Vrus Oncognicos e Cncer

Prof. Dr. Aguinaldo Roberto Pinto

Laboratrio de Imunologia Aplicada
MIP/CCB/UFSC

Cncer
Hipcrates, por volta do ano 400 a.C Cncer: As veias que irradiam a partir de alguns tumores de mama assemelham-se com as pernas de um caranguejo. Ele deu molstia o nome de karkinoma (carcinoma), palavra grega que tambm significa caranguejo, e a mesma associao chegou ao latim.

Clulas cancerosas ou tumorignicas

variantes de clulas normais que perderam a habilidade de controlar seu crescimento com as seguintes alteraes: Imortalizao

Transformao

Metstase

Fibroblastos normais (monocamada)

Fibroblastos transformados (arredondados e em colnias)

Clula Normal

Cncer

Estima-se que 6-7 eventos devem ocorrer (em ~20-40 anos) para induo do cncer (alteraes genticas e epigenticas) em certos casos a propenso ao cncer hereditria

Clula Normal Agentes Carcinognicos: iniciam ou promovem a formao do tumor

Clula Tumoral (transformada)

Fatores carcinognicos
Fumo
pulmo, esfago, bexiga e pncreas

Hbitos alimentares (gorduras saturadas e fibras)

clon

Obesidade
endomtrio, clon, rim, vescula

lcool
trato digestivo e respiratrio

Vrus

Vrus e Cncer
1908, Wilhelm Ellerman & Olaf Bang
Leucemia de galinha podia ser transmitida por inoculao de filtrado de clulas tumorais

1911, F. Peyton Rous

Sarcoma de galinha Nobel em 1966

Vrus e Cncer
1908, Wilhelm Ellerman & Olaf Bang
Leucemia de galinha podia ser transmitida por inoculao de filtrado de clulas tumorais

1911, F. Peyton Rous

Sarcoma de galinha Nobel em 1966

1936, Bittner
Carcinoma mamrio de camundongos causado por vrus transmitido pela me

Gross & Friend

Vrus relacionado leucemia de camundongos

Vrus oncognicos - DNA

Vrus
Papovaviridae Papillomavirus (HPV) Poliomavrus murino

Doena
Verrugas, verrugas genitais

Cncer
Cncer cervical e uterino

Herpesviridae Vrus Epstein-Barr (HHV4) Mononucleose infecciosa Vrus do Sarcoma de Kaposi (HHV8) Hepadnavirus Vrus da Hepatite B (HBV) Adenoviridae Adenovrus Doena respiratria aguda Hepatite B

Linfoma de Burkitt Carcinoma de nasofaringe Sarcoma de Kaposi Cncer de fgado

Adenocarcinomas (cncer de tecidos epiteliais glandulares)

Vrus oncognicos - RNA

Vrus
Vrus linfotrpico de clula T humana (HTLV-1; HTLV-2) Vrus de sarcoma de gatos, galinhas e roedores Vrus da leucemia felina (FeLV)

Cncer
Leucemia de clulas T do adultos Linfomas Sarcomas (cncer de tecidos conectivos)

Leucemia felina

Tumor Viruses
Transformation:
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 transformao maligna

Oncogenes: Genes responsveis pela transformao maligna de clulas (~100)
A verso celular normal do oncogene chamada de protooncogene (genes celulares homlogos de oncogenes que quando alterados (mutados) levam a transformao)

Anti-Oncogenes ou Supressores Tumorais: genes que quando deletados causam aparecimento de cncer (~10)

DNA Tumor Viruses In Human Cancer

ONCOGENE
A 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 X

c-onc

RNA Tumor Viruses

Proto-oncogene
A 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 cells genome

Fatores de crescimento

Receptores de Fatores de crescimento

Classes de protenas que so codificadas por oncogenes

Protenas envolvidadas com a transduo de sinal

Fatores de Transcrio

Oncogenes
Vrus
Rous sarcoma virus Simian sarcoma virus Avian erythroblastosis virus Moloney murine sarcoma virus MC29 avian myelocytoma virus Kirsten murine sarcoma virus

Oncogene
v-src v-sis v-erbA or v-erbB v-mos v-myc 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 contaminao de lotes de vacina contra polio

Polyoma - mouse leukemia, in vitro transformation

Human polyomas (JC and BK) - monkey sarcoma, transformation Possible association of BK with human prostate cancer Early functions are necessary - ONCOGENES

DNA Tumor Viruses In Human Cancer

Adenoviruses
Highly oncogenic in animals

Always the same part Early functions E1A region: 2 T antigens E1B region: 1 T antigen E1A and E1B = Oncogenes

DNA Tumor Viruses In Human Cancer

Herpes Viruses
Considerable evidence for role in human cancer
Some very tumorigenic in animals

DNA Tumor Viruses In Human Cancer

Epstein-Barr Virus
Burkitts Lymphoma
Endemic

Non-endemic

Nasopharyngeal cancer Infectious mononucleosis (glandular fever)

Transforms human B-lymphocytes in vitro

Burkitts lymphoma: malarial infested regions Nasopharyngeal cancer: China, SE Asia diet?

DNA Tumor Viruses In Human Cancer

Human herpes virus 8 Kaposis Sarcoma Herpes Virus
Kaposis sarcoma

DNA Tumor Viruses In Human Cancer

Hepatitis B Virus
DNA genome
RNA polymerase II Host enzyme

RNA Provirus
Reverse transcriptase

DNA genome

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 Viruses

RNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virus REVERSE TRANSCRIPTASE RNA genome
Reverse transcriptase
virus

DNA genome
Integrase
virus

Integrates
Host RNA polymerase II
host

RNA genome

RNA Tumor Viruses

A normal retrovirus has: 3 genes GAG : internal proteins

ENV: Envelope glycoproteins POL: Enzymes

Reverse transcriptase RNase H Integrase

Protease

RNA Tumor Viruses

RNA Tumor Viruses

Retroviruses 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

Como retrovrus causam cncer?

typical retrovirus

U5

GAG

POL

ENV

U3

Rous Sarcoma Virus

R U5 GAG POL ENV SRC U3 R

Substituio de 19 aminocidos do C-terminal por 12 aminocidos diferentes

Some retroviruses have an oncogene instead of their regular genes

Avian Myeloblastosis Virus
R U5 GAG POL MYB U3 R

Feline Sarcoma Virus (FSV) R U5

dGAG

FMS

dENV

U3

Avian Myelocytoma Virus (MC29)

U5

dGAG

MYC

dENV

U3

RNA Tumor Viruses

In contrast:
Avian Leukosis Virus (causes lymphomas)

U5

GAG

POL

ENV

U3

No oncogene! How does it cause a tumor?

RNA Tumor Viruses

ALV can integrate into the host cell genome at MANY locations but 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 Burkitts Lymphoma

8:14 translocation Break in chromosome 14 at q32

myc

Acute myelocytic leukemia 7:15 9:18 11:15:17

Oncogenesis by rearrangement
Tumor
Burkitts lymphoma
B-cell chronic lymphocytic
leukemia T cell chronic lymphocytic

c-onc
myc
bcl-1
bcl-2 tcl-1
(8)

new promotor
Ig heavy (8 to 14) Ig light (8 to 2)
Ig heavy (11 to 14)
Ig heavy (18 to 14) T cell receptor

leukemia
T cell chronic lymphocytic leukemia myc

(14 inversion)
T cell receptor (8 to 14)

Anti-Oncogenes
Retinoblastoma gene
P53 have normal regulatory function in many cells

Anti-Oncogenes
Retinoblastoma Rb Gene Adenovirus E1A

Rb protein

Rb

105kD Rb

Rb

Stops replication

Cell cycle continues

Anti-Oncogenes
p53
P53 gene

P53 gene
Hepatitis C

P53 gene
Papilloma

P53

P53

P53

Papilloma proteolysis
P53 DNA

Stops replication

replication

replication

DNA Tumor Viruses Oncogenes

Adenovirus SV 40 Polyoma BK virus Lymphotropic virus Human papilloma Virus-16 E1A region 2 Large T Large T Large T Large T E7

All have a sequence in common Mutations in this region abolish transformation capacity

CANSEI!