Chapter 10 Virus and Cancer PDF

Chapter 10 Virus and cancer Dra Verónica Veses Jiménez Chapter overview Basic concepts of viral genetics Virus and cancer – Historical antecedents – Oncogenic viruses in humans 2 Definition of Virus A virus is an infectious agent that occupies a...

Chapter 10 Virus and cancer Dra Verónica Veses Jiménez Chapter overview Basic concepts of viral genetics Virus and cancer – Historical antecedents – Oncogenic viruses in humans 2 Definition of Virus A virus is an infectious agent that occupies a place near the boundary between the living and the nonliving. It is a particle much smaller than a bacterial cell, consisting of a small genome of either DNA or RNA surrounded by a protein coat. Viruses enter host cells and hijack the enzymes and materials of the host cells to make more copies of themselves. Viruses cause a wide variety of diseases in bacteria, plants, animals and humans, including AIDS, measles, smallpox, and cancer. 3 Viral structure 4 Classification of viruses Symmetry of the nucleocapsid. Presence or absence of lipid envelope. Species that infect: animal viruses, plants, bacteria. Depending on the type and structure of nucleic acid. 5 Viral genomes 6 VIRUS AND CANCER 7 Historical antecedents In 1908 Ellerman and Bang first showed that avian leukemia could be transmitted by filtered cell-free extracts. In 1911 Peyton Rous demonstrated that sarcomas in chickens could be transmitted through cell-free tumour extracts and thus must be caused by a small transmissible agent, probably a virus. 8 Viruses and cancer in humans The first human tumor virus was discovered in 1964 by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt's lymphoma, and named Epstein-Barr virus. To date, seven viruses have been consistently linked to different types of human cancer (oncogenic viruses). According to WHO data, viral infections are estimated to account for up to 20% of all cancer cases worldwide. 9 Oncogenic viruses in humans Virus Class Tumor Year Epstein-Barr Virus dsDNA Burkitt´s lymphoma 1964 (Human Herpesvirus 4) Hepatitis B virus ds DNA Hepatocellular 1965 carcinoma Human T- ss (+) RNA Adult T cell leukemia 1980 lymphotropic virus-I Human dsDNA Cervical cancer 1983-84 Papillomavirus 16 and 18 Hepatitis C virus ss (+) RNA Hepatocellular 1989 carcinoma Human Herpesvirus 8 dsDNA Kaposi´s sarcoma 1994 Merkel cell dsDNA Merkel Cell 2008 polyomavirus carcinoma 10 Classification of oncogenic viruses Oncogenic viruses have been divided into two broad categories – direct carcinogens, which express viral oncogenes that directly contribute to cancer cell transformation – indirect carcinogens that presumably cause cancer through chronic infection and inflammation, which eventually leads to carcinogenic mutations in host cells Several agents (such as HBV, HCV and HTLV-I), however, do not fit neatly into either the indirect or the direct carcinogen categories 11 Classification of oncogenic viruses II Oncogenic viruses can be divided into two groups on the basis of their genetic material: – DNA tumor viruses Adenovirus: SV40 and Human Papilloma virus Herpesviruses: Epstein Barr virus (EBV) and Kaposi’s Sarcoma Herpes Virus (KSHV) Other: Hepatitis virus B – RNA tumor viruses Retrovirus Other: Hepatitis C virus 12 RNA tumor viruses: retroviruses 13 Retroviruses´ structure Retroviruses have 3 basic genes (gag, pol, and env), which are used for the synthesis of structural proteins, virion-associated enzymes, and envelope glycoproteins LTR-gag-pol-env-LTR 14 Mechanisms of viral transformation in retroviruses I. Retroviral transduction of oncogene II. Oncogene activation by retroviral insertion III. Oncogenesis mediated by essential retrovirus proteins 15 I. Retroviral transduction of oncogene Some retrovirus (acute-transforming retrovirus) can cause rapid tumor development because they encode oncogenic proteins, which are similar to the cellular proteins in cellular growth control. These genes are called viral oncogenes (v-onc). Overproduction of these oncogenic materials or modification in their functions stimulates cellular proliferation. 16 Origin of v-onc genes Acutely transforming viruses usually are generated when a cellular protooncogene from the host is captured by insertion into the viral genome during viral replication. This process usually causes genetic changes in the protooncogene (usually by mutation) resulting in an oncogene, known from that point as a viral oncogen 17 Outcome of Retroviral Transduction “Single hit” carcinogenesis (one event) Polyclonal: tumor growth initiated in every infected cell Tumors form within days Characteristic of animal retroviruses 18 II. Oncogene activation by retroviral insertion These group of retroviruses (slow-transforming retroviruses) cause oncogenesis by integration of their promoter sequences and viral enhancers near the cellular growth-stimulating genes, initiating cell transformation They do not carry viral oncogenes Cellular integration occurs randomly in the DNA 19 Outcome of Oncogene Activation by Retrovirus Insertion Cell transformation rare event because insertion near potential oncogenes is infrequent Monoclonal tumors: proviral sequences integrated at same chromosomal site Tumors induced more slowly (months) since tumor derived from single cell Characteristic of animal retroviruses 20 Acute versus slow transforming retroviruses 21 III- Oncogenesis mediated by essential retrovirus proteins The third group of RNA tumor viruses constitute an exception to the paradigm of retroviral oncogenesis. Example: Human T cell Leukemia Virus type I (HTLV-I), responsible of – Adult T cell leukemia – HTLV-1 associated myelopathy neurodegenerative disease Endemic in parts of Japan, South America, Africa, and the Caribbean with an estimated 10-20 million people infected worldwide. Asymptomatic in majority of individuals with approximately 2-5% of HTLV-I carriers developing disease 20-40 years post infection. 22 Oncogenesis is due to an essential viral protein HTLV-1 oncogenesis involves a nonstructural viral regulatory protein essential (tax) to viral replication Interacts with cellular transcription factors and signaling molecules to enhance or repress cellular gene expression 23 DNA Tumor Viruses 24 DNA tumor viruses Diverse group of viruses with different structures, genome organization, and strategies of replication. Their oncogenic potential is linked to virus replication strategy DNA tumor viruses have two life forms: – In permissive cells, viral replication causes cell lysis and cell death. – In non-permissive cells, viral DNA is mostly integrated into the different sites of cell chromosomes 25 Oncogenic mechanism in DNA tumor viruses Once integrated, the viral genome encodes proteins that interfere with cell-cycle regulating proteins such as p53, retinoblastoma and others. Virus Transforming gene Target HBV HBx P53, DDB1 HHV-4 (EBV) LMP-1 TRAFs HPV E6 and E7 p53, RB HHV8 (KSHV) vGPCR Multiple, including RB 26 Conclusions Carcinogenesis is a multi-step process The process involves mutations of cellular proto- oncogenes and tumor suppressor genes Oncogenic viruses can cause cancer by: – Activation of cellular signal transduction pathways – Interfering with cell cycle control pathways – Interfering with cellular DNA repair impairment Overall, RNA tumors active oncogenes and DNA virus inactivate tumor suppressor genes 27 References National Human Genome Research Institute http://www.genome.gov Alan J. Cann, 2011. Principles of Molecular Virology, Fifth Edition. 5 Edition. Academic Press. Moore and Chang. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer. 2010; 10(12): 878–889. 28