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Viruses and Cancer

Viruses and Cancer. Tumor Virology. Cancer. Cancer is one of the most common diseases in the developed world: 1 in 4 deaths are due to cancer 1 in 17 deaths are due to lung cancer Lung cancer is the most common cancer in men Breast cancer is the most common cancer in women

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Viruses and Cancer

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  1. Viruses and Cancer Tumor Virology

  2. Cancer • Cancer is one of the most common diseases in the developed world: • 1 in 4 deaths are due to cancer • 1 in 17 deaths are due to lung cancer • Lung cancer is the most common cancer in men • Breast cancer is the most common cancer in women • There are over 100 different forms of cancer

  3. Cancer • The division of normal cells is precisely controlled. New cells are only formed for growth or to replace dead ones. • Cancerous cells divide repeatedly out of control even though they are not needed, they crowd out other normal cells and function abnormally. They can also destroy the correct functioning of major organs.

  4. What causes cancer? • Cancer arises from the mutation of a normal gene. • Mutated genes that cause cancer are called oncogenes. • It is thought that several mutations need to occur to give rise to cancer • Cells that are old or not functioning properly normally self destruct and are replaced by new cells. • However, cancerous cells do not self destruct and continue to divide rapidly producing millions of new cancerous cells.

  5. A factor which brings about a mutation is called a mutagen. • A mutagen is mutagenic. • Any agent that causes cancer is called a carcinogen and is described as carcinogenic. • So some mutagens are carcinogenic.

  6. Carcinogens • Ionising radiation – X Rays, UV light • Chemicals – tar from cigarettes • Virus infection – papilloma virus can be responsible for cervical cancer. • Hereditary predisposition – Some families are more susceptible to getting certain cancers. Remember you can’t inherit cancer its just that you maybe more susceptible to getting it.

  7. Viruses cause cancer Why has the study of viruses and cancer been important?

  8. Viruses cause cancer Why has the study of viruses and cancer been important? - We learn about the basic mechanisms of specific types of tumors.

  9. Viruses cause cancer Why has the study of viruses and cancer been important? - We learn about the basic mechanisms of specific types of tumors. - We identify fundamental pathways important for oncogenesis - viruses are lower complexity - We can identify potential unique therapeutic targets for viral associated tumors

  10. Viruses cause cancer • 30-40% of cancers are known to have viral etiology • But as more research is done, • this percentage is likely to be found to be higher

  11. Major human Oncogenic Viruses DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposi’s Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C

  12. Changes in cell that are at the roots of cancer

  13. Changes in cell that are at the roots of cancer • Genetic and epigenetic alterations:

  14. Changes in cell that are at the roots of cancer • Genetic and epigenetic alterations: • Mutations • Deletions • Recombinations • Transpositions • Epigenetic alterations (DNA methylation, imprinting) • Acquisition of viral genetic material

  15. Changes in cell that are at the roots of cancer • Genetic and epigenetic alterations: • Mutations • Deletions • Recombinations • Transpositions • Epigenetic alterations (DNA methylation, imprinting) • Acquisition of viral genetic material • Various combinations of these lead to the development of cancers - some viruses contribute single hits while others contribute multiple hits.

  16. Source of genetic alterations • Inherited • Somatic • Random • Transposition • Exposure to deleterious environmental agents • Radiation • carcinogenic chemicals • Viruses • Other persistent infections

  17. Viruses and Cancer

  18. How do Viruses contribute to cancer? • Integrations that cause activation or inactivation of oncogenes or tumor suppressors (e.g. RNA viruses) • Expression of genes that alter key signal transduction pathways - this is our focus • Chronic activation of inflammatory responses

  19. Why do viruses cause cancer?

  20. Why do viruses cause cancer? • Viruses and cancer cells have similar needs • Proliferation control • Cell death control • Modulation of immune response • Induction of vascularization • Metastasis (tumor)/cell migration (viruses)

  21. If you’re infected, does this mean that you will get cancer?

  22. If you’re infected, does this mean that you will get cancer? • No • Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs

  23. If you’re infected, does this mean that you will get cancer? • No • Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs • Development of tumors almost always requires: • Additional genetic alterations and/or • Compromised host (e.g. immuno-suppression)

  24. Major human Oncogenic Viruses DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposi’s Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C

  25. Small DNA tumor viruses • Adenovirus • Human virus but only causes cancer in non-human cells • SV40 • Mesothelioma • HPV • Cervical Cancer • Squamous cell anal carcinoma • Penile cancer • Oral cancers

  26. Small DNA tumor viruses • HPV • SV40 • Adenovirus • Normally replicate episomally but almost always found integrated in associated tumors - why?

  27. Small DNA tumor viruses • HPV • SV40 • Adenovirus • Normally replicate episomally but almost always found integrated in associated tumors - why? • Replication must be abortive • HPV, viral encoded negative regulatory factor must be deleted

  28. Papilloma Viruses urogenital cancer wart malignant squamous cell carcinoma Papilloma viruses are found in 91% of women with cervical cancer DNA Tumor Viruses In Human Cancer 10% of human cancers may be HPV-linked 16% of all female cancers linked to HPV

  29. DNA Tumor Viruses In Human Cancer • Papilloma Viruses • >100 types identified - most common are types 6 and 11 • Most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers) Effective Vaccine (quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in yeast - Gardasil)

  30. Papilloma Viruses • The important transforming genes in papilloma viruses are the non-structural regulatory genes, E6 and E7 • HPV is normally episomal but is always integrated in tumors

  31. Adenoviruses Highly oncogenic in animals Only part of virus integrated Always the same part Early (regulatory) genes E1A and E1B = Oncogenes

  32. SV40 • The important transforming gene is T Ag - provides similar functions as E1A + E1B (Adenovirus) and E6 and E7 (HPV)

  33. Abortive replication is key to oncogenesis by these small viruses • Expression of early (regulatory) genes in absence of structural genes and virus production • Can occur by infection of non-permissive host • Can occur by integrations that delete regions of viral genome required for replication but leave early genes intact.

  34. Small DNA Tumor Viruses • What are the needs of small DNA tumor viruses that make them oncogenic and • What are the key mechanisms through which they attain their needs?

  35. Small DNA Tumor Viruses DNA viral genome Utilizes Host Cell DNA Replication Machinery Host RNA polymerase Viral mRNA Viral protein Need cells that are in S-phase to replicate viral genome Host enzymes

  36. Inappropriate activation of cell cycle

  37. Inappropriate activation of cell cycle Apoptosis

  38. Inappropriate activation of cell cycle • Apoptosis • e.g. • Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis • Defense mechanism against rogue proliferating cells?

  39. Inappropriate activation of cell cycle Apoptosis e.g. - Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis - Same is true for over-expression of Adenovirus E1A or HPV E7

  40. Encode early genes that inhibit apoptosis Adenovirus E1B HPV E6 SV40 T Ag

  41. SV40 and HPV

  42. Adenovirus E1B is Bcl2 family member - blocks function of pro-apoptotic Bcl2 family members through dimerization

  43. Summary Small DNA tumor viruses usually replicate in episomal form but are found integrated in viral associated tumors Early genes promote cell cycle progression and prevent apoptosis Adenovirus - E1A (cell cycle) and E1B (apoptosis) HPV - E7 (cell cycle) and E6 (apoptosis) SV40 - T Ag (cell cycle and apoptosis)

  44. Herpes viruses • Oncogenic members: • Epstein Barr virus (EBV) • Kaposi’s Sarcoma Herpes virus (KSHV) • Oncogenic mechanisms are distinct from small • DNA tumor viruses • - Don’t need to integrate • - Cell cycle is not driven by lytic replication regulatory genes

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