Cancer Bio (Michaelis Lecture 1 - Viruses and cancer)

Question 1

What are the main 2 causes of cancer? What % of cancers do they cause?

Answer 1

1) Germline mutations (5-10%)

2) Enviromnental factors/somatic mutations (90-95%)

Question 2

What are the 3 main cancer risk factors and their associated percentages?

Answer 2

1) Diet (35%) (obesity (20%))
2) Smoking (30%)

3) Chronic infections (15-20%)
Viruses 70% of that

Question 3

What 3 types of infectious agents can cause cancer and give examples of each

Answer 3

1) Bacteria
- Helicobacter pylori (>60% of gastric cancers)

2) Parasites
- Trematoda

3) Viruses
- largest group of cancer associated pathogens
- over 1.3 million cases worldwide
- HPV, cervical cancer

Question 4

What technique has been utilised in history to show that viruses induce cancer?

Answer 4

• Use of CELL-FREE EXTRACTS
• e.g 1907 Ciuffo: transfer of warts between humans by cell-free extracts
• 1908 Ellerman and Bang: Induction of leukemia in healthy chickens by transfer of cell free extracts from leukemia chicken

Question 5

What are some characteristics of virus-induced cancer

Answer 5

1) Only small amount of infected individuals may develop cancer
2) Virus alone may be insufficient to induce cancer
3) Long periods of latency between infection and cancer formation in some cases
4) Only a few viruses have prerequisite for formation of certain cancers e.g HPV and cervical cancer

Question 6

How does immunodeficiency affect cancer incidence and why?

Answer 6

• Immunodeficiency favours pathogen invasion
• Increases incidence of pathogen associated cancers e.g Kaposi’s sarcoma
• 10,000 fold increase in Kaposi’s sarcoma in AIDS patients

Question 7

What is the consequence of severe combined immunodeficiency syndrome (X-SCID)?

Answer 7

• Defective interleukin-2 receptor

Question 8

What is X-linked lymphoproliferative syndrome (XLP)?

Answer 8

• Rare inherited immunodeficiency

Question 9

What are the 2 types of XLP and what are the deficiencies in each?

Answer 9

XLP-1: SLAM-associated protein (SAP) deficiency

XLP-2: X-linked inhibitor of apoptosis protein (XIAP) deficiency

Question 10

What are XLP patients susceptible too?

Answer 10

To Epstein-Barr virus (EBV) infection

- also EBV associated diseases e.g B cell lymphomas

Question 11

Define direct and indirect viral carcinogenesis

Answer 11

Direct
- express viral oncogenes that directly contribute to cancer formation

Indirect
- chronic infection/inflammation causes carcinogenic mutations in host cells and cancer development

Question 12

How does Hepatitis B virus (HBV) influence hepatocellular carcinoma?

Answer 12

• HBV commonly clonally integrated into cancer cell genomes
• HBX protein can initiate oncogenic transformation in experimental systems
• May have a role in maintainance of malignant cancer phenotype

Question 13

How does Hepatitis C virus influence hepatocellular carcinoma?

Answer 13

• Hepatocellular carcinoma develops in 1-2% of patients with HCV-related liver fibrosis per year
• HCV proteins (e.g NS5A) contribute to maliganant transformation via host protein interaction

Question 14

What cancer is Human T-lymphotropic virus-I (HTLV-I) associated with and how does it influence this cancer formation?

Answer 14

• Associated with adult T-cell leukaemia/lymphoma (ATLL)
• Viral genome integrated as provirus into host DNA
• tax protein can induce malignant transformation

Question 15

How may viral proteins induce carcinogenesis?

Answer 15

• activate oncogenes

- suppress tumour suppressor genes

Question 16

How do retroviruses influence cancer formation?

Answer 16

• Viral RNA converted to cDNA using reverse transcriptase and integrated into host genome
• Activation of proto-oncogenes/inactivation of tumour suppressor genes by insertional mutagenesis
• Activation of oncogenes by viral proteins acting as transcription factors

Question 17

What are the typical functions of tumour suppressor genes?

Answer 17

• Cell cycle regulation
• Regulation of apoptosis
• Regulation of DNA damage repair

Question 18

What are the characteristics of the TP53 tumour suppressor gene?

Answer 18

• Encodes p53
• protein involved in cell cycle arrest, apoptosis, DNA repair and angiogenesis
• Mutations in about 50% of cancers
• p53 signalling pathway impaired in almost every cancer cell

Question 19

What are the characteristics of the RB1 tumour suppressor gene?

Answer 19

• Encodes pRb (retinoblastoma protein)
• RB1 mutations result in retinoblastoma
• Inherited retinoblastomas usually diagnosed in first year of life and normally affect both eyes
• RB1 gene mutations found in approx 30% breast cancers and 65% of osteosarcomas

Question 20

How do many viral proteins interact with tumour suppressor proteins to induce cancer?

Answer 20

Inhibit pRb and/or p53 function

Question 21

How many types of HPV are there? How is it transmitted? What diseases can it cause?

Answer 21

• 77 known types
• Sexually transmitted
• Most types cause no symptoms
• Some cause genital warts
• High-risk HPV types (HPV16 + 18) may persist and cause ovarian cancer
• High risk HPV responsible for almost all cervical carcinomas
• Can also contribute to:
  > vulva and anus cancer (female)
  > penis and anus (men)

Question 22

Describe the process of cervical cancer onset

Answer 22

• 5-10% of infected females develop chronic infection
• Some with chronic infection will develop cervical cancer precursor lesions (CIN3)
• CIN3 likely to progress to cervical cancers over approx 10-15 years

Question 23

How can CIN3 progression be prevented using prevention procedure?

Answer 23

1) Pap/smear test (liquid based cytology)

2) Lesions removed by colposcopy/preventative surgery

Question 24

Name the main vaccine for low risk and high risk HPV

Answer 24

• Gardasil - low risk

- Cervarix - high risk (HPV16/18)

Question 25

How can viruses be used as cancer treatments?

Answer 25

Use of oncolytic viruses

- bind preferentially to cancer cells and kill them

Question 26

What are the modes of action of oncolytic viruses?

Answer 26

• Oncolysis i.e. direct replication in and destruction of cancer cells
• Stimulation of an anti-cancer immune response

Question 27

What are the drawbacks on oncolytic viruses as a cancer therapy?

Answer 27

• Not very effective

- Neutralising antibodies, immune response prevent multiple applications