virusuri si cancere
TRANSCRIPT
![Page 1: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/1.jpg)
1
VIRUSURI SI CANCERE
![Page 2: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/2.jpg)
CARACTERELE CELULELOR TRANSFORMATE
• MORFOLOGICE: aspect, forma variabila, raport N/C, fara inhibitie de
contact, independente de ancorare, aberatii cromozomiale, telomeraza activa
•BIOCHIMICE:glicoliza anaeroba, autocrine, modificari in kinetica
mesagerilor secundari
•ANTIGENICE: NEOANTIGENE codificate de •Gazda: antigene oncofetale (antigen carcinoembrionar; alfa fetoproteina)
•Virusuri: (TSTA-tumor specific transplantation antigens) produse in cursul
infectiei abortive, persistente
![Page 3: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/3.jpg)
Premiul Nobel pentru Medicina 2009
Elizabeth H. Blackburn (USA); Carol W. Greider (USA); Jack W. Szostak (USA)
“for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”
![Page 4: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/4.jpg)
Inactivarea antioncogenelor (p53, Rb)
Rb
CARCINOGENEZA-pierderea controlului ciclului celular
Activarea aberanta a protooncogenelor
RETROVIRUSURI, EBV, HBV HPV
HHV8
Sinteza unor gene
ce mimeaza
complexele cicline-
cdk
![Page 5: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/5.jpg)
VIRUSURI SI CANCERE
RETROVIRIDAE-ONCOVIRINAE
HEPADNAVIRIDAE- VHB
HERPESVIRIDAE- EBV; HHV8
PAPOVAVIRIDAE-PAPILOMAVIRINAE
![Page 6: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/6.jpg)
RETROVIRUSURI ONCOGENE ONCOVIRUSURI
• TRANSFORMANTE in vitro si rapid
oncogene in vivo • au oncogene
• replicare defectiva (cu exceptia Virusului
Sarcomului Rous)
•NON-TRANSFORMANTE in vitro si
lent oncogene in vivo • nu au oncogene
• carcinogeneza prin ACTIVARE INSERTIONALA
Genom ARN
Rt
ADN proviral
Integraza +LTR
Integrare in genom celular
cofactori activatori
genom ARN +PROTEINE
RETROVIRUSURI- ONCOVIRINAE; lentivirinae (HIV) , Spumavirinae
![Page 7: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/7.jpg)
7
LTR U5 GAG POL ENV U3 LTR
LTR U5 GAG POL ENV U3 LTR
gene suplimentare-v-onc
retrovirus “ tipic”
Oncogena
ONCOGENE –gene ce
codifica o proteina
capabila sa induca
transformare celulara in
vitro /in vivo
ONCOVIRUSURI TRANSFORMANTE in vitro
![Page 8: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/8.jpg)
8
Genom ARN
Reverstranscriptaza
ADN proviral
Integraza
integrare ADN celular
transformare celulara
RETROVIRIDAE ONCOVIRINAE
v-onc
v-onc
v-onc
ONCOVIRUSURI TRANSFORMANTE in
vitro, rapid oncogene in vivo-v-onc
integrat in genomul celular induce
transformare celulara
![Page 9: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/9.jpg)
9
ONCOGENE Premiul Nobel pentru medicina sau fiziologie
1989-J. Michael Bishop si Harold E. Varmus – descopera originea celulara a oncogenelor retrovirale
PROTO-ONCOGENE (ONCOGENE CELULARE)- c-onc
Gene reglatorii implicate in controlul ciclului celular
ONCOGENE VIRALE-v-onc-Deriva din protooncogene
--fara introni
-Nu sunt sub actiunea reglatorie a promotorilor celulari
-Mutatii sau deletii ce altereaza produsul proteic
-Produs v-onc e exprimat fuzionat cu alte proteine virale
Retrovirusuri endogene (ERV) -8% din ADN uman reprezinta genom retroviral fosil
+ elemente LINE (long interspersed repetitive/nuclear elements) si alti
retrotranspozoni
![Page 10: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/10.jpg)
PROTO-ONCOGENELE
•Factori de crestere PDGF ~sis
•Receptori pentru factori de crestere:
EGFR, HER2/neu ~ erb B
•Mesageri secundari:
PTK mb: src
PTK solubile, citoplasmatice: ras
Factori de Transcriere: jun,fos, myc
Proto-oncogenele RAS (K-RAS, N-RAS, H-RAS,)
sunt activate prin mutatii punctiforme in > 20% din
cancerele umane ( pancreatic, pulmonar , colon)
Codifica proteine implicate in controlul cresterii si diferentierii celulare
![Page 11: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/11.jpg)
RETROVIRUSURI NON-TRANSFORMANTE –nu au oncogene virale, dar integrarea provirusului ADN se realizeaza intotdeauna langa o protooncogena, care trece
sub controlul promotorului transcriptional viral- activare aberanta
R U5 GAG POL ENV U3 R
ALV-Avian Leukosis Virus
in cazul tumorilor ALV se integreaza in genom celular INTOTDEAUNA in ACELASI LOC- linga
C-myc! - Expresie aberanta/Supraexpresia produs proteic
ONCOGENEZA PRIN ACTIVARE INSERTIONALA
Genom ARN
Rt
ADN proviral
Integraza
Integrare langa o
protooncogena
![Page 12: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/12.jpg)
12
Avian leukosis virus;
Rous sarcoma virus
Murine leukemia virus;
Feline leukemia virus
Bovine leukemia virus;
Human T-lymphotropic virus
Walleye dermal sarcoma virus
Oncovirusuri:
Human T cell lymphotropic virus -1 (HTLV-1)- Adult T
cell leukemia, Sezary T-cell leukemia (Africa, Caribbean,
Japanese Islands)
Human T cell lymphotropic virus -2 (HTLV-2)- Hairy cell
leukemia
Tax activator transcriptional al LTR
Transactiveaza promotori celulari ai sintezei citokinelor
(IL13; IL15); ai receptorilor pentru citokine; molecule
costimulatorii
Stimuleaza crestere celulara prin legare directa de CDK
![Page 13: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/13.jpg)
VIRUSURI ONCOGENE ADN
genom viral ADN
ARN polimeraza
celulara
ARNm viral
INFECTIE PERSISTENTA- Supraexpresia proteinelor virale timpurii
ADN polimeraza
ADN-dependenta
(celulara sau virala)
TRANSFORMARE CELULARA
![Page 14: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/14.jpg)
HEPADNAVIRIDAE- VHB CHP - a 5-a localizare ca frecvenţã a bolii canceroase şi a 3-a ca mortalitate
Incidenţa anualã a CHP, 500 000 cazuri
jumãtate din CHP sunt asociate infecţiei persistente cu VHB
purtãtorii cronici de AgHBs au un risc de 25-37 x > de CHP
China: 500,000 - 1 milioane cazuri noi de CHP/an;
Taiwan: RR CHP de 217 x > la purtatori cronici AgHBs
Incãrcarea viralã; genotipul B peste 50% din cazurile CHP în Taiwan
Factori alimentari- aflatoxina B1- metabolit al ciupercii Aspergillus flavus care
contamineazã hrana vegetalã -substanţe care rup helixul ADN.
In Europa, 90% din CHP dupa ciroza avansate
Coinfecţia cu VHC, HIV
Obezitatea, diabetul,alcoolism
Proces
multifactorial:
![Page 15: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/15.jpg)
•Genomul viral poate induce deleţii în genomul
hepatocitar la situl de integrare--gene care afecteazã
ciclul celular, viabilitatea celularã sau cascade de
semnalizare membranã –nucleu
•Amplificarea genica a unui segment de ADN ce contine
protooncogena-supraexpresia proteinei
•Translocatii cromozomiale ce aduc proto-oncogena sub
controlul unui promotor diferit- expresie aberanta
Proteinele reglatorii codificate
de genele X si pre S2-
hiperexpresia unor inhibitori
ai apoptozei
Genom ADN
RNA polymerase II
ARNm
Reverstranscriptaza
genom ADN si ADNccc integrat
![Page 16: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/16.jpg)
HHV8-gene virale omologe ciclinelor
HERPESVIRIDAE HHV8-SARCOMUL KAPOSI
![Page 17: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/17.jpg)
HERPES VIRUSURI
Epstein-Barr Virus
• Limfom Burkitt
• Carcinom Nasofaringean
•Boala limfoproliferativa
• Transforma limfocitele B umane in vitro
HIPEREXPRESIA UNOR PROTEINE VIRALE TIMPURII:
•FACTORI DE CRESTERE AUTOCRINI PT. LIMFOCITELE B
•RECEPTORI AI FACTORILOR DE CRESTERE
•ACTIVATORI AI UNOR ONCOGENE CELULARE
LIMFOM BURKITT- Latenta cu antigene virale asociate EBNA - Epstein Barr nuclear antigens Boala limfoproliferativã post transplant. antigene asociate LMP – latent membrane proteins,
![Page 18: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/18.jpg)
Procesele neoplazice apar frecvent ca rezultat al translocarii genelor
Limfom Burkitt
Translocatie 8:14
Leucemie mielocitara acuta
7:15
9:18
11:15:17
myc
fes
myc myb
![Page 19: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/19.jpg)
INFECTIE LITICA –productiva
in celule permisive-stratul extern
INFECTIA PERSISTENTA –in
celule nonpermisive din stratul bazal
TRANSFORMARE
PAPILOMAVIRUSURI
![Page 20: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/20.jpg)
Woodman et al. Nature Reviews Cancer 7, 11–22 (January 2007) | doi:10.1038/nrc2050
Genomul HPV mentinut in stare
episomala, expresia secventiala a
genelor timpurii E1-E5, si a genelor
tardive, structurale- L1, L2
INFECTIE LITICA – infectia productiva in celule
permisive din stratul extern ce se exfoliaza
![Page 21: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/21.jpg)
Woodman et al. Nature Reviews Cancer 7, 11–22 (January 2007) | doi:10.1038/nrc2050
INFECTIA
PERSISTENTA in celule
nonpermisive din stratul bazal cu
TRANSFORMARE
Genom HPV integrat– Supraexpresia genelor E6 si E7-pierdere control ciclu celular
gena LCR- Controlul expresiei genelor virale) -contine “enhanceri” care pot fi activati de factori celulari sau virali
![Page 22: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/22.jpg)
E6 HPV- asociat cu P53 =degradare la nivel
proteazom -pierderea controlului ciclinelor –
progresie necontrolata in ciclul celular
E7 HPV asociat cu Rb =
inactivare-eliberare E2F- activare
necontrolata a genelor implicate
in sinteza ADN (c-myc , c-fos,
ADN polimeraza).
Supraexpresia genelor E6 si E7-inactivarea antioncogenelor p53 si Rb- pierdere control ciclu celular
![Page 23: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/23.jpg)
23
papiloame cutanate si mucoase INFECTIA LITICA HPV
papiloame genitale- condiloma accuminata Incubatie variabila (2->6 luni)
Infectie asimptomatica posibila
Infectie multipla posibila
Localizare–uretra, penis, scrot, vulva,
vagin, cervix, perineu, perianal
(autoinoculare; sex nonpenetrativ)
![Page 24: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/24.jpg)
24
Nu orice infectie HPV conduce la aparitia cancerului de col uterin. Majoritatea infectiilor sunt tranzitorii,
autolimitante. DAR, infectii persistente cu HPV genotipuri cu risc oncogen inalt se gasesc la > 95% din
femeile cu cancer de col uterin
Premiul Nobel pentru Medicina 2008- Harald zur Hausen (German Cancer Research Centre Heidelberg)--
rolul etiologic al HPV de risc inalt in aparitia cancerului de col uterin
HPV Risc oncogen inalt :
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68,
73, 82
LGSIL; HSIL ; cancer col uterin ; alte cancere
anogenitale, cancer cap-gat
LSIL-low-grade squamous intraepithelial cells
HSIL-high grade squamous intraepithelial cells
HPV Risc oncogen scazut:
6, 11, 40, 42, 43, 44 , 54, 61, 70, 72, 81
displazie cervicala usoara;
condiloma accuminata; papilomatoza
respiratorie recurenta
![Page 25: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/25.jpg)
LSIL (low-grade squamous intraepithelial cells)
displazie usoara, CIN I (Cervical intraepithelial
neoplasia) - Colposcopie si biopsie
HSIL (high grade squamous intraepithelial cells),
displazie moderata/severa, CIN II/III,carcinom in
situ- Colposcopie si biopsie si/sau chiuretaj
endocervical
Tratament cu LEEP, crioterapie, laser, conizatie
sau histerectomie
Screening
Citologie Pap conventionala sau in faza
lichida +/- testare ADN HPV si genotipare
La 3 ani de la inceperea vietii sexuale/ sau la 21
ani
Progresia de la infectia HPV persistenta la cancer invaziv 10-15 ani. Leziuni cervicale pre-invasive
gradate pe baza aspectului histopatologic CIN 1 -CIN 3 (cea mai scazuta probabilitate de regresie
spontana)
Incidenta cancer cervical
pre-PAP 30- 40/100 000
post PAP 8.8/ 100 000 (cca 75% reducere)
![Page 26: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/26.jpg)
26
CANCER DE COL UTERIN
ROMANIA
3 448 CAZURI NOI/AN
2 094 DECESE/AN
RATA STANDARDIZATA PE VARSTA- 23.9 / 100 000 FEMEI
RATA MORTALITATII 13 / 100 000 FEMEI
Sursa: IARC Globocan Cancer Base No. 5, version 2.0., 2002 Cancer incidence,
mortality and prevalence worldwide. (http://www-
dep.iarc.fr/globocan/downloads.htm, accessed 26 March 2008).
![Page 27: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/27.jpg)
27
Site
HPV
(%)
HPV 16,
18 (%)
% of all
cancers
Cervix 100 70 3.18
Penis 40 63 0.06
Vulva, vagina 40 80 0.12
Anus 90 92 0.23
Mouth 3 95 0.07
Oro-pharynx 12 89 0.05
Source: Parkin DM, Bray F. Vaccine, 2006, 24(Suppl. 3):S11–S25.
![Page 28: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/28.jpg)
28
VACCIN ANTI HPV RECOMBINANT - PARTICULE "VIRUS-LIKE“ (VLP)-PROTEINA CAPSIDARA MAJORA L1 ANTICORPI NEUTRALIZANTI SPECIFICI DE TIP
![Page 29: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/29.jpg)
VACCINAREA ANTI HPV- PROFILACTIC
GARDASIL Merck-cvadrivalent- genotipurile HPV 16/18; HPV 6/11-
– 3 doze 0, 2 ,6 luni-acceptat iunie 2006 de FDA si septembrie 2006 de EMEA (vaccinarea fetelor cu varste 9-15 ani)
– introdus in UE (27 tari)- din octombrie 2007 si alte tari din regiunea europeana OMS (Bosnia si Herzegovina, Croatia, Islanda, Israel, Liechtenstein, Norvegia, Rusia, Serbia, Elvetia, FYR Macedonia, Turcia.) .
– Protectie impotriva displaziei cervicale si vulvare de grad inalt, cancer cervical si
papiloame genitale produse de infectia cu HPV 6, 11, 16, 18
CERVARIX® Glaxo Smith Kline - bivalent genotipurile HPV 16/18 In Septemberie
2007, autorizatie de marketing de la EMEA pentru prevenirea leziunilor cervicale
precanceroase (CIN grad 2 si 3) si cancer cervical determinat de infectia cu HPV 16 si 18
Din Octombrie 2007, inregistrat si in Islanda, Kazakhstan si Norvegia
– a 2a jumatate a lui 2009 in SUA
29
![Page 30: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/30.jpg)
30
Postvaccinare - raspuns umoral cu titru inalt de anticorpi (de 10- 10 000 de ori > decat in
infectiile naturale)
![Page 31: Virusuri Si Cancere](https://reader034.vdocuments.pub/reader034/viewer/2022042512/55cf9924550346d0339bd316/html5/thumbnails/31.jpg)
VACCINURI ANTI HPV INFORMATII DIN STUDII PRELIMINARE
– inalt imunogene si sigure, protectie pentru 5 ani- 98% seropozitivitate anti HPV-16/18
– 96.9% eficienta impotriva aparitiei de noi infectii cu HPV16 ; HPV18
– 94.3% impotriva persistentei infectiei
– 100% eficienta impotriva leziunilor de neoplazie cervicala intraepiteliala
– protectie impotriva dezvoltarii altor leziuni histologice si impotriva infectiilor noi cu genotipuri inrudite structural
– HPV 31, 33, 52, 58 similare HPV 16
– HPV 39, 45, 59 similare HPV 18
• 17 ţări din Uniunea Europeană au recomandari privind introducerea vaccinului împotriva cancerului de col uterin în calendarele naţionale de vaccinare: Austria, Belgia, Danemarca, Germania, Marea Britanie, Franţa, Italia, Spania, Grecia, Irlanda, Luxemburg, Norvegia, Olanda, Portugalia, Suedia, Elvetia. La acestea se adaugă SUA, Canada, Australia, etc.
31
VACCINAREA NU INLOCUIESTE SCREENINGUL CITOLOGIC/VIRUSOLOGIC PERIODIC SI NU TREBUIE SA AFECTEZA MASURILE DE PROFILAXIE IMPOTRIVA BTS