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Oncogenic virus

Oncogenic virus



Oncogenic virus

Oncogenic virus



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    Oncogenic virus Oncogenic virus Presentation Transcript

    • ONCOGENIC VIRUS Dr.T.V.Rao MD basics10/6/2012 Dr.T.V.Rao MD 1
    • Distinguishing Characteristics of Viruses Obligate intracellular parasites Extreme genetic simplicity Contain DNA or RNA Replication involves disassembly and reassembly Replicate by "one-step growth”10/6/2012 Dr.T.V.Rao MD 2
    • Viruses enter the body of the hostin a variety of ways, for example...10/6/2012 Dr.T.V.Rao MD 3
    • Routes of entry: Inhalation ingestion Blood organ t/plant inoculation Congenital / vertical sexual10/6/2012 Dr.T.V.Rao MD 4
    • WHO Estimates• Worldwide, the WHO International Agency for Research on Cancer estimated that in 2002, 20% of human cancers were caused by infection, of which 10–15% are caused by one of seven different viruses. The importance of this is that some of these cancers might be easily prevented through vaccination10/6/2012 Dr.T.V.Rao MD 5
    • What is Cancer• Cancer results from alterations in critical regulatory genes that control cell proliferation, differentiation, and survival. Studies of tumor viruses revealed that specific genes (called oncogenes) are capable of inducing cell transformation, thereby providing the first insights into the molecular basis of cancer.10/6/2012 Dr.T.V.Rao MD 6
    • How virus causes Cancers:• The viral agents causing cancer in eukaryotic animals by integrating in host genome *A virus associated with malignancies in natural host, experimental animals or cell cultures. *viruses which modified proto- oncogene, obligatory host specific, with the ability immortalization, possess genes which stimulate growth and cause cancer.10/6/2012 Dr.T.V.Rao MD 7
    • Early History• The theory that cancer could be caused by a virus began with the experiments of Oluf Bang and Vilhelm Ellerman in 1908 who first show that avian erythroblastosis (a form of chicken leukemia) could be transmitted by cell- free extracts. This was subsequently confirmed for solid tumors in chickens in 1910-1911 by Peyton Rous.10/6/2012 Dr.T.V.Rao MD 8
    • Research History In 1908, Ellerman & Bang first discovered virus, producing leukemia in chicken. In 1911 Peyton Rous 1st shows the presence of filterable sarcoma material that induce10/6/2012 the CANCER. Dr.T.V.Rao MD 9
    • Relationship of viruses with malignancy Ellerman & Bang (1908) – leukemia in fowls Rous (1911) – fowl sarcoma Shope isolated Rabbit fibroma virus (1932), papilloma virus (1933) Bittner (1936) –Breast Ca in mice10/6/2012 Dr.T.V.Rao MD 10
    • Oncovirus• An oncovirus is a virus that can cause cancer. This term originated from studies of acutely-transforming retroviruses in the 1950–60s, often called oncornaviruses to denote their RNA virus origin. It now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus".10/6/2012 Dr.T.V.Rao MD 11
    • by transforming cells cancer • When a virus infects a cell, it expresses proteins that cause the cell to proliferate and/or block apoptosis • Cancer is multi-factorial: Oncogenic viruses are very common, only a small % of people infected actually get cancer10/6/2012 Dr.T.V.Rao MD 12
    • Major viral cancersViruses are involved in about 15% of human cancers: – Cancer of the cervix – Cancer of the liver – Certain leukemias & lymphomas – Kaposi’s sarcoma 10/6/2012 Dr.T.V.Rao MD Copyright John Valentine DMD 1999 13
    • Classification OncovirusDNA oncogenic RNA oncogenic viruses viruses10/6/2012 Dr.T.V.Rao MD
    • Major human Oncogenic Viruses DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - 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 15
    • Oncogenic viruses may be RNA or DNA • 20% of human cancers believed to be of viral origin • These include: – Cervical cancer – Burkitt’s lymphoma – Hepatocarcinoma – Kaposi’s sarcoma • Virus is not only factor10/6/2012 Dr.T.V.Rao MD 16
    • Viruses Associated With The Development Of Human Neoplasia VIRUSES NEOPLASMS DNA VIRUSES Human papilloma virus Cervical Ca, warts, ano- genital carcinoma Herpes simplex virus II Cervical carcinoma Epstein-Barr virus NPCa, African Burkitt’s Human Herpes virus 8 Kaposi’s sarcoma Hepatitis B virus Hepatocellular Ca Herpes simplex virus 6 Certain B cell (HBLV) lymphomas10/6/2012 Dr.T.V.Rao MD 17
    • Viruses Associated With The Development Of Human Neoplasia VIRUSES NEOPLASMS RNA VIRUSES Human T-cell leukemia virus I Some T-cell leukemia, Lymphoma Human T-cell leukemia virus II Some cases of hairy cell leukemia Human immunodeficiency virus Lymphoma; Kaposi’s sarcoma10/6/2012 Dr.T.V.Rao MD 18
    • RNA viruses• Some RNA viruses have also been associated such as the hepatitis virus as well as human T-lymphotropic• virus (HTLV-1).10/6/2012 Dr.T.V.Rao MD 19
    • • Oncogenic viruses • Oncogenesis is the result of genetic changes that alter the expression or function of proteins that play critical roles in the control of cell growth and division • •Oncogenic viruses cause cancer by inducing changes that affect cell growth and division 10/6/2012 Dr.T.V.Rao MD 20
    • Oncogenic Retroviruses• More than 40 different highly oncogenic retroviruses have been isolated from a variety of animals, including chickens, turkeys, mice, rats, cats, and monkeys. All of these viruses, like RSV, contain at least one oncogene In some cases, different viruses contain the same oncogenes, but more than two dozen distinct oncogenes have been identified among this group of viruses10/6/2012 Dr.T.V.Rao MD 21
    • Changes in cell that are at the roots of cancerGenetic and epigenetic alterations: • Mutations • Deletions • Recombinations • Transpositions • Epigenetic alterations (DNA methylation, imprinting) • Acquisition of viral genetic material 22
    • Changes in cell that are at the roots of cancerGenetic and epigenetic alterations: • Mutations • Deletions • Recombinations • Transpositions • Epigenetic alterations (DNA methylation, imprinting) • Acquisition of viral genetic material • Various combinations of these lead to the development of cancers - some viruses contribute single hits while others contribute multiple hits. 23
    • How do Viruses contribute to cancer?• Integrations that cause activation orinactivation of oncogenes or tumorsuppressors (e.g. RNA viruses)• Expression of genes that alter key signaltransduction pathways - this is our focus• Chronic activation of inflammatoryresponses 24
    • 10/6/2012 Dr.T.V.Rao MD 25
    • Viruses causing human malignancies• Hepatitis B & C viruses: Hepatocellular Cancer.• E-B virus: Nasopharyngeal Ca, Burkitt’s lymphoma• HPV 16 & 18: Ca Cx• HTLV: Adulât T cell leukemia• HHV 8: Kaposi’s sarcoma10/6/2012 Dr.T.V.Rao MD 26
    • 10/6/2012 Dr.T.V.Rao MD 27
    • Retroviruses:• 1.Avian leukosis viruses• 2.Murine leukosis viruses• 3.Murine mammary tumor virus• 4.Leukosis-sarcoma viruses• 5.Human T cell leukemia virus 10/6/2012 Dr.T.V.Rao MD 28
    • Retroviridae• Any virus capable of inducing tumors. The RNA tumor viruses (family Retroviridae), which are well defined and rather homogeneous, or the DNA viruses, which contain a number of viruses capable of inducing10/6/2012 Dr.T.V.Rao MD 29
    • Cancer• Cancer arises from a combination of dominant gain of function mutations in proto- oncogenes and recessive loss of function mutations in tumor suppressor genes10/6/2012 Dr.T.V.Rao MD 30
    • Understanding Cancer CANCER Cancer is an overgrowth of cells bearing cumulative genetic injuries that confer growth advantage over the normal cells [Nowell’s Law] Cancer cells can be characterized as antisocial, fairly autonomous units that appear to be indifferent to the constraints and regulatory signals imposed on normal cells [Robbin’s]10/6/2012 Dr.T.V.Rao MD 31
    • CANCER CELLS AND NORMAL CELLS CANCER CELLS NORMAL CELLSFrequentmitoses Normal cell Nucleus Few Blood vessel mitoses Abnormal heterogeneous cells Loss of contact inhibition Oncogene expression is rare Increase in growth factor secretion Intermittent or co-ordinated Increase in oncogene expression growth factor secretion Loss of tumor suppressor genes Presence of tumor suppressor genes 10/6/2012 Dr.T.V.Rao MD 32
    • CHARACTERISTICS OF CANCER Clonality• Cancer is a genetic disease at the cellular level.• Genetic mutations play a critical role in pathogenesis of cancer.• Consequences of genetic instability: – Phenotypic heterogeneity – Tumor progression• Proto-oncogenes and oncogenes• Dominant and recessive mutations10/6/2012 Dr.T.V.Rao MD 33
    • Cancer Genetics• Tumors arise as clones from a single cell. At the cellular level, cancer is a genetic disease.• The development of the malignant clone is due to mutations in DNA due to: – Random replication errors – Exposure to carcinogens – Faulty DNA repair process10/6/2012 Dr.T.V.Rao MD 34
    • Cancer Genes• Proto-oncogenes – normally promote normal cell growth; mutations convert them to oncogenes.• Tumor suppressor genes – normally restrain cell growth; loss of function results in unregulated growth.• Mutator or DNA repair genes – when faulty, result in an accumulated rate of mutations.10/6/2012 Dr.T.V.Rao MD 35
    • ONCOGENE FAMILY Mouse fibroblast cell line NIH 3T3 can take up foreign D + oncogenes Mouse fibroblast cell line NIH 3T3 can take up foreign DNA, incorporate them into their genome and express them Oncogenes extracted from human tumour cells can transform NIH 3T3 •DNA •Such transforming genes have been shown to be identical with cellular  promote cell proliferation oncogenes 14NA, incorporate them into their genome and express them  dominant & highly conserved •DNA extracted from human tumour cells can transform NIH 3T3 •Such transforming genes have been shown to be identical with cellular  types: viral oncogenes [v-oncs] oncogenes 14 cellular oncogenes [c-oncs] Proto-oncogene  “Mutation”  Oncogene10/6/2012 Dr.T.V.Rao MD 36
    • Viral Carcinogenesis • Viral carcinogens are classified into RNA and DNA viruses. • Most RNA oncogenic viruses belong to the family of retroviruses that contain reverse transcriptase mediates transfer of viral RNA into virus specific DNA.10/6/2012 Dr.T.V.Rao MD 37
    • Statistical Prevalence in Different Worlds10/6/2012 Dr.T.V.Rao MD 38
    • DNA Tumor Viruses In Human CancerAdenovirusesHighly oncogenic in animalsOnly part of virus integratedAlways the same partEarly functionsE1A region: 2 T antigensE1B region: 1 T antigenE1A and E1B = Oncogenes 10/6/2012 Dr.T.V.Rao MD 39
    • Two Major Classes of Tumor Viruses DNA Tumor VirusesDNA viral genome DNA-dependent DNA polymerase Host RNA (Host or viral) polymerase Viral mRNA Viral protein 10/6/2012 Dr.T.V.Rao MD 40
    • RNA Tumor VirusesViral RNA genome Reverse transcriptase (Virus-encoded)Viral DNA genome (integrated) IMPORTANT DNA-dependent RNA polymerase(Host RNA pol II)Viral genomic RNA Splicing (Host splicing enzymes)messenger RNA Important: Use HOST RNA polymerase to make its genomeviral protein An enzyme that normallyVirus makes mRNA 10/6/2012 Dr.T.V.Rao MD 41
    • Small DNA tumor viruses• Adenovirus • Human virus but only causes cancer in non- human cells• SV40 • Mesothelioma• HPV • Cervical Cancer • Squamous cell anal carcinoma • Penile cancer • Oral cancers 42
    • DNA Tumor Viruses In Human Cancer Papilloma Viruses urogenital cancer wart malignant squamous cell carcinoma Papilloma viruses are found in 91% of women with cervical cancerSquamous cell carcinoma:LarynxEsophagus All histologically similarLung 10% of human cancers may be HPV-linked 43
    • DNA Tumor Viruses In Human Cancer Herpes Viruses Considerable evidence for role in human cancer • Some very tumorigenic in animals • Viral DNA found in small proportion of tumor cells: “hit and run”• Epstein-Barr Virus • Burkitt’s Lymphoma • Nasopharyngeal cancer • Infectious mononucleosis • Transforms human B-lymphocytes in vitro 10/6/2012 Dr.T.V.Rao MD 44
    • DNA Tumor Viruses In Human Cancer Hepatitis B continued Epidemiology:Strong correlation between HBV andhepatocellular carcinomaChina: 500,000 - 1 million newcases of hepatocellularcarcinoma per yearTaiwan: Relative risk of gettingHCC is 217 x risk of non-carriers10/6/2012 Dr.T.V.Rao MD 45
    • DNA Tumor Viruses In Human CancerPapilloma Viruses•51 types identified - most common aretypes 6 and 11• most cervical, vulvar and penilecancers are ASSOCIATED with types 16and 18 (70% of penile cancers) 10/6/2012 Dr.T.V.Rao MD 46
    • Human Papillomavirus (HPV)• Human Papillomavirus (HPV) is a double- stranded DNA virus of the family Papovaviridae. It infects only epithelial cells in humans such as skin and mucus membranes. It can affect the lower genital tract including the vulva, vagina, urethra, pe nis, anal canal and perianal skin10/6/2012 Dr.T.V.Rao MD 47
    • DNA viruses Human Papilloma virus• (HPV), a DNA virus, causes transformation in cells through interfering with tumor suppressor proteins such as p53. Interfering with the action of p53 allows a cell infected with the virus to move into a different stage of the cell cycle, enabling the virus genome to be replicated. Forcing the cell into the S phase of the cell cycle could cause the cell to become transformed types of HPV increase the risk of, e.g., cervical cancer.10/6/2012 Dr.T.V.Rao MD 48
    • 10/6/2012 Dr.T.V.Rao MD 49
    • Epstein Barr virusPathologies in immuno-competent individuals• Infectious mononucleosis• Burkitt’s Lymphoma• Hodgkin’s lymphoma • Nasopharyngeal carcinomaPathologies in immuno-compromised individuals• Post-transplant lymphoproliferative diseases (PTLD)• Hodgkin’s lymphoma• A variety of non-Hodgkin’s lymphoblastic malignancies 50
    • Epstein-Barr virus (Human herpes virus 4)• EBV is the herpes virus that is most strongly associated with cancer. It infects primarily lymphocytes and epithelial cells. In lymphocytes, the infection is usually non- productive, while virus is shed (productive infection) from infected epithelial cells.10/6/2012 Dr.T.V.Rao MD 51
    • Burkitts lymphoma• Burkitts lymphoma in the tropics, where it is more common in malaria-endemic regions• Nasopharyngeal cancer, particularly in China and SE Asia, where certain diets may act as co-carcinogens• B cell lymphomas in immune suppressed individuals (such as in organ transplantation or HIV)• Hodgkins lymphoma in which it has been detected in a high percentage of cases (about 40% of affected patients)• X-linked lymphoproliferative Disease (Duncans syndrome)10/6/2012 Dr.T.V.Rao MD 52
    • Infectious mononucleosis• EBV also causes infectious mononucleosis, otherwise known as glandular fever. This is a self-resolving infection of B- lymphocytes which proliferate benignly. Often infection goes unnoticed (it is sub-clinical) and about half of the population in western countries has been infected by the time they reach 20 years of age. Why this virus causes a benign disease in some populations but malignant disease in others is unknown10/6/2012 Dr.T.V.Rao MD 53
    • Kaposi’s Sarcoma Herpes Virus - HHV-8 Kaposi’s sarcoma Hematologic malignancies • Primary effusion lymphoma • Multicentric Castlemans disease (MCD) – a rare lymphoproliferative disorder (AIDS) • MCD-related immunoblastic/plasmablastic lymphoma • Various atypical lymphoproliferative disorders 54
    • Human Herpes Virus 8 (HHV- 8, Kaposis Sarcoma Herpes Virus)• HHV-8 infects lymphocytes and epithelial/endothelial cells and is the causative agent of Kaposis sarcoma. It has also been associated with hematologic malignancies, including primary effusion lymphoma, Multicentric Castlemans (also Castelmans) disease (MCD), MCD-related immunoblastic/plasmablastic lymphoma and various atypical lymphoproliferative disorders10/6/2012 Dr.T.V.Rao MD 55
    • Kaposis sarcoma-associated herpesvirus• Kaposis sarcoma-associated herpesvirus (KSHV or HHV-8) is associated with Kaposi’s sarcoma, a type of skin cancer. Epstein-Barr virus (EBV or HHV-4) is associated with four types of cancers Merkel cell polyomavirus – a polyoma virus – is associated with the development of Merkel cell cancer10/6/2012 Dr.T.V.Rao MD 56
    • RNA oncogenic viruses• Retroviridae – Human T cell leukemia viruses • (HTLV-1 and HTLV-2) – Causes » Adult T – cell leukemia » Lymphoma – Feline leukemia virus (FeLV) • Contagious • Causes leukemia and lymphoma in cats – Related to presence of reverse transcriptase – Some contain promoters that turn on other10/6/2012 oncogenes Dr.T.V.Rao MD 57
    • RNA Tumor VirusesGroups of Retroviruses• Oncovirinae important Tumor viruses and similar• Lentiviruses important Long latent period Progressive chronic disease Visna HIV• Spumavirinae 58
    • VIRAL AGENTS: DNA viruses Human Papillomavirus [HPV types 16, 18, 31, 33 & 35] Interruption of the E1/E2 ORF E2 is not expressed10/6/2012 Over-expression MD E6 & E7 Dr.T.V.Rao of 59
    • VIRAL AGENTS: DNA virusesEpstein-Barr Virus [EBV]  in Burkitt’s, B-cell & Hodgkin’s lymphomas + NP ca  tropism: CD21+ cells [e.g., B cells, epithelial cells]  mechanism: viral entry  episomal existence  latency  (+) LMP-1, EBNA-1, EBNA-2  immortalizationHepatitis B virus [HBV]  induction of chronic hepatocyte injury  (+) HBx  HBx activates protein kinase c for transformation10/6/2012 Dr.T.V.Rao MD 60
    • Hepatitis B • DNA virus with RNA intermediate • In tumors virus is integrated with little gene expression • Believed to be from chronic liver damage/loss and replacement causing increased mutations • (similar to SOS response?)10/6/2012 Dr.T.V.Rao MD 61
    • DNA Tumor Viruses In Human CancerHepatitis B VirusDNA genome RNA polymerase II Host enzymeRNA Provirus Reverse transcriptase Viral enzymeDNA genome 62
    • HEPADNAVIRIDAE HEPATITIS B VIRUS• Hepatitis B virus is very different from the other DNA tumor viruses. Indeed, even though it is a DNA virus, it is much more similar to the oncornaviruses (RNA tumor viruses) in its mode of replication. The DNA is transcribed into RNA not only for the manufacture of viral proteins but for genome replication. Genomic RNA is transcribed back into genomic DNA. This is called reverse transcription. The latter is not typical of most DNA tumor viruses but reverse transcription is a very important factor in the life cycles of RNA- tumor viruses10/6/2012 Dr.T.V.Rao MD 63
    • HCC is one of the most common tumors worldwide10/6/2012 Dr.T.V.Rao MD 64
    • Hepatocellular carcinoma• Hepatocellular carcinoma (HCC, also called malignant hepatoma) is a primary malignancy (cancer) of the liver. Most cases of HCC are secondary to either a viral hepatitide infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis).In countries where hepatitis is not endemic, most malignant cancers in the liver are not primary HCC but metastasis (spread) of cancer from elsewhere in the body, e.g., the colon.10/6/2012 Dr.T.V.Rao MD 65
    • 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• Human T cell lymphotropic virus -2 (HTLV-2) Hairy cell leukemia 10/6/2012 •Dr.T.V.Rao ? HIVMD 66
    • Proto-oncogenes Dominant Heterozygote mutations Homozygote Allele 1 Allele 2 Allele 1 Allele 2 Normal Mutant Mutant Mutant Binds under Mutant Mutant Mutant special always always always circumstances binds binds binds Always binds Always binds10/6/2012 Function gained Dr.T.V.Rao MD Function gained 67
    • Anti-Oncogenes Recessive mutations Mutation growth Rb Gene Mutant Rb Mutant Rb Mutant Rb RbRb protein Heterozygote Homozygote Function lost Rb Binds and controls cell cycle No binding - Growth continues 10/6/2012 Dr.T.V.Rao MD 68
    • Anti-OncogenesRetinoblastoma gene has normalregulatory function in many cellsInvolved inRetinoblastomaLung carcinomasBreast carcinomas 69
    • RNA Tumor VirusesWhat do oncogenes encode?Proteins that are involved in growth control anddifferentiation Growth factors Growth factor receptors Signal transduction proteins Transcription factors 70
    • Anti-OncogenesRetinoblastoma gene has normal regulatoryfunction in many cellsInvolved inRetinoblastomaLung carcinomasBreast carcinomas 10/6/2012 Dr.T.V.Rao MD 71
    • Anti-Oncogenes Retinoblastoma Rb Gene Adenovirus E1ARb protein Rb 105kD Rb Rb 10/6/2012replication Stops Dr.T.V.Rao MD Cell cycle continues 72
    • Anti-OncogenesP53Inactivated by• deletion• point mutationIn a series of colorectal cancers all showed:• Allele 1: partial or complete deletion• Allele 2: Point mutation 73
    • Anti-Oncogenes p53 P53 gene P53 gene P53 gene Hepatitis C Papilloma P53 P53 P53 Papilloma proteolysis DNAP53Stops replication10/6/2012 replicationDr.T.V.Rao MD replication 74
    • For more articles of Interest on Infectious Diseases visit me….10/6/2012 Dr.T.V.Rao MD 75
    • • Programme Created by Dr.T.V.Rao MD for Medical and Health care Professionals in the Developing World • Email • doctortvrao@gmail.com10/6/2012 Dr.T.V.Rao MD 76