Virus and Cancer


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It describes the etiology of cancer mediated by Virus both DNA and RNA virus

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Virus and Cancer

  1. 1. This presentation is for teaching purpose only Cancer and Therapeutics The Etiology of Cancer Dr. Manash K. Paul Department of Biology Indian Institute of Science Education and Research Mohali;
  2. 2. The Etiology of Cancer Viruses (papilloma. Epstein-Barr, hepatitis B, retrovirus) Radiation exposure Environmental/ industrial carcinogens * Asbestos * Aromatic amines Textbook & Readings: As a general background source Alberts B. et al., The * Bischloromethyl ethers Molecular Biology of the Cell 4th Edition (2002) * Beta-naphthalene and benzedrine Garland Science Press, ISBN 0-8153-3218-1 is recommended. As a detailed source Robert A. Weinberg, * Polycyclic hydrocarbons The Biology of Cancer Garland Science Press, ISBN 0-8153-4078-8 (2007). Lauren Pecorino, Molecular * Drug-induced cancers (alkylators: Biology of Cancer, Oxford University Press. ISBN 978-0-19-921148-7 (2008). M. Molls, P. Vaupel, C. melphalan and cyclophosphamide) Nieder, M.S. Anscher. The impact of tumor biology on cancer treatment and multidisciplinary strategies, * Nickel Springer. ISBN 978-3-540-74385-9 (2009). Yi Lu, R. I. * Vinyl chloride Mahato, Pharmaceutical perspectives of cancer therapeutics, Springer. ISBN 978-1-4419-0130-9 (2009). * Isopropyl alcohol Robert Gallo, Virus Hunting: Aids, Cancer, And The Human Retrovirus, Basic Books. ISBN13:9780465098156 * Diet and nutrition Tobacco and alcohol consumption Immunodeficiency syndromes: HIV is associated with Kaposi's sarcoma, non-Hodgkin's lymphoma Genetic susceptibility syndromes
  3. 3. VIRUSES Pic ref: /2009/04/computer-virus-bugs Viruses are infectious agents that can replicate only within the cells of other living organisms. Humans are affected by a variety of viruses. Some cause minor illnesses like the common cold; others can lead to more serious conditions like influenza and AIDs. Pic ref: Pic ref:
  4. 4. Structure of Viruses Structure of viruses Virion Capsid Capsomere Genome Nucleocapsid Envelope DNA containing Viruses Hepatitis B virus HBV Human Papiloma virus HPV Adenovirus Parvovirus RNA containing Viruses Rota virus Paramyxo virus Entero virus Influenza virus Source: Viruses;
  5. 5. History of study for Tumor Viruses As early as 1876, a researcher in Russia reported the transmission of a tumor from one dog to another. In 1908, Wilhelm Ellerman and Olaf Bang in Copenhagen reported the extract from chicken leukemia cells could cause tumor. In 1909, Rous found that the extract from sarcoma of chicken could induce tumor. Harry Rubin discovered that RSV-infected chicken embryo fibroblasts could survive for several months to produce viral particles.
  6. 6. Early Cancer Research on Rous Sarcoma Virus (RSV) Redrawn as per The Biology of Cancer (© Garland Science 2007)
  7. 7. Major human Oncogenic Viruses At least 6 viruses are thought to contribute to cancers (15 – 20%): DNA Viruses Small DNA tumor viruses - Human Papilloma virus (HPV) - SV40 - Adenovirus Herpesviruses (large) Hepatitis B virus HBV Human Papillomavirus - Epstein Barr virus (EBV) - Kaposi’s Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA Viruses Human T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C 80% of viral-associated cancers Adeno virus Hepatitis virus C Cervical cancer (HPV) Liver cancer (HBV and HCV)
  8. 8. How do Viruses Enter and Exit the body Attachment/Adsorption Penetration Uncoating Biosynthesis Assembly Release Maturation False colored transmission electron micrograph images showing virus budding off from cell surface
  9. 9. DNA tumor Viruses Life cycle of DNA tumor Viruses DNA Virus Coat Protein Needs Entry into cell and Cell in uncoating of DNA S-Phase Uses host enzymes Viral DNA Transcription Uses host enzymes Replication RNA Translation DNA Coat Protein Assembly of progeny virus partcile followed by exit from the cell 9 Redrawn as per The Biology of Cancer (© Garland Science 2007) Paul Graphics
  10. 10. RNA tumor Viruses Life cycle of RNA tumor Viruses Integration of viral DNA into host chromosome DNA Provirus Reverse transcriptase RNA Assembly of many makes DNA/RNA and virus particle DNA then DNA/DNA Capsid RNA Transcription Envelope Reverse transcriptase* RNA copies Translation RNA Entry into cell and + + shedding of envelope Envelope Capsid Reverse Paul Graphics * virus encoded protein protein transcriptase Redrawn as per The Biology of Cancer (© Garland Science 2007)
  11. 11. Oncogenesis & Oncogenes Oncogene – A gene that has the potential to convert a normal cell to a cancerous or transformed cell Viral oncogene (v-onc) – A viral gene responsible for the oncogenicity of the virus ● Retroviruses may carry altered cellular genes that are tumor promoters Proto-oncogene – Cellular genes that promote the normal growth and division of cells.
  12. 12. How do Viruses contribute to cancer? Integrations that cause activation or inactivation of oncogenes or tumor suppressors (e.g. RNA viruses) Expression of genes that alter key signal transduction pathways - this is our focus Chronic activation of inflammatory responses Can You Guess What are these?
  13. 13. Human Papilloma Virus (HPV) DNA TUMOR VIRUS Small (52-55 nm in diameter) Non-enveloped Icosahedral-shaped Circular dsDNA genome (~8000 bp in length) 100 types identified - most common are types 6 and 11 HPV infections most common among sexually active adults and adolescents. There are over 100 different types of HPV’s (low, medium and high-risk). Low-risk types cause warts or papillomas (e.g. genital warts). High-risk types cause cervical, vulva, vagina, anus and penis cancers (e.g. types 16 and 18). 10% of human cancers may be HPV-linked 16% of all female cancers linked to HPV Papilloma viruses are found in 91% of women with cervical cancer 13
  14. 14. Discoverers of Cancer Viruses Win Nobel Human Papilloma virus (HPV) • HPV causes cancer of the cervix, anal, perianal, vulvar, penile cancers and close to 20% of oropharyngeal cancers. Recent evidence also points to a possible role of other HPV infections in squamous cell carcinomas of the skin. Dr. Harald zur Hausen
  15. 15. The Human Papilloma virus story • Rigoni-Stern in the mid 19th century correlated uterine cancer with marraige • Kennaway, Dorn and Cutler, Levin etc, 1940-60 had the similar inferences • Rotkin, 1962-72, onset of sexuality and multiple sexual consorts • Search for a carcinogenic principle, Hausen HZ, postulates the presence of a DNA virus. Curr. Top. Microbiol. Immunol., 1977, 78: 1-30 • Existance of human papilloma virus type 6 (HPV 6) was obtained from human genital warts. Int J. Cancer, 1980, 25: 605-9 • DNA homologue HPV 6 was found in majority of the genital worts but not associated with tumorigenicity. Int J. Cancer, 1982, 29: 143-6 • Viral DNA from a laryngeal papilloma was cloned. J. Virol. 1982, 44: 393-400 • This DNA had 25 % similarity with that of HPV 6, labelled it as HPV 11 15
  16. 16. The Human Papilloma virus story • Presence of HPV 11 DNA was reported in genital, laryngeal papillomas and in some cervical cancers. PNAS. 1983, 80: 560-3; PNAS. 1983, 80: 3812-5 • HPV types 6, 10, and 11 were preferentially found in benign lesions whereas HPV 16 prevails in malignant and in pre-malignant proliferations. P.Takamatsu Symp, 1983; 14: 147-52 • Papillomavirus DNA in human tongue and oral carcinomas. Int. J. Cancer, 1985, 36: 575-8; Med. Microbiol. Immunol., 1986, 174: 287-94 • The complete nucleotide sequence of HPV11 DNA (7931 bp) was determined. Virology, 1986, 151: 124-30 • The etiology of cancer of the cervix has been linked to HPV16. Laryngol. Rhinol. Otol., 1986; 65: 177-9 • Discovered HPV 18 16
  17. 17. Human Papilloma Virus and cancer The important transforming genes in papilloma viruses are the non-structural regulatory genes, E6 and E7 HPV is normally episomal but is always integrated in tumors Schematic representation of the genomic organization of HPV 16 17 Ref: Clinical Science (2006) 110, (543–552) Human papillomavirus in cervical screening and vaccination, Emma J. CROSBIE and Henry C. KITCHENER
  18. 18. HPV gene expression and cancer Changes in viral gene expression accompanying the progression from cervical intraepithelial neoplasia to squamous cell carcinoma. Expression of E6/E7 oncogenes increases with the severity of the lesion. In cervical carcinoma the virus is integrated into the host cell chromosomes, this leads to further deregulation of E6/E7 expression. CIN: Cervical intraepithelial neoplasia. 18 Source: Human papillomavirus E6/E7 mRNA testing as a predictive marker for cervical carcinoma. A Kathrine Lie, Gunnar Kristensen, Expert Review of Molecular Diagnostics, July 2008, Vol. 8, No. 4, Pages 405-415.
  19. 19. Schematic representation of HPV entry and growth Source:
  20. 20. Human Papilloma virus – mechanism Composed of eight genes - E1, E2, E4, E5, E6, E7, L1 and L2, expressed at different times during the HPV life cycle - categorized as early or late HPV virion infects epithelial tissues through micro-abrasions and enters the basal epithelial cells, genome exists as 20-100 copy episome Viral genome then enters the cell nucleus and now the early E1 and E2 genes replicate the virus genome. E1 and E2 then build messenger RNA molecules As the host epithelial cells divide and differentiate, a transcription cascade takes place E4 and E5 genes, respectively, assist in the virus genome production E7 interfere with the work of the human genes Rb gene that regulate normal cell division The function of Rb is to accumulate important proteins like the E2F protein that are essential for cell division; if enough proteins are not accumulated, Rb prevents cell division from taking place E6 binds & stops p53 from repairing cell damage or causing the damaged cell to die Leading to continued cell division of damaged cells, and can end up causing cancer or tumors. The L1 and L2 genes help create viral capsid proteins required to build new viruses. The entire HPV life cycle depends strictly on the process of epithelial cell differentiation.
  21. 21. The p53 Tumor Suppressor Gene Most cancers result from mutations in P53 mediated G1 arrest several genes. A gene mutated in about 1⁄2 of Induction of DNA lesions human cancers is p53. Tumors arise when the second p53 allele is mutated, so the trait is inherited as an autosomal dominant. The P53 protein p53 tumor suppressor protein (393 amino Stabilization of P53 acids) is involved in many processes, by unknown means including: a). Transcription b). Cell cycle Gene activation control c). DNA repair and d). Apoptosis WAF1 (programmed cell death). Promoter Damage to cellular DNA causes p53 to initiate Cdk2 p21 Cyclin E the cascade of events leading to G1 arrest. Kinase No Kinase activity At least 17 cellular and viral proteins interact activity blocks transition to S with p53. Virus proteins typically inactivate G1 S p53, allowing products needed for replication Paul Graphics Arrest in G1 to be expressed. 21 Cascade of events by which DNA lesions cause a p53 dependent arrest in G1 Redrawn as per Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
  22. 22. HPV E6 oncoproteins and cancer The HPV E6 and E7 oncoproteins inactivate the p53 and pRB tumor suppressors. HPV E7 proteins interact with pRB and the related “pocket proteins” p107 and p130. Together regulate the activities of the E2F family of transcription factors that control multiple cell cycle transitions. E6 do not directly associate with p53 but form a complex with the cellular E6-AP protein, which is essential for p53 interaction. E6 Schematic outline of critical steps of high-risk HPV- retarget E6-AP to induce induced carcinogenesis. Inactivation of the pRB and p53 ubiquitination and rapid tumor suppressor pathways and expression of the catalytic proteasomal degradation of p53 telomerase subunit hTERT constitute a subset of the steps that have been shown to be necessary for the generation of fully transformed human epithelial cells in vitro. HPV E6 can activate telomerase Mechanisms of Human Papillomavirus-Induced Oncogenesis, Munger et al; hTERT transcription. Journal of Virology, November 2004, p. 11451-11460, Vol. 78, No. 21
  23. 23. RNA Tumor Viruses (RETROVIRUSES) A normal retrovirus has: 3 genes; Structure of RNA Virus GAG : internal proteins Transmembrane Glycoprotein ENV: Envelope glycoproteins Membrane associated protein POL: Enzymes Capsid Reverse transcriptase RNA Integrase Lipid membrane Reverse Protease transcriptase •Retroviruses causes cancers Surface Glycoprotein •Hepatitis C Virus Paul Graphics Hepatocellular carcinoma •Human T cell lymphotropic virus -1 (HTLV-1) Adult T cell leukemia and Sezary T-cell leukemia •Human T cell lymphotropic virus -2 (HTLV-2) Hairy cell leukemia
  24. 24. Hepatitis virus C Hepatitis C virus is an enveloped RNA virus of the flavivirus family, a blood borne virus. The world health organization estimates that approximately 170 million people worldwide are infected with hepatitis C. It is capable of causing both acute and chronic hepatitis in humans by infecting liver cells. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to primary hepatocellular carcinoma (HCC). HC is an aggressive tumor that can occur in the setting of liver disease resulting from infections with hepatitis B and/or hepatitis C virus, although the exact mechanism of oncogenesis by these viruses is unclear. Long latency period to development of HCC is 20-30 years. Mechanism is probably due to chronic inflammatory response. HOW IT INDUCES CANCER? Hepatitis virus C
  25. 25. The structure of the HCV genome. Envelope glycoproteins E1 and E2 are integral for cell recognition and viral fusion NS2 and NS3 autocatalytically cleaves to release a serine proteinase situated at the N region of the NS3. NS3 then cleaves the rest of the non-structural proteins when complexed with its co-factor NS4A to release NS4B, NS5A and NS5B. NS4B is involved in the replication complex of HCV. NS5A is thought to interact with the cell pathways and NS5B acts as RNA-dependent RNA polymerase. HCV core interact with RNA-activated protein kinase, PKR. PKR is activated by IFN and phosphorylates the eukaryotic initiation factor, eIF2a, limiting protein synthesis and inhibiting cell and viral growth. Core may mediate G2/M phase arrest via a p53-independent manner. Core phosphorylates PKR at threonine 446, which alters PKR activity on different substrates and prevent apoptosis. Mutations of PKR at residue 446 in mice have been shown to cause tumours. Core protein is able to bind to p53 and p21WAF1/CIP leading to G1 arrest. Bioscience Horizons, Volume 1, No. 2, 2008, 167-175.
  26. 26. FOR DISCUSSION - in the next class Gui Tran, The role of hepatitis C virus in the pathogenesis of hepatocellular carcinoma. Bioscience Horizons, Volume 1, No. 2, 2008, 167-175.