Human Papillomaviruses
 Early viral transcription causes synthesis of replication-associated proteins = basal cell hyperplasia
 Late viral transcription = synthesis of structural proteins = viral release, formation of virions, cytolysis
 E6 and E7 are the main transforming proteins
o E6 – binds to and inactivates the action of p53 protein on G1 arrest and apoptosis
o E7 – binds to Rb protein, preventing Rb-binding and sequestration of E2-F transcription
factors, leading to disruption of cell cycle control
Adenovirus
- Only oncogenic in experimental conditions, when inoculated into foreign hosts (mostly hamsters, mice, rats)
- Viral DNA becomes integrated into host DNA
- Replication divided into early and late stages
 Early genes (E1A and E1B) code for proteins that interfere with p53, resulting in cell cycle
progression, uncontrolled proto-oncogene expression, and neoplastic transformation of infected cells
Herpesvirus
- Consist of a linear, double-stranded DNA surrounded by a capsid (lipid envelope)
- Viral replication takes place in the host cell nucleus (capsid is acquired during transition from nucleus to ER)
- Lifelong infection with latency
- Oncogenesis frequently requires immunosuppression (as in HIV, FIV)
 But also may require chronic immune stimulation
- Some viruses are only oncogenic when outside of normal host
Exampels of oncogenic herpesviruses
- 7 animal viruses
 Lucké tumor herpesvirus (LTV)
o Induces renal neoplasms in Northern leopard frogs
 Herpesvirus saimiri (T-cell lymphoma)
o Latent herpesvirus isolated from squirrel monkeys (Saimiri sciureus)
o Can cause lymphoma and leukemia when inoculated into animal recipients
 Lymphomas are of T cell origin
o Encodes two proteins important in cellular transformation, which stimulate signal transduction
and transcription factors and inhibit apoptosis
 stpC – inactivates GTPase activity of cellular ras-protein (remains in “on” position)
 tip
 Avian Herpesvirus-2 (Marek’s disease of chickens)
 Ovine herpesvirus-2 (Malignant catarrhal fever)
 Herpesvirus ateles
 Herpesvirus sylvilagus
 Rhesus lymphocryptovirus (B-cell)
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2 human viruses
 Kaposi-sarcoma virus (HHV-8)
o Produces cutaneous, highly vascular lesions in immunosuppressed individuals
 Epstein-Barr Virus (HHV4)
o Most thoroughly studied oncogenic herpesvirus
o Cause of the benign syndrome, infectious mononucleosis
o Also causes various types of neoplasms
 Burkitt’s lymphoma
 B-cell lymphoma (in immunosuppressed individuals)
 Hodgkin’s lymphoma (some cases)
 Nasopharyngeal carcinoma
o Numerous oncoproteins are essential for B lymphocyte immortalization
 EBNA1 – DNA binding protein that causes transcriptional activation
 EBNA2 – DNA binding protein that causes transcriptional activation and up-regulation
of viral and cellular genes
 EBNA3A and EBNA3C – interact with cellular activator CBF1
 EBNA-LP – phosphoprotein involved in transcriptional regulation of EBNA2 protein
 LMP1 – promotes cellular survival, activates NFkB and NFkB regulatory genes, antiapoptotic action, up-regulation of BCL-2
 LMP-2 – important for establishing latency, reduces or delays viral replication
Hepadnavirus
- Double-stranded DNA viruses
- Infects humans and chimpanzees, though woodchucks and ducks are important animal models
- Viral DNA becomes integrated into host DNA in multiple copies
- Viral replicative cycle is quite complicated
- Virus does not encode for oncogenes or transforming proteins
- Commonly associated with hepatocellular carcinoma
- Most studied virus is Human Hepatitis B Virus