Apresenta

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

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Células cancerosas ou tumorigênicas variantes de
células normais que perderam a habilidade de
controlar seu crescimento com as seguintes
alterações
Imortalização Transformação
Metástase
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Fibroblastos normais (monocamada)
Fibroblastos transformados (arredondados e em
colônias)
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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

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Célula Normal
Agentes Carcinogênicos iniciam ou promovem a
formação do tumor
Célula Tumoral (transformada)
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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

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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

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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

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Vírus oncogênicos - DNA
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Vírus oncogênicos - RNA
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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

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Classes de genes que quando mutados causam
transformação maligna

• Oncogenes Genes responsáveis pela
  transformação maligna de células (100)

A versão celular normal do oncogene é chamada de
proto-oncogene (genes celulares homólogos de
oncogenes que quando alterados (mutados) levam a
transformação)

• Anti-Oncogenes ou Supressores Tumorais genes
  que quando deletados causam aparecimento de
  câncer (10)

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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
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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

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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
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Oncogenes
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Como surgiram os oncogenes retrovirais
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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

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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)
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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

Possible association of BK with human prostate
cancer
Early functions are necessary - ONCOGENES
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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
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DNA Tumor Viruses In Human Cancer

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

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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?

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DNA Tumor Viruses In Human Cancer
Human herpes virus 8 Kaposis Sarcoma Herpes
Virus
Kaposis sarcoma
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DNA Tumor Viruses In Human Cancer
Host enzyme
Viral enzyme
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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 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
host
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RNA Tumor Viruses
A normal retrovirus has 3 genes
GAG internal proteins
ENV Envelope glycoproteins
POL Enzymes Reverse transcriptase RNase
H Integrase Protease
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RNA Tumor Viruses
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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
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Como retrovírus causam câncer?
typical retrovirus
R U5 GAG POL ENV
U3 R
SRC
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Substituição de 19 aminoácidos do C-terminal por
12 aminoácidos diferentes
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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 R
Avian Myelocytoma Virus (MC29)
R U5 dGAG MYC
dENV U3 R
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RNA Tumor Viruses
In contrast
No oncogene! How does it cause a tumor?
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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)
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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
Burkitts Lymphoma 814 translocation Break in
chromosome 14 at q32
myc
Acute myelocytic leukemia715918111517
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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
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Anti-Oncogenes
Retinoblastoma gene P53 have normal regulatory
function in many cells
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Anti-Oncogenes
Retinoblastoma
Adenovirus E1A
Rb Gene
Rb protein
Rb
105kD
Rb
Rb
Cell cycle continues
Stops replication
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Anti-Oncogenes
p53
P53 gene
P53 gene
P53 gene
Papilloma
Hepatitis C
P53
P53
P53
Papilloma proteolysis
P53
DNA
Stops replication
replication
replication
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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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