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!