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HPV: Understanding oncogenic mechanisms -

HPV: Understanding oncogenic mechanisms -. José Eleutério Junior Prof. Adjunto – Ginecologia – FAMED - UFC. HPV: Understanding oncogenic mechanisms -. Rigoni-Stern (1842) Death certificates of women in Verona between 1760-1839.

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HPV: Understanding oncogenic mechanisms -

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  1. HPV: Understanding oncogenic mechanisms - José Eleutério Junior Prof. Adjunto – Ginecologia – FAMED - UFC

  2. HPV: Understanding oncogenic mechanisms - • Rigoni-Stern (1842) • Death certificates of women in Verona between 1760-1839. • High frequency of cervical cancer in married women, widows and prostitutes. Rare in virgins and nuns.

  3. HPV: Understanding oncogenic mechanisms - • First reports characterizing the double stranded circular DNA of HPV (Crawfor, 1965; Klug and Finch, 1965). • An early suggestion for antigenic differences between cutaneous and genital wart papillomavirus particles originated from electon microscopic analysis of particle agglutination studies (Almeida et al, 1969)

  4. Harald zur Hausen’s laboratory was the first to demonstrate that genital warts contain human papillomavirus (HPV) genomes. Subsequent low-stringency hybridization experiments with HPV sequences isolated from genital warts performed in his laboratory led to the discovery of related HPV sequences in cervical cancer tissues .

  5. 35 Worldwide Incidence of Cancers Attributable to HPV 30 25 20 15 10 5 0 HPV association Estimatuive to new cases, USA (2006) CERVIX+,1,2 Vaginal/ Vulvar2,4 Penile2,4 Anal 2,4 Oro- Pharyngeal2-4 Larynx and aerodigestive tract2,4 1. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19. 2. American Cancer Society. Disponível em: http://www.câncer.org. Acessado em 30 de março de 2006.3. Herrero R, Castellsagué X, Pawlita M, et al. J Natl Cancer Inst. 2003;95:1772–1783. 4. World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1–22.

  6. Common Cancers in Women Adapted from Parkin et al, Eur J Cancer 37:S4, 2001

  7. HPV: Understanding oncogenic mechanisms - • Papillomaviruses are small nonenveloped viruses with 55- nm-diameter • icosahedral capsids that contain double-stranded DNA genomes of approximately 8,000 bp. Münger et al, 2004

  8. HPV6&11 HPV18 70% of cervical cancers HPV16 90% of genital warts HPVs Are a Diverse Family cutaneous, mostly asymptomatic foot warts genital mucosa, cancer- associated hand warts >75% lifetime infection risk! genital warts

  9. HPV: Understanding oncogenic mechanisms - • Approximately 200 different HPVs have now been characterized, and new types are regularly added to this list. Münger et al, 2004

  10. Estimates of worldwide incidence of HPV - Diseases and Related Diagnoses Cancer of the cervix: 0.493 million at 2002 1 Lesions pre-cancerous high-grade: 10 million2 Cervical lesions of low grade: 30 million2 Genital warts: 30 million3 Attributed to oncogenic types of HPV Attributed to non-oncogenic types of HPV HPV infection without detectable abnormalities: 300 million2 1. Parkin DM, Bray F, Ferlay J, Pisani P. CA Cancer J Clin 2005;55:74–108. 2. World Health Organization. Genebra, Suíça: World Health Organization; 1999:1–22. 3. World Health Organization. WHO Office of Information. WHO Features 1990;152:1–6.

  11. Rates of infection with HPV and Cervical Cancer-Specific Age+,1 25 20 (n= 3752) HPV prevalence (%) 15 Cancer Incidence Rate(×105) 10 5 0 +Two different cohorts (transversal study) followed for the same period to measure the rate of HPV infection in a high-risk and the rate of cervical cancer in another. 1. Adaptado de Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV. J Clin Pathol. 2002;55:244–265, sob permissão de BMJ Publishing Group.

  12. Cancer of the uterine cervix Endogenous hormones Contraceptive High parity Smoking HIV Diet Genetic factors Co-infection with other sexually transmited diseases HPV Established and Potential Associated Factors Involved in Carcinogenesis of HPV1 1. Adaptado de Castellsagué X, Muñoz N. J Natl Cancer Inst Monogr 2003;31:20–28.

  13. Risk of Cervical Cancer by Type of HPV1 0,1 10 100 1000 10.000 HPV Negative 16 18 45 31 52 33 58 35 59 51 6 11 Probability (CI 95%++) 1. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527.

  14. HPV: Understanding oncogenic mechanisms - • Low-risk mucosal HPVs such as HPV-6 and HPV-11 cause genital warts (condyloma accuminata).

  15. HPV: Understanding oncogenic mechanisms - • High-risk HPVs cause squamous intraepithelial lesions that can progress to invasive squamous cell carcinoma.

  16. HPV: Understanding oncogenic mechanisms - • HPV-16 is by far the most prevalent mucosal high-risk HPV type, followed by HPV-18, HPV-31, and others

  17. Progression to Cancer is Accompanied by Deregulation of Viral Gene Expression CIN 1 CIN 2 CIN 3 Common molecular events: •Viral genome integration into cellular DNA •Loss of E2 leads to increased E6/E7 expression Doorbar, J Clin Virol 32:7-15, 2005

  18. Precursor Lesions of Cervical Carcinoma Cytology: LSIL HSIL Histology: CIN 1 CIN 2 CIN 3 Mild Moderate Severe Carcinoma NormalDysplasia Dysplasia Dysplasia in situ Productive HPV Infection Non-Productive Integration High E6 & E7 (p53) (pRb) X X LSIL = Low Grade Squamous Intraepithelial Lesion CIN = Cervical Intraepithelial Neoplasia HSIL = High Grade Squamous Intraepithelial Lesion

  19. HPV: Understanding oncogenic mechanisms - • Papillomaviruses initially infect basal epithelial cells, which constitute the only cell layer in an epithelium that is actively dividing. The nature of the HPV receptor(s) remains unclear, although integrin has been implicated. Münger et al, 2004

  20. Woodman et al. Nature Reviews Cancer 7, 11–22 (January 2007) | doi:10.1038/nrc2050

  21. HPV: Understanding oncogenic mechanisms - • Cervical carcinogenesis thus is a multifactorial process and involves genetic, environmental, hormonal and immunological factors in addition to HPV. • Stanley, 2003

  22. HPV: Understanding oncogenic mechanisms - • Schreiber and colleagues have proposed the use of a broader term “cancer immunoediting” comprising of three phases termed the “three Es” - Elimination, Equilibrium, and Escape. • Schreiber, 2005

  23. Jayshree et al, 2009

  24. HPV: Understanding oncogenic mechanisms - • Cell intrinsic phenomena in HPV-induced cervical carcinogenesis • HPV integration • HPV oncoproteins deregulate cell cycle regulators • E6 and E7 in apoptosis

  25. HPV: Understanding oncogenic mechanisms - • Cell extrinsic phenomena in HPV induced cervical carcinogenesis • Immune infiltrates • The lymphocytic infiltrate comprises predominantly of CD4+ T cells in cervical stroma below the area of dysplasia and of CD8+ T cells within the dysplastic epithelium. However, the latter cells are thought to be anergic which might play a role in the persistence and progression of HPV induced lesions. • Kobayashi et al, 2000

  26. HPV: Understanding oncogenic mechanisms - • Cell extrinsic phenomena in HPV induced cervical carcinogenesis • Immune infiltrates • in HSIL is: that there is increased expression of IL2R, IL4, TGFβ and IL10 but decreased expression of IL2 and IFNγ reflecting an immunoregulatory milieu. • Kobayashi et al, 2008 • Lesions of SCC are infiltrated with higher CD4+ and CD8+ cells when compared to CIN III, HPV positive cervicitis and normal cervix. • Jayshree et al, 2009

  27. HPV: Understanding oncogenic mechanisms - • Cell extrinsic phenomena in HPV induced cervical carcinogenesis • Natural Tregs have been observed to predominantly infiltrate tumour masses especially in the early phase of tumour progression. • Wang et al, 2004

  28. HPV: Understanding oncogenic mechanisms - • Among the cutaneous HPV types, HPV-5 and HPV-8 may be classified as high risk, as they are associated with the development of epidermodysplasia verruciformis (EV), an exceedingly rare skin condition. Münger et al, 2004

  29. HPV: Understanding oncogenic mechanisms - • One of the key events of HPV-induced carcinogenesis is the integration of the HPV genome into a host chromosome.

  30. HPV: Understanding oncogenic mechanisms - • Integration follows a more specific pattern with respect to the HPV genome. Expression of the viral E6 and E7 genes is consistently maintained, whereas other portions of the viral DNA are deleted or their expression is disturbed Münger et al, 2004

  31. HPV: Understanding oncogenic mechanisms - • Continued E6/E7 expression in cervical cancers is necessary for the maintenance of the transformed phenotype. • Godwin & DiMaio, 2000 • Wells et al, 2000

  32. HPV: Understanding oncogenic mechanisms - • The fact that E5 expression is not generally detected in cervical cancers after viral genome integration demonstrates that E5 is not necessary for the maintenance of the transformed phenotype. Münger et al, 2004

  33. HPV: Understanding oncogenic mechanisms - • Expression of the high-risk HPV E6/E7 genes • is necessary for the induction of premalignant alterations • directly contributes to malignant progression by subverting genomic stability • Duesing & Münger, 2004

  34. HPV: Understanding oncogenic mechanisms - • The HPV E7 proteins interact with the retinoblastoma tumor suppressor protein pRB and the related “pocket proteins” p107 and p130 through a conserved LXCXE sequence within CR2 sequences • Dyson et al, 1992

  35. HPV: Understanding oncogenic mechanisms - • High-risk HPV-derived E7 proteins interact with pRB more efficiently than E7 proteins encoded by low-risk mucosal HPVs • Gage et al, 1990

  36. HPV: Understanding oncogenic mechanisms - • In addition to pRB binding and degradation, E7 has other cellular targets that are relevant to cellular transformation. HPV E7 can override the growth-inhibitory activities of cyclindependent kinase inhibitors, including p21CIP1 and p27KIP1. • Zerfass-Thome et al, 1996 • Funk et al, 1997

  37. HPV: Understanding oncogenic mechanisms - • High-risk HPV proteins E6 do not directly associate with p53 but form a complex with the cellular E6-AP protein, which is essential for p53 interaction. • Huibregtse et al, 1995

  38. HPV: Understanding oncogenic mechanisms - • HPV-16 E6 proteins may also interact with additional cellular factors that are important for the transcriptional transcriptional activity of p53, including p300 and the transcriptional coactivator ADA3. • Patel et al, 1999 • Kumar et al, 2002

  39. McLaughlin-Drublin & Münger, 2009

  40. Cell Cycle Control Go Oncogene Suppressor gene G1 M S G2

  41. HPV: Understanding oncogenic mechanisms - • Each round of DNA replication leads to erosion of the chromosomal telomeric termini. Telomere shortening represents a cell-autonomous mechanism that restricts the proliferative capacity of normal somatic cells. Certain cell types that must undergo a large number of cell divisions, such as stem cells, express telomerase, a ribonucleoprotein that prevents telomere erosion.

  42. HPV: Understanding oncogenic mechanisms - • Ectopic expression of the catalytic telomerase subunit, hTERT, in primary human cells causes life span extension and facilitates immortalization. The majority of human tumor cells are telomerase positive, suggesting that aberrant telomerase activity may be critical for human tumorigenesis.

  43. HPV: Understanding oncogenic mechanisms - • In combination with E7, high-risk HPV E6 proteins contribute to immortalization of primary human epithelial cells through the induction of telomerase activity. • Kiyono et al, 1998

  44. HPV: Understanding oncogenic mechanisms - • Human carcinogenesis has been characterized as a disease of genomic instability, and the majority of human solid tumors display evidence of chromosomal aberrations, most notably aneuploidy. • Klausner, 2002

  45. HPV: Understanding oncogenic mechanisms - • High-risk HPV E6 and E7 oncoproteins can each independently induce genomic instability in normal human cells . They cooperate to generate mitotic defects and aneuploidy through the induction of centrosome abnormalities in normal human epithelial cells, and the characteristic multipolar mitoses in cervical lesions are caused by centrosome abnormalities. • Duensing et al, 2000 • White et al, 1994

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