Cancer Bio (Michaelis Lecture 1 - Viruses and cancer) Flashcards
What are the main 2 causes of cancer? What % of cancers do they cause?
1) Germline mutations (5-10%)
2) Enviromnental factors/somatic mutations (90-95%)
What are the 3 main cancer risk factors and their associated percentages?
1) Diet (35%) (obesity (20%))
2) Smoking (30%)
3) Chronic infections (15-20%)
Viruses 70% of that
What 3 types of infectious agents can cause cancer and give examples of each
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
What technique has been utilised in history to show that viruses induce cancer?
- 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
What are some characteristics of virus-induced cancer
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
How does immunodeficiency affect cancer incidence and why?
- 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
What is the consequence of severe combined immunodeficiency syndrome (X-SCID)?
- Defective interleukin-2 receptor
What is X-linked lymphoproliferative syndrome (XLP)?
- Rare inherited immunodeficiency
What are the 2 types of XLP and what are the deficiencies in each?
XLP-1: SLAM-associated protein (SAP) deficiency
XLP-2: X-linked inhibitor of apoptosis protein (XIAP) deficiency
What are XLP patients susceptible too?
To Epstein-Barr virus (EBV) infection
- also EBV associated diseases e.g B cell lymphomas
Define direct and indirect viral carcinogenesis
Direct
- express viral oncogenes that directly contribute to cancer formation
Indirect
- chronic infection/inflammation causes carcinogenic mutations in host cells and cancer development
How does Hepatitis B virus (HBV) influence hepatocellular carcinoma?
- 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
How does Hepatitis C virus influence hepatocellular carcinoma?
- 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
What cancer is Human T-lymphotropic virus-I (HTLV-I) associated with and how does it influence this cancer formation?
- Associated with adult T-cell leukaemia/lymphoma (ATLL)
- Viral genome integrated as provirus into host DNA
- tax protein can induce malignant transformation
How may viral proteins induce carcinogenesis?
- activate oncogenes
- suppress tumour suppressor genes
How do retroviruses influence cancer formation?
- 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
What are the typical functions of tumour suppressor genes?
- Cell cycle regulation
- Regulation of apoptosis
- Regulation of DNA damage repair
What are the characteristics of the TP53 tumour suppressor gene?
- 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
What are the characteristics of the RB1 tumour suppressor gene?
- 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
How do many viral proteins interact with tumour suppressor proteins to induce cancer?
Inhibit pRb and/or p53 function
How many types of HPV are there? How is it transmitted? What diseases can it cause?
- 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)
Describe the process of cervical cancer onset
- 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
How can CIN3 progression be prevented using prevention procedure?
1) Pap/smear test (liquid based cytology)
2) Lesions removed by colposcopy/preventative surgery
Name the main vaccine for low risk and high risk HPV
- Gardasil - low risk
- Cervarix - high risk (HPV16/18)
How can viruses be used as cancer treatments?
Use of oncolytic viruses
- bind preferentially to cancer cells and kill them
What are the modes of action of oncolytic viruses?
- Oncolysis i.e. direct replication in and destruction of cancer cells
- Stimulation of an anti-cancer immune response
What are the drawbacks on oncolytic viruses as a cancer therapy?
- Not very effective
- Neutralising antibodies, immune response prevent multiple applications