11 - Viral Carcinogenesis Flashcards

1
Q

What causes cancer

A
  • Viruses / bacteria
  • Some chemicals
  • Radiation
  • Influenced by heredity, diet and hormones
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2
Q

How do viruses cause cancer

A

Virus inserts and changes genes for cell growth

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3
Q

Virus replication cycle

A
  • Virus attached to cell
  • Virus penetrates cells membrane and injects nucleic acid into cell
  • Viral nucleic acid replicates using host cellular machinery
  • New viral nucleic acids are packaged into viral particles and released from cell
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4
Q

Viruses

A
  • Non-living
  • Cannot reproduce or produce protein without a host cell
  • Do not undergo cell division
  • Lab growth is only possible in animals, embryonated chicken eggs, or cell/tissue cultures systems
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5
Q

What does a complete virus particle (virion) typically consist of

A
  • Genome and capsid (make up nucleocapsid)
  • Membrane and ligands (makes up envelope)
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6
Q

Capsid

A

Composed of capsomeres

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7
Q

Membrane

A

Host cell derived

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8
Q

Ligands

A

Glycoprotein complex

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9
Q

Features of virus

A
  • Small size (10-300 nm)
  • DNA or RNA genome (ds or ss)
  • Helical, polyhedral or complex shape
  • Envelope or no envelope
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10
Q

Helical Viruses

A

Nucleic acid core is surrounded by hollow cylinder of protein (capsid) that is wrapped around it for form helical

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11
Q

Polyhedral Viruses

A

The nucleic acid core is
surrounded by a polyhedral (usually icosahedral) capsid

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12
Q

Binal / Complex Viruses

A

Capsid is irregularly shaped or complex in structure

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13
Q

Oncovirus

A
  • Virus that can cause cancer
  • Currently 7
  • ~12% of human cancers are caused by infections
  • Second most important risk factor for cancer development after tobacco
  • FIrst human oncovirus identified was EBV
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14
Q

Examples of oncoviruses

A
  • HBV
  • HCV
  • HPV
  • EBV
  • Herpes virus 8 (Karposi’s sarcoma)
  • HIV-1
  • HTLV-1
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15
Q

Where do DNA tumour viruses replicate

A

Nucleus

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16
Q

Where do RNA tumour viruses replicate

A

Cytoplasm

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17
Q

Main difference between normal viruses and oncoviruses

A
  • Normal virus cycle is lytic
  • Oncovirus cycle is latent
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18
Q

Lytic cycle

A

Once virus has invaded the cell, they replicate their genome and package into protein, then lyse the cells to release progeny to continue their infectious life cycle

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19
Q

Steps of latent life cycle

A

Virus infects cell –> Viral genome integration into host genome –> transformation

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20
Q

Latent life cycle

A
  • Some virus-specific proteins expressed (early functions) but no mature virus formed
  • Viral structural proteins are not expressed
  • Sometimes latency may terminate (cells must be infected by complete viurs
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21
Q

Transformation

A
  • Ability to form tumours
  • Viral genes interfere with control of cell replication and other aspects of cell phenotype
  • Both DNA and RNA tumor viruses can transform cells
  • Similar mechanisms of transformation by each type of tumor virus
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22
Q

Other aspects of cell phenotype viral genes interfere with

A
  • Loss of growth control
  • Reduced adhesion
  • Motility
  • Invasion
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23
Q

Life cycle of viruses with dsDNA genomes

A
  • Introduction of nucleocapsid into cell
  • Uncoating of viral DNA
  • Translocation into nucleus
  • Replication by cellular DNA polymerases OR transcription by cellular RNA polymerase 2
  • Encapsidation of progeny DNA in viral proteins OR translation by cellular ribosomes
24
Q

Proto-oncogenes

A
  • Positive growth regulators present in normal, healthy cells
  • 803 human proto-oncogenes have been identified
25
Oncogenes
- Gene that has the potential to transform a normal cell into a malignant cell - Has been altered or mutated from its original form (the proto-oncogene) - Oncogene transmitted by virus is known as viral oncogene
26
Examples of oncogenes
- MYC - RAS - HER2 - EGFR - Bcr-Abl
27
Oncogene activation
- Activation of endogenous retroviral (ERV) genomes - Proto-oncogenes can be activated by genetic changes affecting either protein expression or structure (e.g. gene amplification, viral insertion, chromosomal translocations) - ERVs also activated by environmental mutagens
28
How much of the human genome derives from endogenous retroviral genomes
8%
29
Tumour suppressor genes
- Controllers of cellular proliferation - Responsible for maintaining a healthy cell - Regulate cell cycle, apoptosis and genomic stability - Negative growth regulator (proto-oncogene is positive growth regulator)
30
Examples of tumour suppressor genes
- p53 - Retinoblastoma protein
31
p53
- In a normal cell p53 is inactivated by its negative regulator, mdm2. - Upon DNA damage or other stresses, p53 will induce cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell
32
Which virus caused 10% of human cancer
HPV (cervical, vulval, uterine)
33
HPV
- 150+ HPV serotypes known to infect humans (skin and mucosa) - Transmitted by sexual or close contact - Infect skin epithelial cells and mucous membranes - Non-enveloped, icosahedral circular dsDNA viruses
34
HPV 6 & 11
Warts (benign)
35
HPV 16 & 18
Cancer
36
E5, E6, E7
- Oncoproteins - E6 and E7 genes code for proteins that inactivate p53 and Rb) - E5 onco-protein interacts with EGF-R1 signaling pathways and pro-apoptotic proteins to affect cellular transformation
37
L1 gene
- Codes for a protein that self assembles into capsid of virus - Empty L1 capsid form VLPs which are used in vaccines
38
LCR
- Long control region - Early E non structural genes and late structural capsid genes
39
EGF-R1 signalling pathways
MAP kinase and PI3K/Akt
40
HPV genome
- 8 kb, encoding 9 genes - E1, E2, E4, E5, E6, E7, L1, L2, LCR
41
L2
- Minor capsid component and lacks the capacity to form VLPs - Co-assembles with L1 into VLPs, enhancing their assembly.
42
HPV life cycle
- Infects the keratinocytes in basal layers of a stratified squamous epithelium - Tightly regulated by keratinocyte differentiation
43
Disease progression of HPV
- Persistent infection can cause irreversible changes leading to invasive cancer - Other co factors important in progression (e.g. smoking, age at first intercourse, genetics, contraception use)
44
L/GSIL
Low/High grade squamous intraepthielial lesion
45
CIN
Cervical intra-epithelial neoplasia
46
Main way of preventing cervical cancer
Regular screening (instead of pap test)
47
Examples of HPV Vaccines
- Cervirax (bivalent) - Gardasil (quad-valent) - Both protec against HPV 16, 18)
48
What does gardasil 9 protect against
- Serotypes 16 and 18 (two types that cause the majority of HPV-related cancers) - The five next most common HPV types associated with cervical cancer (serotypes 31, 33, 45, 52 and 58) - Two non-cancer-causing HPV types (serotypes 6 and 11), which cause 90% of genital warts.
49
Epstein Barr Virus (EBV)
- Virus of herpes family (herpesvirus 4) - One of the most common viruses in humans (glandular fever / mononucleosis) - Infects B cells and epithelial cells - Infection occurs by oral transfer of saliva - Complex virus
50
Diseases associated with EBV
- Burkitt's lymphoma - Hodgkin's lymphoma - Nasopharyngeal carcinoma - B cell lymphoma - Duncans syndrome
51
How is EBV diagnosed
EBER in situ hybridisation in formalin fixed tissue section
52
Burkitt's lymphoma
- EBV induces chromosomal translocation of chromosome 8 and 14 - Break in chromosome 14 at q32
53
Theory 1 of malarial infection and EBV
- BL correlates roughly with malaria infection in Africa - Malaria infection induces B-cell activation, predisposing B cells to acquisition of IG/MYC translocations.
54
Theory 2 of malarial infection and EBV
- Malaria infection reactivates latent (endemic) EBV infection in memory B cells. - Inducing proliferation of B cells and increase probability of IG/MYC translocations - EBV inhibits the apoptosis of premalignant tumor cells, allowing transforming events to occur
55
TCF-3
Rendered constitutively active in Burkitt lymphoma by two related mechanisms
56
Two related mechanism of TCF-3
1. Somatic mutations that inactivate its negative regulator ID3, 2. Somatic mutations in TCF-3 that block the ability of ID3 to bind and interfere with its activity as a transcription factor.
57