Viruses and Cancer

1. Viruses and Cancer Infectious agents play a role in 20% of human cancers

2. Blood What is cancer? Replication of cells is tightly controlled metastasis Causes: Damage to genes that control cell growth Environmental toxins Inherited defects Infectious agents

3. Metastases in the liver Lung: Primary tumour

4. Control the expression of host genes Cancer is a disease of aberrant gene expression Viruses replicate inside cells Host cell

5. Many years Only a small percentage of infected individuals develop cancer Oncogenesis is a multi-step process: Normal cell Cancer cell infection Carcinogens persistence

6. 0.2 m 1909 Peyton Rous and Rous sarcoma virus Virus = Filterable agent A filterable agent can cause tumours in chickens

7. A few weeks later: Rous sarcoma virus 1966 Nobel prize

8. Lysis ~ ~ ~ ~ ~ Expression transforms cells proliferation 3. 1963 Viruses can transform cells in culture….. Immortalised Rapid proliferation Loss of contact inhibition Altered morphology

9. Hela cells 1951 Henrietta Lacks, a 31 year woman from Baltimore USA is ill She visits her doctor who fears the worst and takes a scraping of cells from her cervix to send to the laboratory Cervical cancer is confirmed and she dies 8 months later Henrietta Lack’s cells (HeLa cells) remain alive in laboratories all around the world, more than 50 years after her death

10. Viruses use an array of mechanisms to transform cells. Each is unique 3 common mechanisms: • Trans-activation of cellular genes • Inactivation of tumour suppressor proteins • Action of viral oncogenes • Unknown The virus is not enough

11. promoter Host DNA Host transcription factor ATG Gene expression promoter Host DNA viral transcription factor ATG Gene expression 1. Trans-activation: Virus-encoded transcription factors activate host genes Cis-activation Trans-activation

12. Tax protein Expression of host genes Uncontrolled Cell proliferation e.g. HTLV1 Host DNA

13. DNA repair (e.g. p53) Initiate apoptosis G1 Cell division DNA synthesis M S mitosis Chromosome duplication G2 Cell with duplicated chromosome 2. Inactivation of tumour suppressor genes: Human papillomavirus 1. excessive proliferation 2. Failure of damaged cells to repair their DNA 3. Failure of damaged cells to undergo apoptosis

14. oncogene 3. Viral oncogenes Certain viruses have genes that they have “stolen” from host cells: Oncogenes: Host genes that have become altered in structure or function. Some of these can behave as oncogenes e.g. Rous sarcoma virus Code for proteins that play a role in cell proliferation: growth factors growth factor receptors DNA binding proteins cytoplasmic signalling

15. Viruses associated with human cancers: Human papilloma virus Ca cervix, penis, vulva, anus squamous carcinomas (skin) Epstein Barr virus Non Hodgkin’s lymphomas naso-pharyngeal carcinoma HTLV1 Human T cell leukaemia Hepatitis B Hepato-cellular carcinoma Hepatitis C Hepato-cellular carcinoma HHV8 Kaposi sarcoma Body cavity lymphomas

16. Human papillomavirus (HPV) Epithelial surfaces Proliferative lesions on epithelial surfaces Warts >100 HPV types Site specific [mucosal vs cutaneous] Can cause benign or malignant lesions

17. warts cutaneous mucosal

18. Normal replication cycle: Differentiating epithelium HPV induces cell Proliferation by inactivating p53

19. 16, 18, 31 33, 35, 39, 45, 51, 52, 56, 58,59, 68, 63, 82 Increasing risk 26, 53, 66 62, 71, 83, 84, 85, 89 6, 11, 42, 43, 44 Some Mucosal tropic HPV types are oncogenic: Infection with high risk HPVs may lead to cancer: • Low risk • High risk High risk HPV types suppress p53 more effectively

20. HPV infection Persistent HPV infection Cellular dysregulation High grade CIN Invasive cancer Immunologic factors Co-carcinogens Steps in HPV Induced Cervical Cancer Sexually transmitted > 80% of women are exposed 1 % develop Ca cervix Pap smears: screens for pre malignant lesions

21. Latency in B lymphocytes Epstein Bar Virus herpesvirus 90-100% adults have been exposed Persistent infections Primary infection reactivation Shed in saliva

22. EBV is associated with various pre-malignant and malignant disorders: Disease cell type Burkits NHL B cells Lympho proliferative disorders B cells NHL in transplant, AIDS B cells Naso-pharyngeal carcinoma squamous epithelial cells EBV transforms B lymphocytes

23. Burkitt’s lymphoma 1958 Denis Burkitt Cell of origin = B lymphocyte Central Africa, New Guinea children extra-nodal masses: jaw, orbit, ovaries Malaria is a co-factor Sporadic form occasionally seen in SA

24. NHL in immuno-suppressed patients e.g. transplant AIDS Commonly involves the CNS Post transplant: children

25. HTLV1 Retrovirus Human retroviruses: HTLV1 and 2 HIV 1 and 2 Persistent infections Infects T cells: tax protein transforms T cells T cell leukaemia

26. HTLV1 Epidemiology: SW Japan, West Africa, Caribbean Transmission: Mother to child via breast feeding Sexual intercourse Clinical features: Most infections are asymptomatic Disease manifests many years post infection

27. Clinical features: aggressive tumour cells infiltrate skin and brain T cell leukaemia Early infection very long latent period life time risk 5% Flower cell

28. Hepatitis B virus Infects liver cells High prevalence in SSA and SEA Commonest cancer in black males in SSA Especially rural dwellers

29. Acute hepatitis Short lived infection Recovery and immunity Chronic infection. Liver disease and liver cancer

30. Early infection persistence cirrhosis HCC Co-carcinogens aflatoxins iron overload alcohol Chronic infection: 100 fold risk of HCC Mechanism of oncogenesis unclear Cycles of cell death and proliferation sensitises liver cells to co-carcinogens Chronic infection with hepatitis C virus also leads to HCC

31. HHV8 1994 DNA cloned from Kaposi sarcoma Vascular, lymphatic or mesenchymal endothelial cells