Prof. Dr.

Aguinaldo Roberto Pinto

Laboratrio de Imunologia Aplicada
MIP/CCB/UFSC
Vrus Oncognicos e Cncer
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
Clula Tumoral
(transformada)
Agentes Carcinognicos: iniciam
ou promovem a formao do
tumor
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 Doena Cncer
Papovaviridae
Papillomavirus (HPV)
Poliomavrus murino
Verrugas, verrugas genitais Cncer cervical e uterino
Herpesviridae
Vrus Epstein-Barr (HHV4)
Vrus do Sarcoma de
Kaposi (HHV8)

Mononucleose infecciosa
Linfoma de Burkitt
Carcinoma de nasofaringe
Sarcoma de Kaposi
Hepadnavirus
Vrus da Hepatite B (HBV)
Hepatite B Cncer de fgado
Adenoviridae
Adenovrus
Doena respiratria aguda Adenocarcinomas (cncer
de tecidos epiteliais
glandulares)
Vrus oncognicos - RNA
Vrus Cncer
Vrus linfotrpico de clula T humana
(HTLV-1; HTLV-2)
Leucemia de clulas T do adultos
Linfomas
Vrus de sarcoma de gatos, galinhas e
roedores
Sarcomas (cncer de tecidos conectivos)
Vrus da leucemia felina (FeLV) 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)
Anti-Oncogenes ou Supressores Tumorais: genes que
quando deletados causam aparecimento de cncer (~10)
A verso celular normal do oncogene chamada de proto-
oncogene (genes celulares homlogos de oncogenes que
quando alterados (mutados) levam a transformao)
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

c-onc

X
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
Classes de
protenas que
so
codificadas
por
oncogenes
Fatores de crescimento
Receptores de Fatores de crescimento
Protenas envolvidadas com a transduo de sinal
Fatores de Transcrio
Oncogenes
Vrus 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
contaminao 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
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

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?
Epstein-Barr Virus
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
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 Viruses

RNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virus
REVERSE TRANSCRIPTASE
RNA genome
Reverse transcriptase
DNA genome
Integrase
Integrates
Host RNA polymerase II
RNA genome
virus
virus
host
RNA Tumor Viruses
POL: Enzymes
Reverse transcriptase RNase H
Integrase
Protease
A normal retrovirus has:
3 genes

GAG : internal proteins
ENV: Envelope glycoproteins
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
R U5 GAG POL ENV U3 R
Rous Sarcoma Virus
R U5 GAG POL ENV U3 R
Como retrovrus causam cncer?
typical retrovirus
SRC
Substituio de 19 aminocidos do C-terminal
por 12 aminocidos 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 Viruses
In contrast:
No oncogene! How does it cause a
tumor?
R U5 GAG POL ENV U3 R
Avian Leukosis Virus (causes lymphomas)
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
Acute myelocytic leukemia
7:15
9:18
11:15:17
myc
Oncogenesis by rearrangement

Tumor c-onc new promotor
Burkitts 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-Oncogenes
Retinoblastoma gene
P53
have normal regulatory function in
many cells

Anti-Oncogenes
Rb Gene
Rb
Rb
protein
Rb
Stops replication
Rb
Adenovirus E1A
Cell cycle continues
Retinoblastoma
105kD
Anti-Oncogenes
p53
P53 gene
P53 gene P53 gene
P53
P53
DNA
Stops replication
Hepatitis C
P53
replication replication
Papilloma
proteolysis
P53
Papilloma
DNA Tumor Viruses
Oncogenes
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!