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Prof. Dr. Aguinaldo Roberto PintoLaboratório de Imunologia Aplicada
MIP/CCB/UFSC
Vírus Oncogênicos e Câncer
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.
Células cancerosas ou tumorigênicasvariantes de células normais que perderam a
habilidade de controlar seu crescimento com as seguintes alterações:
Imortalização
Transformação
Metástase
Fibroblastos normais (monocamada)
Fibroblastos transformados (arredondados e em colônias)
Célula Normal Câncer
Estima-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
Célula Normal
Célula Tumoral (transformada)
Agentes Carcinogênicos: iniciam ou promovem a
formação do tumor
Fatores carcinogênicos• Fumo
– pulmão, esôfago, bexiga e pâncreas• Hábitos alimentares (gorduras saturadas e fibras)
– cólon• Obesidade
– endométrio, cólon, rim, vesícula• Álcool
– trato digestivo e respiratório• Vírus
Vírus e Câncer• 1908, Wilhelm Ellerman & Olaf Bang
– Leucemia de galinha podia ser transmitida por inoculação de filtrado de células tumorais
• 1911, F. Peyton Rous– Sarcoma de galinha – Nobel em 1966
Vírus e Câncer• 1908, Wilhelm Ellerman & Olaf Bang
– Leucemia de galinha podia ser transmitida por inoculação de filtrado de células tumorais
• 1911, F. Peyton Rous– Sarcoma de galinha – Nobel em 1966
• 1936, Bittner– Carcinoma mamário de camundongos causado por vírus
transmitido pela mãe• Gross & Friend
– Vírus relacionado à leucemia de camundongos
Vírus oncogênicos - DNAVírus Doença Câncer
PapovaviridaePapillomavirus (HPV) Poliomavírus murino
Verrugas, verrugas genitais Câncer cervical e uterino
Herpesviridae Vírus Epstein-Barr (HHV4)Vírus do Sarcoma de Kaposi (HHV8)
Mononucleose infecciosaLinfoma de BurkittCarcinoma de nasofaringeSarcoma de Kaposi
Hepadnavirus
Vírus da Hepatite B (HBV) Hepatite B Câncer de fígado
Adenoviridae Adenovírus
Doença respiratória aguda Adenocarcinomas (câncer de tecidos epiteliais glandulares)
Vírus oncogênicos - RNA
Vírus CâncerVírus linfotrópico de célula T humana (HTLV-1; HTLV-2)
Leucemia de células T do adultosLinfomas
Vírus de sarcoma de gatos, galinhas e roedores
Sarcomas (câncer de tecidos conectivos)
Vírus da leucemia felina (FeLV) Leucemia felina
Tumor VirusesTransformation:
• Loss of growth control• Reduced adhesion• Motility• Invasion• Ability to form tumors - viral genes interfere with control of
cell replication and other aspects of the cell phenotype
• Transformed cells frequently exhibit chromosomal aberrations
Classes de genes que quando mutados causam transformação
maligna Oncogenes: Genes responsáveis pela transformação maligna de células (~100)
Anti-Oncogenes ou Supressores Tumorais: genes que quando deletados causam aparecimento de câncer (~10)
A versão celular normal do oncogene é chamada de proto-oncogene (genes celulares homólogos de oncogenes que quando alterados (mutados) levam a transformação)
DNA Tumor Viruses In Human Cancer
ONCOGENEA gene that codes for a protein that potentially can transform
a normal cell into a malignant cell
An oncogene may be transmitted by a virus in which case it is known as a VIRAL ONCOGENE
v-onc c-oncX
RNA Tumor Viruses
Proto-oncogeneA cellular (host) gene that is homologous with a similar gene that is found in a transforming virus
A cellular oncogene can only induce transformation after
• mutation• some other change in the cell’s genome
Classes de proteínas que são codificadas por oncogenes
Fatores de crescimento
Receptores de Fatores de crescimento
Proteínas envolvidadas com a transdução de sinal
Fatores de Transcrição
OncogenesVírus Oncogene
Rous sarcoma virus v-src
Simian sarcoma virus v-sis
Avian erythroblastosis virus v-erbA or v-erbB
Moloney murine sarcoma virus v-mos
MC29 avian myelocytoma virus
v-myc
Kirsten murine sarcoma virus v-kras
Como surgiram os oncogenes retrovirais
DNA Tumor Viruses In Human Cancer
Papilloma Viruses• cause natural cancers in animals• cause benign warts• ubiquitous• epitheliotropic - most human tumors are malignancies of epithelial
cells
DNA Tumor Viruses In Human Cancer
Papilloma Viruses• 51 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)
EPIDEMIOLOGIAL STUDIES BUT:HPV 16 and HPV 18 do transform human keratinocytes
Effective Vaccine(quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in
yeast - Gardasil)
DNA Tumor Viruses In Human Cancer
Polyoma Viruses• Simian virus 40 - juvenile hamster sarcomas, transformation
• contaminação de lotes de vacina contra polio• Polyoma - mouse leukemia, in vitro transformation• Human polyomas (JC and BK) - monkey sarcoma,
transformation
Early functions are necessary - ONCOGENES
Possible association of BK with human prostate cancer
DNA Tumor Viruses In Human CancerAdenoviruses
Highly oncogenic in animals
Always the same partEarly functions
E1A region: 2 T antigensE1B region: 1 T antigen
E1A and E1B = Oncogenes
DNA Tumor Viruses In Human Cancer
Herpes VirusesConsiderable evidence for role in human cancer• Some very tumorigenic in animals
DNA Tumor Viruses In Human Cancer
• Burkitt’s Lymphoma• Endemic
• Non-endemic
• Nasopharyngeal cancer• Infectious mononucleosis (glandular fever) • Transforms human B-lymphocytes in vitro
• Burkitt’s lymphoma: malarial infested regions• Nasopharyngeal cancer: China, SE Asia – diet?
Epstein-Barr Virus
DNA Tumor Viruses In Human CancerHuman herpes virus – 8
Kaposi’s Sarcoma Herpes VirusKaposi’s sarcoma
DNA Tumor Viruses In Human Cancer
Hepatitis B VirusDNA genome
RNA polymerase II
RNA Provirus Reverse transcriptase
DNA genome
Host enzyme
Viral enzyme
DNA Tumor Viruses In Human Cancer
Epidemiology:• Strong correlation between
HBV and hepatocellular carcinoma
• China: 500,000 - 1 million new cases of hepatocellular carcinoma per year
RNA Tumor VirusesRNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virusREVERSE TRANSCRIPTASE
RNA genome
Reverse transcriptase
DNA genome
Integrase
Integrates
Host RNA polymerase II
RNA genome
virus
virus
host
RNA Tumor Viruses
POL: EnzymesReverse transcriptase – RNase H
IntegraseProtease
A normal retrovirus has:3 genes
GAG : internal proteinsENV: Envelope glycoproteins
RNA Tumor Viruses
RNA Tumor VirusesRetroviruses known to cause human cancer
Human T cell lymphotropic virus -1 (HTLV-1)Adult T cell leukemia, Sezary T-cell leukemia
Africa, Caribbean, Some Japanese Islands, S. America (Peru, Bolivia)1-4% of infected people
R U5 GAG POL ENV U3 R
Rous Sarcoma Virus
R U5 GAG POL ENV U3 R
Como retrovírus causam câncer?“typical retrovirus”
SRC
Substituição de 19 aminoácidos do C-terminal por 12 aminoácidos diferentes
Feline Sarcoma Virus (FSV)
R U5 dGAG FMS dENV U3 R
Avian Myelocytoma Virus (MC29)
R U5 dGAG MYC dENV U3 R
Avian Myeloblastosis Virus
R U5 GAG POL MYB U3 R
Some retroviruses have an oncogene instead of their regular genes
RNA Tumor VirusesIn contrast:
No oncogene! – How does it cause a tumor?
R U5 GAG POL ENV U3 R
Avian Leukosis Virus (causes lymphomas)
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)
RNA Tumor Viruses
Could C-oncs be involved in NON-VIRAL cancers?
Cancers often result from gene translocations
Burkitt’s Lymphoma8:14 translocation
Break in chromosome 14 at q32
Acute myelocytic leukemia7:159:18
11:15:17
myc
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)
T cell chronic lymphocytic tcl-1 T cell receptor leukemia (14 inversion)T cell chronic lymphocytic myc T cell receptor (8 to 14)leukemia
Anti-OncogenesRetinoblastoma gene
P53have normal regulatory function in
many cells
Anti-OncogenesRb Gene
RbRb protein
Rb
Stops replication
Rb
Adenovirus E1A
Cell cycle continues
Retinoblastoma
105kD
Anti-Oncogenesp53
P53 gene P53 gene P53 gene
P53
P53 DNA
Stops replication
Hepatitis C
P53
replication replication
Papilloma proteolysis
P53
Papilloma
DNA Tumor VirusesOncogenes
• Adenovirus E1A region 2• SV 40 Large T• Polyoma Large T• BK virus Large T• Lymphotropic virus Large T• Human papilloma Virus-16 E7
All have a sequence in common Mutations in this region abolish transformation capacity
CANSEI!