16. Viruses and Cancer 1 Flashcards
1. Describe different human tumour viruses 2. Know how viruses are shown to be associated with cancer 3. understand how viruses cause cancer 4. Describe cancer treatments targeting viruses
What factors can impact the cell and lead to cancer?
- UV
- Radiation
- spontaneous mutations
- other carcinogens
What happens to most cells with mutations?
- They are repaired
- The cell is sent into apoptosis
Viruses and cancer
- Viruses are infectious agents that can lead to cancer.
- Tumour viruses can alter the cells and they then accumulate secondary genetic changes that can then become cancer.
- BUT this does lead to a potential route that we can vaccinate against these cancers.
Cancer and Oncogenic viruses
- Cancer can be an infectious disease and you can catch it from someone else.
- 20% of all cancers are virus-associated with their first mutation being due to a virus.
- Can be DNA or RNA genomes.
- If a virus is going to cause cancer it needs to be a chronic infection and be in the body for a long time to cause mutations.
- They are widespread viruses but only cause cancer in the minority of cases.
- Immunity suggest vaccination of possibilities
What proportion of liver cancer is caused by Hepatitis B and C?
75%
What cancers do viruses causes?
Cancers of the tissues that they infect and replicate in.
What are the 7 oncogenic viruses?
Direct cancer induction:
1. Epstein-Barr virus
2. HPV
3. Human T-cell leukaemia virus
4. Kaposi sarcoma herpesvirus
5. Merkel cell polyomavirus
Cancer induction through chronic inflammation:
6. Hepatitis B
7. Hepatitis C
What virus causes liver cancer?
Hepatitis B and C
What virus causes cervial cancer?
HPV
What virus causes lymphoma and nasopharynx carcinoma?
Epstein-Barr virus
What virus causes adult T-cell lymphoma?
Human T-cell lymphotropic virus type 1
What virus causes Merkel cell carcinoma?
Merkel cell polyomavirus
What virus causes Kaposi sarcoma of the skin, mouth or gut?
Kaposi sarcoma virus
How does hepatitis B and C cause cancer?
- They cause chronic inflammation that causes cell damage and cancer
- They have some genes that contribute to the carcinogenesis
What 4 things are need to prove the association of virus with the cancer?
- Epidemiological links using population studies and observing cancer in virus patients.
- The virus and its products are found in the tumour cells.
- The virus induces tumours in animal models and then infer it also causes cancer in humans.
- Vaccination with viral production can prevent the tumour by reducing infection.
How were animal viruses used in oncogene discovery?
- Many oncogenes come from viruses and are inserted into the genome.
- Normally retroviruses have only 3 genes for replication but they can have an extra gene.
- These regions are inserted and being expressed and cause cancer.
What is src?
- An oncogene
- named for Rous sarcoma
- discovered in chickens and then found in humans
- It is a dominant mutation
- A tyrosine kinase that activates signalling.
What oncogene did Rous Sarcoma virus insert?
Src
What oncogene did Myelocytomatosis insert?
Myc
What oncogene did Avian erythroblastosis insert?
ErbB - the EGF receptor
What is the main way oncoviruses trigger cancer?
Through loss of growth regulation
What can viral loss of growth regulation cause?
- Changes in cell shape.
- Increased growth rate leading to increased mutation rate.
- Reduce dependence on attachment signals.
- Production of growth factors so they can self perpetuate.
What does the Ras oncogene do?
Lots of growth and cause the cell to pile on top of each other and lose contact inhibition
What oncogene did Harvey and Kirsten rat sarcoma virus insert?
Ras - H-Ras and K-Ras
What oncogene did Simian Sarcoma virus insert?
Sis
How can Anchorage-independent growth aid cancer cells?
- The cells don’t need a solid surface or integral attachment to be able to survive
- They have independent growth and can proliferate with ECM adhesions
What hallmarks of cancer do oncoviruses influence?
- Resisting cell death.
- Sustain proliferative signalling.
- Evading growth suppressors .
How does Epstein-Barr virus cause sustained proliferative signalling?
- Its latent membrane protein 1 (LMP1) mimics CD40 to stimulate B cell proliferation.
- When CD40L binds CD40 it binds the tyrosine kinase JAK3 which recruits proteins.
- These trigger 3 signalling pathways and production of 3 signalling factors: STAT, JNK and NF-kB.
- The LMP1 cytoplasmic tail is very similar to CD40 so it leads to the activation of the same proliferative signalling pathways without external binding.
What is JNK?
Jun N-terminal kinase
How does Epstein-Barr virus mimic BCR signalling?
- Its latent membrane protein 2a (LMP2a) can mimic the BCR due to the similar cytoplasmic tail.
- Normally a BCR is activated and triggers proliferation to respond to infection.
- Tyrosine kinases Lyn, Btk, Syk phosphorylate proteins which leads to survival signals and proliferation.
- LMP2a causes the same signalling without the antigen binding so absence of infection.
How does HPV cause sustained proliferative signalling?
- Normally growth factors bind Platelet-derived growth factor receptor and epidermal growth receptor.
- This causes dimerisation and phosphorylation that triggers proliferative signalling.
- HPV E5 protein is a transmembrane protein that causes the dimerisation instead of the growth factor.
- E5 acts from within the plasma membrane causing dimerisation, cell signalling and growth.
What oncoviral proteins interact with growth suppressors?
- HTLV1’s Tax binds p53 and Rb
- HPV’s E6 binds p53 and E7 binds Rb
- KSHV’s LANA binds p53 and v-CYC and LANA binds Rb
What are growth suppressors?
molecules that prevent the cell dividing
How does HPV E7 prevent Rb’s function?
- E7 binds RB
- It pulls Rb off E2F
- This means the cell cycle can continue independent of cyclin function
- similar action to the phosphorylation of Rb by cyclin D
How does HPV E6 suppress p53?
- p53 is a transcription factor produced to inhibit cell growth.
- E6 binds p53 and prevents it from activating genes even when there is DNA damage.
- It can also mark p53 for degradation.
How does HPV resist cell death?
- If E6 binds p53 it cannot produce the death inducers it normally does.
- this prevents the accumulation of death inducers.
- The cell survives and proliferates even when there is DNA damage
How does EBV LMP1 resist cell death?
- It can induce proliferation and promote survival even when death inducers are present.
- NF-kB and JNK blocks the transcription of apoptotic factors
- promotes cell survival
