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Prof. Dr. Aguinaldo Roberto Pinto Laboratório de Imunologia Aplicada MIP/CCB/UFSC Vírus Oncogênicos e Câncer

Virus Oncogenicos e Cancer

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Page 1: Virus Oncogenicos e Cancer

Prof. Dr. Aguinaldo Roberto PintoLaboratório de Imunologia Aplicada

MIP/CCB/UFSC

Vírus Oncogênicos e Câncer

Page 2: Virus Oncogenicos e Cancer

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.

Page 3: Virus Oncogenicos e Cancer

Células cancerosas ou tumorigênicasvariantes de células normais que perderam a

habilidade de controlar seu crescimento com as seguintes alterações:

Imortalização

Transformação

Metástase

Page 4: Virus Oncogenicos e Cancer

Fibroblastos normais (monocamada)

Fibroblastos transformados (arredondados e em colônias)

Page 5: Virus Oncogenicos e Cancer

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

Page 6: Virus Oncogenicos e Cancer

Célula Normal

Célula Tumoral (transformada)

Agentes Carcinogênicos: iniciam ou promovem a

formação do tumor

Page 7: Virus Oncogenicos e Cancer

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

Page 8: Virus Oncogenicos e Cancer

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

Page 9: Virus Oncogenicos e Cancer
Page 10: Virus Oncogenicos e Cancer

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

Page 11: Virus Oncogenicos e Cancer

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)

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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

Page 13: Virus Oncogenicos e Cancer

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

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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)

Page 16: Virus Oncogenicos e Cancer

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

Page 17: Virus Oncogenicos e Cancer

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

Page 18: Virus Oncogenicos e Cancer

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

Page 19: Virus Oncogenicos e Cancer

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

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Como surgiram os oncogenes retrovirais

Page 21: Virus Oncogenicos e Cancer
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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

Page 23: Virus Oncogenicos e Cancer

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)

Page 24: Virus Oncogenicos e Cancer

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

Page 25: Virus Oncogenicos e 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

Page 26: Virus Oncogenicos e Cancer

DNA Tumor Viruses In Human Cancer

Herpes VirusesConsiderable evidence for role in human cancer• Some very tumorigenic in animals

Page 27: Virus Oncogenicos e Cancer

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

Page 28: Virus Oncogenicos e Cancer

DNA Tumor Viruses In Human CancerHuman herpes virus – 8

Kaposi’s Sarcoma Herpes VirusKaposi’s sarcoma

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DNA Tumor Viruses In Human Cancer

Hepatitis B VirusDNA genome

RNA polymerase II

RNA Provirus Reverse transcriptase

DNA genome

Host enzyme

Viral enzyme

Page 30: Virus Oncogenicos e Cancer

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

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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

Page 32: Virus Oncogenicos e Cancer

RNA Tumor Viruses

POL: EnzymesReverse transcriptase – RNase H

IntegraseProtease

A normal retrovirus has:3 genes

GAG : internal proteinsENV: Envelope glycoproteins

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RNA Tumor Viruses

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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

Page 35: Virus Oncogenicos e Cancer

R U5 GAG POL ENV U3 R

Rous Sarcoma Virus

R U5 GAG POL ENV U3 R

Como retrovírus causam câncer?“typical retrovirus”

SRC

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Substituição de 19 aminoácidos do C-terminal por 12 aminoácidos diferentes

Page 37: Virus Oncogenicos e Cancer

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

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RNA Tumor VirusesIn contrast:

No oncogene! – How does it cause a tumor?

R U5 GAG POL ENV U3 R

Avian Leukosis Virus (causes lymphomas)

Page 39: Virus Oncogenicos e Cancer

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)

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RNA Tumor Viruses

Could C-oncs be involved in NON-VIRAL cancers?

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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

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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

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Anti-OncogenesRetinoblastoma gene

P53have normal regulatory function in

many cells

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Anti-OncogenesRb Gene

RbRb protein

Rb

Stops replication

Rb

Adenovirus E1A

Cell cycle continues

Retinoblastoma

105kD

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Anti-Oncogenesp53

P53 gene P53 gene P53 gene

P53

P53 DNA

Stops replication

Hepatitis C

P53

replication replication

Papilloma proteolysis

P53

Papilloma

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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

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CANSEI!