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Cancer > Lecture 6 - Infectious Agents and Cancer > Flashcards

Lecture 6 - Infectious Agents and Cancer Flashcards

1
Q

Early work on viruses

A

1908 - Ellerman and Bang identify infectious leukaemia in chickens

1911 - Francis Peyton Rous shows a virus could induce sarcomas in chickens (Rous sarcoma virus - RSV)

1933 - Rabbit papillomavirus identified

1936 - mouse mammary tumour virus discovered (MMTV)

1950s - mouse leukaemia and polyoma viruses identified

1962 - adenovirus and SV40 shown to incude tumour in rodents

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2
Q

The Rous Experiment

A
  1. Chicken with sarcoma in breast muscle
  2. Sarcoma removed and broken up into small chunks of tissue
  3. Grind up sarcoma with sand
  4. Collected filtrate that has passed through fine-pour filter
  5. Injected filtrate into young chicken
  6. Observe sarcoma in injected chicken
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3
Q

Rous Sarcoma virus characteristics

A

Retrovirus

env encodes surface glycoprotein

gag encodes the coat proteins

pol encodes reverse transcriptase that plays role in lifecycle

Lipid bilayer acquired from infected cell

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4
Q

Retrovirus lifecycle

A
  1. Entry into cell and shedding of envelope
  2. Reverse transcriptase makes DNA/RNA and then DNA/DNA double helix
  3. Integration of DNA copy into host chromosome
  4. Assembly of new viral particles, each containing reverse transcriptase in protein coats
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5
Q

Abberant growth caused by RSV infection

A

Work carried out in the Dulbecco lab in the early 1950s by Howard Temin. Chicken fibroblasts grown in a dish. When the virus was introduced, the cell survived but also grew clusters (foci) of cells. This is something we’ve seen in a previous lecture!

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6
Q

Cancerous phenotype requires presence of active viral proteins

A

Normal morphology at 37 degrees

Normal cells infected with ts RSV mutant at 37 degrees to cause transformed morphology

Temperature increased to 41 degrees - Phenotype lost

Temperature decreased back to 37 degrees - Transformed morphology returns

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7
Q

src oncogene

A

ALV: 5’–gag-pol-env–AAAAAA….3’

RSV: 5’–gag-pol-env-src–AAAAAA….3’

src avian in origin and derived from host genome

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8
Q

What does c-Src do?

A
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9
Q

ALV can itself induce cancer via insertional mutagenesis

A

Avian leukosis virus (ALV)

Slowly transforming retrovirus

Provirus inserts randomly into host gene

Very occasionally (1 in 10 million) inserts upstream of c-myc

Induction of cancer is a rare event (cf RSV)

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10
Q

Examples of human cancer viruses

A

Epstein-Barr - dsDNA hepresvirus - Burkitt’s lymphoma and nasopharyngeal carcinoma. Some Hodgkin’s and non-Hodgkin’s lymphoma - 1964

Hepatitis B virus (HBV) - ssDNA and dsDNA hepadenovirus - Hepatocellular carcinoma - 1965

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11
Q

Immunosuppression increases risk

A
  • Kaposi’s sarcoma is a low grade first identified in the late 1800s, but very rare until the 1980s
  • Cluster of cases in gay men in New Yorj was reported in 1981 - associated with HIV/AIDS
  • Causative agent (KSHV) not identified until 1994
  • KS 800x more likely in people with HIV/AIDS
  • Similar effects seen for other immunocompromised individuals and for other infections
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12
Q

HPV and cervical cancer

A

Cervical cancer – 4th most common cancer in women worldwide: 660,000 new cases and 350,000 deaths in 2022 (source GLOBOCAN)

94% of deaths are in low and middle income countries (source WHO

9th most common cancer in women from UK

2nd most common cancer in women aged 15-44

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13
Q

How does HPV cause cervical cancer

A

HPV - dsDNA

Many subtypes, most innocuous

Show tissue tropism

HPV causes >95% of cervical cancer

14 HPV subtypes linked to cervical cancer

‘High risk’ HPVs 16 and 18 cause >2/3 of cervical cancer

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14
Q

High risk E7 binds RB and targets it for degradation

A

RB binds E2F -> no transcription of E2F target genes -> no proliferation

RB binds E7 -> Degraded in proteasome:
E2F target genes are transcribed -> Cell cycle entry proliferation

It also binds to RB-related proteins (p105, p107, p130), inhibiting their function too

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15
Q

High risk E6 targets p53 for degradation

A

E6 - derepresses expression of hTERT (a component of telomerase)

E6 stimulates VEGF expression (angiogenic factor)

E6 and E7 stimulate genomic instability

E6 binds E6AP and p53 -> Ubiquitylation of p53 -> Degradation by proteosome

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16
Q

Other infections linked to cancer

A

Southeast Asian liver fluke (Opisthorchis viverrini) and liver cancer

Bilharzia (Schistosoma hematobium) and bladder cancer

Helicobacter pylori and stomach cancer

Cancer (11 decks)

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