TumorViruslecture2010

1,Paper DiscussionNext weekPegtel et al.“Functional delivery of viral miRNAs via exosomes”Proc. Natl. Acad. Sci. 2010 April 6; 107(14): 63286333. ,2,Viruses cause cancer,Download lecture at: ,3,Viruses cause cancer,Why has the study of viruses and cancer been important?,4,Viruses cause cancer,Why has the study of viruses and cancer been important?- We learn about the basic mechanisms of specific types of tumors.,5,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 viralassociated tumors,6,Viruses cause cancer,30-40% of cancers are known to have viral etiologyBut as more research is done, this percentage is likely to be found to be higher,7,Major human Oncogenic Viruses,DNA VirusesSmall DNA tumor viruses- Adenovirus- SV40- Human Papilloma virus (HPV)Herpesviruses (large)- Epstein Barr virus (EBV)- Kaposis Sarcoma Herpesvirus (KSHV)Other- Hepatitis virus BRNA virusesHuman T-cell Leukemia Virus 1 (HTLV1)XMRV (Xenotropic Murine Leukemia Virus)Hepatitis virus C,8,Changes in cell that are at the roots of cancer,9,Changes in cell that are at the roots of cancer,Genetic and epigenetic alterations:,10,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,11,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.,12,InheritedSomatic Random Replication errors DNA repair errors Transposition (e.g. retrotransposons) Exposure to deleterious environmental agents Radiation carcinogenic chemicals Viruses Other persistent infections,Source of genetic alterations,13,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,How do Viruses contribute to cancer?,14,Why do viruses cause cancer?,15,Viruses and cancer cells have similar needs Proliferation control Cell death control Modulation of immune response Induction of vascularization Metastasis (tumor)/cell migration (viruses),Why do viruses cause cancer?,16,If youre infected, does this mean that you will get cancer?,17,No Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs,If youre infected, does this mean that you will get cancer?,18,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),If youre infected, does this mean that you will get cancer?,19,Major human Oncogenic Viruses,DNA VirusesSmall DNA tumor viruses- Adenovirus- SV40- Human Papilloma virus (HPV)Herpesviruses (large)- Epstein Barr virus (EBV)- Kaposis Sarcoma Herpesvirus (KSHV)Other- Hepatitis virus BRNA virusesHuman T-cell Leukemia Virus 1 (HTLV1)XMRV (Xenotropic Murine Leukemia Virus)Hepatitis virus C,20,Adenovirus Human virus but only causes cancer in non-human cells SV40 Mesothelioma HPV Cervical Cancer Squamous cell anal carcinoma Penile cancer Oral cancers,Small DNA tumor viruses,21,HPV SV40 Adenovirus Normally replicate episomally but almost always found integrated in associated tumors - why?,Small DNA tumor viruses,22,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,Small DNA tumor viruses,23,DNA Tumor Viruses In Human Cancer,10% of human cancers may be HPV-linked16% of all female cancers linked to HPV,24,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),25,Papilloma Viruses,The important transforming genes in papilloma viruses are the non-structural regulatory genes, E6 and E7HPV is normally episomal but is always integrated in tumors,26,27,AdenovirusesHighly oncogenic in animalsOnly part of virus integrated,Always the same partEarly (regulatory) genesE1A and E1B = Oncogenes,28,SV40,The important transforming gene is T Ag- provides similar functions as E1A + E1B (Adenovirus) and E6 and E7 (HPV),29,Abortive replication is key to oncogenesis by these small viruses,Expression of early (regulatory) genes in absence of structural genes and virus productionCan occur by infection of non-permissive hostCan occur by integrations that delete regions of viral genome required for replication but leave early genes intact.,30,Small DNA Tumor Viruses,What are the needs of small DNA tumor viruses that make them oncogenic andWhat are the key mechanisms through which they attain their needs?,31,Need cells that are in S-phase to replicate viral genome,Host enzymes,32,33,34,Inappropriate activation of cell cycle,35,Inappropriate activation of cell cycle,Apoptosis,36,Inappropriate activation of cell cycle,Apoptosise.g. Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis Defense mechanism against rogue proliferating cells?,37,Inappropriate activation of cell cycle,Apoptosise.g. - Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis- Same is true for over-expression of Adenovirus E1A or HPV E7,38,Encode early genes that inhibit apoptosis,Adenovirus E1BHPV E6SV40 T Ag,39,SV40 and HPV,40,Adenovirus,E1B is Bcl2 family member - blocks function of pro-apoptotic Bcl2 family members through dimerization,41,Summary,Small DNA tumor viruses usually replicate in episomal form but are found integrated in viral associated tumorsEarly genes promote cell cycle progression and prevent apoptosisAdenovirus - E1A (cell cycle) and E1B (apoptosis)HPV - E7 (cell cycle) and E6 (apoptosis)SV40 - T Ag (cell cycle and apoptosis),42,Herpes viruses,Oncogenic members:Epstein Barr virus (EBV)Kaposis Sarcoma Herpes virus (KSHV) Oncogenic mechanisms are distinct from small DNA tumor viruses- Dont need to integrate- Cell cycle is not driven by lytic replication regulatory genes,43,Herpes viruses,Hallmark of herpesviruses:,44,Herpes viruses,Hallmark of herpesviruses:Existence of latent stage (in addition to lytic/replicative stage),45,Herpes viruses,Lytic replication phase for herpesviruses:,46,Herpes viruses,Lytic replication phase for herpesviruses:- Herpesviruses are large and encode 80-100 lytic associated genes- Encode their own DNA polymerase and replication accessory enzymes- Therefore, they dont require an S-phaseenvironment for replication- Encode early genes that induce cell cyclearrest,47,Herpes viruses,Latency:- Small subset of viral genes are expressed that are not expressed during lytic replication.- Latency is partly a way for virus to hide from immune system- In cases of EBV and KSHV, latency genes can alsoinduce cell differentiation/activation programsthat facilitate expansion of infected cell populationand induce trafficking to specific lymphoid compartments that are suited to the life cycleof the virus,48,Herpes viruses,Human Herpesviruses and latency function:Epstein Barr virus (EBV) - multiple functionsKaposis Sarcoma Herpes virus (KSHV) - multiple functionsCytomegalovirus (CMV) - Stealth mechanismHerpes Simplex (HSV) - Stealth mechanism,49,Epstein Barr virus,Pathologies in immuno-competent individuals Infectious mononucleosis Burkitts Lymphoma Hodgkins lymphoma Nasopharyngeal carcinoma,Pathologies in immuno-compromised individuals Post-transplant lymphoproliferative diseases (PTLD) Hodgkins lymphoma A variety of non-Hodgkins lymphoblastoid malignancies,50,Epstein Barr virus,Latency genesNon-antigenic EBNA1 (Epstein Barr Nuclear Antigen 1) - episomal replication and segregation function,Antigenic EBNA2 EBNA3A, 3B, 3C EBNA-LP LMP1 (Latent Membrane Protein 1) LMP2A,Those in Red are key regulatory genes involved in B cell activation,51,52,Epstein Barr virus,4 different types of latencyTrue Latency - no viral gene expressionEBNA1 only - EBNA1 (non-antigenic)Default - EBNA1, LMP1, and LMP2 (moderately antigenic)Growth - EBNA1, LMP1, LMP2, EBNA2, EBNA-LP, EBNA3A, 3B, 3C (highly antigenic),Growth programInitial infection (prior to immune response) Immuno-compromised individuals- in vitro infection of nave peripheral blood lymhocytes,53,54,55,Epstein Barr virus,Greater than 90%