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Flashcards in Viral Oncogenesis Deck (30):
1

Common traits of human viral oncogenesis

  • Oncoviruses are necessary but not sufficient for cancer development - most people who are infected do not develop cancer from the virus
  • Viral cancers appear in the context of persistent infections and occur many years to decades after acute infection
  • The immune system can play a deleterious or a protective role in virally induced oncogenesis

2

How do viruses cause cancer INDIRECTLY

Chronic inefction causes cirrhosis, inflammation, tissue damage, high levels of cell division. This cycle vastly increases the probability that hepatocytes will develop mutations and chromosomal aberrations that derail their growth control

3

How do viruses cause cancer DIRECTLY

Upon infection, some DNA viruses stimulate the cells to enter S phase of the cell cycle and ready themselves for DNA synthesis. The virus needs this environment for its own replication. If the infected cell is not killed, the same viral proteins can continue to direct the cell to override normal controls on cell growth 

4

Viruses most clearly associated with human cancer

Hepatitis B: hepatocellular carcinoma

Hepatitis C: hepatocellular carcinoma

EBV: lymphoma; nasopharyngeal carcinoma

HHV8: Kaposi's sarcoma KSHV

HTLV: adult T cell leukemia

HPV: cervical cancer; head and neck cancer

5

Merkel Cell Carcinoma

Aggrressive skin cancer in elderly and immunosuppressed patients

6

Papillomavirus characteristics

  • Member of the papovavirus family
  • Infect cutaneous and mucosal epithelia hands, feet, anogenital tract
  • Small circular, double stranded DNA genome
  • Many subtypes (about 100)
  • 1/3 subtypes infect genital tract (sexually transmitted)

7

Early and Late genes encoded by virus

  • E1 and E2 mediate the replication and transcription of the viral DNA
  • E4 disrupts cytokeratins to facilitate virus egress
  • L1 and L2 compose the capsid
  • E5 stimulates constitutive growth factor receptor signaling
  • E6 and E7 neutralize the major "brakes" that regulate the cell cycle - p53 and Rb - and hence uncouples cell division from key regulatory controls

8

Which viral encoded genes are associated with oncogenesis

E5, E6, E7

9

Course of Papillomavirus infections

Papillomavirus ⇒ Inoculation of epithelium ⇒ Hand, foot, throat, or cervix ⇒ Local multiplication ⇒ Wart ⇒ Resolution (latency)/Cell transformation

10

How does HPV affect the epithelium

HPV stimulation of cell cycle causes cells in the stratum spinosum to replicate. Normally, only the stratum basale cells replicate

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11

What are CDKs and how are they regulated

Cyclin dependent kinases move the cell cycle ahead by phosphorylating key substrates

Regulated in many ways:

  • Temporally regulated synthesis
  • Proteasome-mediated degredation of their cyclin subunits
  • Stimulatory and inhibitory phosphorylation events
  • Stoichiometric inhibitors

12

Rb protein

A key "brake" that blocks progression into the S phase

When sufficient Cdk/cyclin has accumulated in G1, Rb becomes phosphoryalted and inactivated and the cell can move into S phase

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13

How is E7 a key regulator of cell cycle progression

The E7 protein binds to Rb, targets it for proteosomal degradation, and so prevents it from blocking the progression to S phase

14

How is E6 a key regulator of cell "accuracy'' and why is it important in cellular immortality

  • E6 protein recruits a ubiquitin ligase that targets p53 for degradation and therefore prevents it from blocking the progression to S phase or inducing apoptosis
    • E6 protein induces the expression of telomerase, which enables cells to maintain their chromosomal telomeres and avoid senescence

15

What does p53 do?

"guardian of the genome"

Activated by innapropriate entry into cell cycle

Induces the production of Cdk/cyclin inhibitors, and stops the cell cycle - major inducer of apoptosis

16

What data support the hypothesis that HPV causes cervical cancer

  • Sexually active populations have a higher risk of cervical cancer; sexually inactive populations have an extremely low risk
  • Greater than 99% of all cervical cancer specimens show evidence of infection with "high risk" strains of HPV strains
  • In vitro analysis show a correlation between "high risk" strains and the activity of the E6 and E7 proteins in  in-vitro assays of cellular transformation

17

p53 and Rb are called ______ ______ ______

tumor suppressor genes

18

During earlier stages of acute and persistent infection, the viral DNA is maintained as an ________

episome

19

What is the significance of integration?

  • Development of carcinoma is associated with integration of DNA into the host chromosome
  • Integration disrupts the expression of the E2 gene which is a transcriptional repressor, and allows increased levels of E6 and E7 expression

20

___ and ___ are always retained in cancer cells

E6, E7

21

Where does the virus enter the epithelium?

Basal layer

22

LSIL:

HSIL:

CIN:

LSIL: Low grade squamous intraepithelial lesion

HSIL: High grade

CIN: Cervical intraepithelial neoplasia

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23

Tests to diagnose those patients whose HPV lesions are likely to progress to cervical cancer?

Pap test

HPV DNA

E6/E7 mRNA

L1 protein

p16INK4A protein

 

24

Pap smear for CIN I, CIN II, and Cervical carcinoma

Cytological evidense of displasia or neoplasia; detection of koilocytotic cells which are rounded and appear in clumps

25

Hybrid Capture Assay for detection, Strain analysis, and quantification of HPV DNA

  1. Release Nucleic Acids - base solution releases target DNA
  2. Hybridise RNA probe with target DNA
  3. Capture Hybrids - universal capture antibodies specific for RNA:DNA hybrids
  4. Label for detection - conjugated with alkaline phosphatase
  5. Detect, Read and Interpret results - chemiluminescent dioxetane substrate

26

What are the issues associated with the development of a vaccine that prevents genital infection with HPV?

  • Need for mucosal infection due to route of infection
  • Need to recognize multiple high risk strains
  • Administration of a vaccine that included oncogenes not possible
  • Societal issues - is this a vaccine to prevent cancer or STD?

27

Capsid Protein L1

Induces protective humoral immunity

Can be produced in culture

Self-assembles into virus-like particles (VLPs) that resemble virions and induce appropriate immunological response

28

Vaccine containing purified VLPs: what does it do?

Induces protective humoral immunity

Antibodies present at mucosal surface prevent incoming HPV from establishing infection

29

Currently Licensed Vaccines

Gardasil

Cervarix

 

30

True Or False? THe HPV vaccine should only be used in women

FALSE!

Vaccination of boys/men will benecessary to also protect men and deplete the high risk HPV strains from the population