1. Viruses and Cancer BTY328: Virology wstafford@uwc.ac.za

2. Some viruses cause cancer Viruses are one of the main factors that cause normal cells to proliferate and to become malignant: up to 15% of all human cancers are associated with single or multiple virus infections Viruses have evolved many strategies to prevent infected cells from becoming apoptotic and to evade the innate and adaptive immune responses of their hosts. Changes in critical cellular funtions such as cell cycle control, cellular signalling, DNA repair, apoptosis or tumour supression lead to cancer

3. Viruses associated with cancers

5. How do viruses cause cancer? 1. Transducing viruses Oncogenes of retroviruses arose by transduction of cellular genes by recombination events. Originally recognized from studies of the oncogene (v-src) of Rous sarcoma virus (RSV) and its cellular progenitor (c-src).

6. Transducing virus oncogenes

7. EGF receptor and transducing virus version The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

8. Non- transducing viruses and cancer 2. Non transducing viruses: Retroviruses integrate into host genomes and can disrupt coding regions of host genes (deletions truncations, rearrangements)‏ Integration into the host genome alters host genome expression (eg. LTR can act as enhancers or repressors of host gene expression). Cis acting viral sequences. Produce changes in cell metabolism through the action of viral proteins acting as trans-acting factors (protein-protein and protein-DNA interactions

9. Insertional activation of cellular oncogene (c-onc)‏ Insertional activation can be by action of promoter or enhancer c-onc can be a host protein critical for cell cycle control/cellular signalling/apoptosis Eg. Ras., myc activation

10. Human papillomavirus E5 protein Human papillomavirus E5 protein increases the EGF cell surface receptor concentration of infected cells Inhibits the endosomal H + ATPase thus slowing degradation of EGF

11. p53- a master tumour supresor

12. Inactivation of the p53 protein by adeno- and papo- viral proteins Normal response to remove infected cells…. Viral proteins inactivate or remove p53 (tumour repressor) thereby causing oncogenesisis

14. EBV Epstein-Barr virus (EBV), is a herpesvirus family and very common. The virus occurs worldwide, and most people become infected with EBV sometime during their lives. > 95% of adults between 35 and 40 years of age have been infected. Many children become infected with EBV, usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 50% of the time. Also called glandular fever or the “kissing disease”

15. Diseases Driven by Epstein-Barr Virus (EBV) Infectious mononucleosis Chronic Active EBV X-linked lymphoproliferative disease Lymphoproliferative disease Oral hairy leukoplakia Hodgkin disease EBV EBV-Driven Nasopharyngeal carcinoma Gene Cell T cell lymphoma Expression Proliferation Burkitt lymphoma

16. EBV Viral Load is Increased in Patients with Lymphoproliferative Disease Riddler, Blood 1994 Viral Load Used to Monitor Transplant Patients:Increased EBV load at onset of LPD Used to initiate preemptive therapy

17. Burkitt Lymphoma EBV+: 90% of cases in developing countries – jaw tumors 20% cases in US – children with abdominal tumors AIDS patients – tumors in lymph nodes Dysregulation of c-myc oncogene Only EBV EBNA-1 expressed

18. EBV-Associated Smooth Muscle Tumors Occur in transplant recipients, AIDS patients, congenitial immunodeficiency Pathology: leiomyosarcomas and leiomyomas in various organs and lymph nodes

19. EBV Lymphoproliferative Disease Occurs with immunodeficiency (AIDS, congenital) or after transplantation, RA and MTX Symptoms: Infectious Mononucleosis Mass lesions in organs (less often lymph nodes)‏ Cohen NEJM 2000

20. LMP-1 is the EBV Oncogene LMP-1 mediates signaling through the Tumor necrosis factor-alpha/CD40 pathway.Tumor necrosis factor-alphaCD40 LMP-1 Expression in transgenic mice leads to B cell lymphoma; expression in fibroblasts leads to tumors in nude mice B Cell Proliferation : Upregulates adhesion molecules, CD23, CD40, IL-6, IL-10, etc. Activates NF-  B Inhibition of apoptosis: Upregulates Bcl-2, A20, Mcl-1

21. Signalling pathway of TNF TNF stimulates the inflammatory response and causes apoptotic cell death…

22. Summary Viruses can cause cancer (uncontrolled cell growth). Either through the recombination and capture of host oncogenes (transducing viruses) or by several mechanisms to alter cellular growth, differentiation and/or signalling (non-transducing viruses) including: Retroviruses integrate into host genomes and can disrupt coding regions of host genes (deletions truncations, rearrangements)‏ Integration into the host genome alters host genome expression (eg. Cis acting viral sequences act as repressors of host gene expression). Produce changes in cell metabolism through the action of viral proteins acting as trans-acting factors (protein- protein and protein-DNA interactions The associations beweeen viruses and cancers are becoming clearer with better epidemiology and methods to isolate and study viruses.