Apresentação em tema: "Vírus Oncogênicos e Câncer"— Transcrição da apresentação:
1 Vírus Oncogênicos e Câncer Prof. Dr. Aguinaldo Roberto PintoLaboratório de Imunologia AplicadaMIP/CCB/UFSC
2 Câncer Hipócrates, por volta do ano 400 a.C Câncer: As veias que irradiam a partir de alguns tumores de mama assemelham-se com as pernas de um caranguejo.Ele deu à moléstia o nome de karkinoma (carcinoma), palavra grega que também significa caranguejo, e a mesma associação chegou ao latim.
3 Células cancerosas ou tumorigênicas variantes de células normais que perderam a habilidade de controlar seu crescimento com as seguintes alterações:ImortalizaçãoTransformaçãoMetástase
4 Fibroblastos normais (monocamada) Fibroblastos transformados (arredondados e em colônias)
5 Célula NormalCâncerEstima-se que 6-7 eventos devem ocorrer (em ~20-40 anos) para indução do câncer (alterações genéticas e epigenéticas)em certos casos a propensão ao câncer é hereditária
6 Agentes Carcinogênicos: iniciam ou promovem a formação do tumor Célula NormalAgentes Carcinogênicos: iniciam ou promovem a formação do tumorCélula Tumoral (transformada)
7 Fatores carcinogênicos Fumopulmão, esôfago, bexiga e pâncreasHábitos alimentares (gorduras saturadas e fibras)cólonObesidadeendométrio, cólon, rim, vesículaÁlcooltrato digestivo e respiratórioVírus
8 Vírus e Câncer 1908, Wilhelm Ellerman & Olaf Bang 1911, F. Peyton Rous Leucemia de galinha podia ser transmitida por inoculação de filtrado de células tumorais1911, F. Peyton RousSarcoma de galinha – Nobel em 1966
10 Vírus e Câncer 1908, Wilhelm Ellerman & Olaf Bang 1911, F. Peyton Rous Leucemia de galinha podia ser transmitida por inoculação de filtrado de células tumorais1911, F. Peyton RousSarcoma de galinha – Nobel em 19661936, BittnerCarcinoma mamário de camundongos causado por vírus transmitido pela mãeGross & FriendVírus relacionado à leucemia de camundongos
11 Vírus oncogênicos - DNA DoençaCâncerPapovaviridaePapillomavirus (HPV)Poliomavírus murinoVerrugas, verrugas genitaisCâncer cervical e uterinoHerpesviridaeVírus Epstein-Barr (HHV4)Vírus do Sarcoma de Kaposi (HHV8)Mononucleose infecciosaLinfoma de BurkittCarcinoma de nasofaringeSarcoma de KaposiHepadnavirusVírus da Hepatite B (HBV)Hepatite BCâncer de fígadoAdenoviridaeAdenovírusDoença respiratória agudaAdenocarcinomas (câncer de tecidos epiteliais glandulares)
12 Vírus oncogênicos - RNA CâncerVírus linfotrópico de célula T humana (HTLV-1; HTLV-2)Leucemia de células T do adultosLinfomasVírus de sarcoma de gatos, galinhas e roedoresSarcomas (câncer de tecidos conectivos)Vírus da leucemia felina (FeLV)Leucemia felina
13 Tumor Viruses Transformation: Loss of growth controlReduced adhesionMotilityInvasionAbility to form tumors - viral genes interfere with control of cell replication and other aspects of the cell phenotypeTransformed cells frequently exhibit chromosomal aberrationsViral genes interfere with cell replication control mechanism. NOTE: The early functions of DNA viruses do not make structural proteins but control cellular and viral genome replication.
15 Classes de genes que quando mutados causam transformação maligna Oncogenes: Genes responsáveis pela transformação maligna de células (~100)A versão celular normal do oncogene é chamada de proto-oncogene (genes celulares homólogos de oncogenes que quando alterados (mutados) levam a transformação)Anti-Oncogenes ou Supressores Tumorais: genes que quando deletados causam aparecimento de câncer (~10)
16 DNA Tumor Viruses In Human Cancer ONCOGENEA gene that codes for a protein that potentially can transform a normal cell into a malignant cellAn oncogene may be transmitted by a virus in which case it is known as a VIRAL ONCOGENEv-oncc-oncX
17 RNA Tumor Viruses Proto-oncogene A cellular (host) gene that is homologous with a similar gene that is found in a transforming virusRemember: A virus has only one end: to reproduce. This means that the genome and proteins have to be made in large numbers. So many more copies of the v-onc mRNA are made than the c-onc RNA. This over expression may be the basis of the transformation that is seenA cellular oncogene can only induce transformation aftermutationsome other change in the cell’s genome
18 Classes de proteínas que são codificadas por oncogenes Fatores de crescimentoClasses de proteínas que são codificadas por oncogenesReceptores de Fatores de crescimentoProteínas envolvidadas com a transdução de sinalFatores de Transcrição
22 DNA Tumor Viruses In Human Cancer Papilloma Virusescause natural cancers in animalscause benign wartsubiquitousepitheliotropic - most human tumors are malignancies of epithelial cells
23 DNA Tumor Viruses In Human Cancer Papilloma Viruses51 types identified - most common are types 6 and 11Most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers)No final proof that these viruses cause cancer as Koch’s postulates cannot be fulfilled.Papilloma viruses cannot be grown in cultureIt appears that there is free plasmid in the cell rather than integrationEPIDEMIOLOGIAL STUDIES BUT:HPV 16 and HPV 18 do transform human keratinocytesEffective Vaccine(quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in yeast - Gardasil)
24 DNA Tumor Viruses In Human Cancer Polyoma VirusesSimian virus 40 - juvenile hamster sarcomas, transformationcontaminação de lotes de vacina contra polioPolyoma - mouse leukemia, in vitro transformationHuman polyomas (JC and BK) - monkey sarcoma, transformationSV40 was in early batches of polio vaccineNormally these viruses cause lytic infection and transform when they are incompletePossible association of BK with human prostate cancerEarly functions are necessary - ONCOGENES
25 DNA Tumor Viruses In Human Cancer AdenovirusesHighly oncogenic in animalsAdenovirus can be involved in RETINOBLASTOMA and maybe in some other rare cancersAlways the same partEarly functionsE1A region: 2 T antigensE1B region: 1 T antigenE1A and E1B = Oncogenes
26 DNA Tumor Viruses In Human Cancer Herpes VirusesConsiderable evidence for role in human cancerSome very tumorigenic in animalsMost people have antibodies against EBVWhy some populations get mononucleosis while others get tumors in not knownCauses lymphoma in marmosets
27 DNA Tumor Viruses In Human Cancer Epstein-Barr VirusBurkitt’s LymphomaEndemicNon-endemicNasopharyngeal cancerInfectious mononucleosis (glandular fever)Transforms human B-lymphocytes in vitroMost people have antibodies against EBVWhy some populations get mononucleosis while others get tumors in not knownCauses lymphoma in marmosetsBurkitt’s lymphoma: malarial infested regionsNasopharyngeal cancer: China, SE Asia – diet?
28 DNA Tumor Viruses In Human Cancer Kaposi’s Sarcoma Herpes Virus Human herpes virus – 8Kaposi’s Sarcoma Herpes VirusKaposi’s sarcoma
29 DNA Tumor Viruses In Human Cancer Hepatitis B VirusDNA genomeRNA polymerase IIRNA ProvirusReverse transcriptaseHost enzymeViral enzyme
30 DNA Tumor Viruses In Human Cancer Epidemiology:Strong correlation between HBV and hepatocellular carcinomaChina: 500, million new cases of hepatocellular carcinoma per year
31 RNA Tumor Viruses RNA Genome - Retroviruses RNA-dependent DNA Polymerase encoded by virusREVERSE TRANSCRIPTASERNA genomeReverse transcriptaseDNA genomeIntegraseIntegratesHost RNA polymerase IIReverse transcriptase is not a capacity possessed by normal eucaryotic cellsMany features are unique to retrovirusesVery unusual mode of replication which gives them the potential to transform the cellBut when it comes to how these viruses cause neoplasia, they may be very similar to DNA virusesRous sarcoma virus in chickens was the first retrovirus to be discovered. It causes an aggressive acute cancer in chickensvirushost
34 RNA Tumor Viruses Retroviruses known to cause human cancer Human T cell lymphotropic virus -1 (HTLV-1)Adult T cell leukemia, Sezary T-cell leukemiaAfrica, Caribbean, Some Japanese Islands, S. America (Peru, Bolivia)1-4% of infected people
35 Como retrovírus causam câncer? “typical retrovirus”R U GAG POL ENV U RA normal retrovirus has three genes, GAG, OPL, ENV – only these are necessary for the virus to replicate to more virus. Many, however, have another gene that allows them to transform the cell.NOTE: This extra gene is NOT necessary for a productive infection. C.f. DNA tumor viruses in which the oncogene is necessary for BOTH replication and transformationFirst oncogene to be discovered was the src gene of RSV. It is an extra gene at the 3’ end of the viral RNARous Sarcoma VirusR U GAG POL ENV U3 RSRC
36 Substituição de 19 aminoácidos do C-terminal por 12 aminoácidos diferentes
37 Some retroviruses have an oncogene instead of their regular genes Avian Myeloblastosis VirusR U GAG POL MYB U RThese viruses cannot make all of their proteins and so need a co-infecting “helper” virusViral oncogenes have three letter names e.g. src, mybFeline Sarcoma Virus (FSV)R U5 dGAG FMS dENV U RAvian Myelocytoma Virus (MC29)R U5 dGAG MYC dENV U R
38 Avian Leukosis Virus (causes lymphomas) RNA Tumor VirusesIn contrast:R U GAG POL ENV U RAvian Leukosis Virus (causes lymphomas)No oncogene! – How does it cause a tumor?
39 ALV can integrate into the host cell genome at MANY locations RNA Tumor VirusesALV can integrate into the host cell genome at MANY locationsbut in tumor it is always at the SAME site (or restricted number of sites)
40 Could C-oncs be involved in NON-VIRAL cancers? RNA Tumor VirusesCould C-oncs be involved in NON-VIRAL cancers?
41 Cancers often result from gene translocations Burkitt’s Lymphoma8:14 translocationBreak in chromosome 14 at q32Could the break and exchange of parts of chromosomes bring the c-onc under the control of a very active cell promotor? In Burkitt’s lymphoma there is a 8:14 translocation. Myc is at the break site on chromosome 8. What does it come next to on chromosome 14?mycAcute myelocytic leukemia 7:15 9:18 11:15:17
42 Oncogenesis by rearrangement Tumor c-onc new promotorBurkitt’s lymphoma myc (8) Ig heavy (8 to 14)Ig light (8 to 2)B-cell chronic lymphocytic bcl-1 Ig heavy (11 to 14)leukemia bcl-2 Ig heavy (18 to 14)Thus in Burkitt’s lymphoma, the myc gene is brought under the control of a Ig promotor which is very active in this lymphocyte. Thus this is similar to putting the cellular oncogene under the control of the very active promotor in the viral LTRProof that deregulated c-myc may be involved in tumor formation comes from transgenic mice. If a gene consisting of c-myc linked to the Ig promotor is integrated into the chromosomes of these mice there is a high frequency of lymphomas.T cell chronic lymphocytic tcl-1 T cell receptorleukemia (14 inversion)T cell chronic lymphocytic myc T cell receptor (8 to 14)leukemia
43 have normal regulatory function in many cells Anti-OncogenesRetinoblastoma geneP53have normal regulatory function in many cells
44 Anti-Oncogenes Retinoblastoma Adenovirus E1A Rb Gene Rb protein Rb It is found that in adenovirus cells, the virus E1A gene makes a protein that complexes with a 105kD cellular protein. This turned out to be Rb protein. Binding Rb protein so that it cannot control growth is the same as mutating both copies of the gene for the Rb protein and so the cell continues to replicateRb105kDRbRbCell cycle continuesStops replication
45 Papilloma proteolysis Anti-Oncogenesp53P53 geneP53 geneP53 geneHepatitis CPapillomaA similar thing happens to p53 protein in hepatitis C-infected cells and p53 is bound so that it becomes inactive. Again, lack of p53 results in loss of growth control. In papilloma-infected cells, things happen a little differently. In this case the virus makes a protease that destroys p53 protein.Thus, our knowledge of how RNA tumor viruses cause tumors led to the discovery of viral oncogenes. This led to the discovery of cellular oncogenes which in turn led to anti-oncogenes. The discovery of anti-oncogenes showed how DNA tumor viruses cause tumors.P53P53P53Papilloma proteolysisP53DNAStops replicationreplicationreplication
46 DNA Tumor Viruses Oncogenes Adenovirus E1A region 2SV Large TPolyoma Large TBK virus Large TLymphotropic virus Large THuman papilloma Virus-16 E7All have a sequence in commonMutations in this region abolish transformation capacityThe oncogenes of DNA viruses such as polyoma or adenovirus have been identified to early function genes and all of these seem to have characteristics in common, indeed, they have some sequence similarities and mutations in this common region abolish tumorigenicity