Viruses and Cancer
Folder Title: CxVirus(NoTP)
Updated: April 15, 2015
Importance of Virology toCancer Biology and Cancer Medicine
• Need to Control Potentially Infectious Exposure
• Development of Prophylactic and Therapeutic Vaccines
• Learning About Cancer Biology from Viruses:
How Do They Do It?
What do those mechanisms of transformation tell us about cancer biology?
Infectious Agents in Neoplasia Non-Viral Agents• Parasitic Worms - Hepatic Sarcomas and
Bladder Cancers in Dogs• Crown Gall Tumor in Plants:
Agrobacter Tumifaciens• Helicobacter pylori: Stomach cancer
Viral Causation• Ellerman and Bang Avian Leucosis
Virus 1909• Rous Sarcoma Virus in Chickens 1911• Shope Papilloma Virus in Rabbits 1930• Bittner Milk Factor in C3H Mice 1936• Gross Murine Leukemia Virus 1945• Friend Erythroleukemia Virus 1957• Human T-Cell Lymphotrophic Virus
(HTLV-1) 1980 (Bernie Poiesz and Robert Gallo)
Why So Hard to Identify Viral Causative Agents in Cancer?
Difficult to Infect Outbred Adult Hosts.Virally Transformed Cells Need Not (and usually don't)• Shed, bud, otherwise produce, or even show the presence
of virus particles• Viruses can sometimes be recovered ("rescued") from
transformed cellsViruses are exquisitely specific for target species, tissue, and
conditions of binding and insertion.Viruses tend to transform host cells other than their normal
infectious target.
How Might Viruses Cause Cell Transformation & Oncogenesis?
• Carry and directly transfer cancer causing genes by infecting target cells?
• Be present in the germ line as provirus copies in the host DNAFrom infection in times pastReactivated by carcinogenic events?
• Be inserted into the host cell genome and misregulate endogenous host genes?
• Infect host cells and produce viral proteins that alter host cell genetics and phenotype?
General Structural Features of Oncogenic Viruses
DNA Viruses:• DNA Genome• Double Stranded Linear• Double Stranded Closed Circular• Single StrandedRNA Viruses ("Retro-Viruses")• RNA Genome• Two Copies of Single Stranded RNA• Retroviral Genome replication by reverse transcription• Makes a DNA "Provirus" Copy• Can be naked or enveloped (See Adnoviruses)DNA and RNA Tumor Viruses:Have Potential to Alter Host DNA Structure or Expression
During Viral Infection of the Cell
Structure of DNA Tumor Viruses: 1Naked DNA Tumor VirusesDouble-stranded DNA & Capsid Proteins (No
Envelope)
Papova Viruses: Polyoma, Papilloma, Vacuolating Viruses
Papova Viruses: Shope Papilloma,
Simian Vacuolating Virus 40 : SV40
Polyoma Virus : Multiple Tumor Foci
Structure of DNA Tumor Viruses: 2Enveloped DNA Tumor Viruses:
• Double-stranded DNA & Capsid Proteins
• Glycoprotein - Lipid Envelope
Examples
Herpes Simplex Viruses 1 and 2
Epstein-Barr Virus
Cytomegalovirus
Hepadna Viruses (Hepatitis B)
Naked Enveloped
Figure 3.3 The Biology of Cancer (© Garland Science 2007) p. 60
Infection Cycle for DNA-Virus
Figure 3.4a The Biology of Cancer (© Garland Science 2007) p. 62
Structure of an RNA-Virus
(Retrovirus)
Structure of Enveloped RNA Viruses and RNA Tumor viruses
Retroviral Infection of DNA-Genome Cells: Provirus Insertion
Figure 3.17 The Biology of Cancer (© Garland Science 2007) p. 74
RNA-Virus Infection of a Cell with DNA-Genome
StartHere
HIVInfect
HIVBud
HIVExit
Structure of RNA (“Retro”) Viruses:and RNA Tumor Viruses
Enveloped Virus with RNA Genome• Single Stranded, Diploid, Non-complementary• Positive Polarity: Acts Directly as Message• 9 kb; 3 to 4 million mw per strand• Viral envelope host-derivedRNA-Directed DNA Polymerase ("Reverse transcriptase)• Transcribes RNA to complementary DNA: ProvirusVirus coded protein spikes in envelop:• Control host rangeVirus coded proteins in core membraneNucleoid inside core with genome, some RNA's, and reverse transcriptase
RNA Tumor Virus May carry additional genetic information or may perturb host cell genetic information by virtue of insertion
How Might Viruses Cause Cell Transformation & Oncogenesis?
• Carry and directly transfer cancer causing genes by infecting target cells?
• Be present in the germ line as provirus copies in the host DNAFrom infection in times pastReactivated by carcinogenic events?
• Be inserted into the host cell genome and misregulate endogenous host genes?
• Infect host cells and produce viral proteins that alter host cell genetics and phenotype?
• See Also Slide 5
Examples of Oncogenic RNA Viruses(from Ruddon, 3rd Ed, Table 6.2)
Acute Transforming Viruses
Rous Sarcoma (non-defective)Chicken SarcomaAvian Erythroblastosis Chicken LeukemiaAvian Myeloblastosis Chicken LeukemiaAvian Myelocytomatosis Chicken Abelson Leukemia Mouse LeukemiaHarvey Sarcoma Rat SarcomaKirsten Sarcoma Rat SarcomaFeline Sarcoma Cat SarcomaSimian Sarcoma Monkey Sarcoma
See Table 3.3, p.81, Weinberg, for comprehensive listing
Examples of Oncogenic RNA VirusesAcute Transforming Viruses
What Genetic Information Makes Them Oncogenic?
Virus Disease
Rous Sarcoma Chicken Sarcoma
Avian Erythroblastosis Chicken Leukemia
Avian Myeloblastosis Chicken Leukemia
Avian Myelocytomatosis Chicken Leucoproliferation
Abelson Leukemia Mouse Leukemia
Harvey Sarcoma Rat Sarcoma
Kirsten Sarcoma Rat Sarcoma
Feline Sarcoma Cat Sarcoma
Simian Sarcoma Monkey Sarcoma
Extra GenesrcerbmybMyc
ablHa-rasKi-rasfmssis
Figure 3.22 The Biology of Cancer (© Garland Science 2007)
Acquisition by a sub-acutely transforming virus
of a c-onc Gene to produce a v-onc gene
Figure 3.19 The Biology of Cancer (© Garland Science 2007)
ALV: Sub-acutely transforming virus with no endogenous oncogene
RSV: Rous Sarcoma Virus carrying endogenous oncogene (src)
Examples of Oncogenic RNA Viruses(from Ruddon, 3rd Ed, Table 6.2)
Sub-Acute Chronic Type
Avian Leucosis Transforms Hematopoietic Cells
Murine Leukemia Mouse Leukemia
Feline Leukemia Cat Leukemia
Friend Murine Leukemia Reticulum Cell Sarcoma & Erythroleukemia
Mouse Mammary Tumor Mammary Cancers (Vertical transmission)
Human T Lymphotropic Cutaneous T-Cell Lymphoma
See Table 3.4, p. 85 Weinberg for comprehensive listing. (Shown in subsequent slide)
Figure 3.23b The Biology of Cancer (© Garland Science 2007) p. 83
Insertional Mutagenesis:
Viral Promoter Control of Expression of Endogenous c-Oncogenes
ALV = Avian Leucosis Virus: (Sub-acutely
Transforming)
C onc gene!
p. 85
Avian & Mammalian
Turning Point Question
Please clear desk of notes and devices other than the TP Transmitter
Families of DNA Tumor Viruses Causing or Possibly-causing Naturally Occurring Neoplasms
or Able to Transform Mammalian Cells in VitroHepadna Hepatitis B Human Hepatocellular Carcinoma
Woodchuck, Duck, Squirrel
Papilloma Shope Rabbit Benign Papilloma(Papova A) Canine, Equine, Human
Human Cervical Carcinoma
Papova B Polyoma Mouse UnknownSV40 MonkeyHuman papova
Adenovirus Human UnknownOvine Sheep
Herpes Marek's Chicken LymphosarcomaPig herpes Guinea pig LeukemiaBovine Cattle LymphomaEpstein-Barr Human Burkitt's Lymphoma
Nasopharyngeal carcinoma
OncDNA
Table 4.6 The Biology of Cancer (© Garland Science 2007) p. 114
Human Cancers
Some DNA Tumor Viruses in Humans(from Tannock & Hill)
Cancers and Related DiseasesEpstein-Barr Virus Burkitt's Lymphoma (C)
Nasopharyngeal Carcinoma (A)Infectious Mononucleosis (C)Lymphoma in X-linked
Lymphoproliferative Syndrome (C)Papilloma Viruses Cervical Carcinoma (C)Papova Viruses Meningiomas (A)
Progressive Leucencephalopathy (C)Hepatitis B (Hepadna) Hepatocellular Carcinoma (C) ("C" = Causative "A" = Associated)
DNAManCx
Mechanism of Action of Tumorigenic Viruses
Turning Point Question
Please clear desk of notes and devices other than the TP Transmitter
End Cancer Virology Here
HTLVI
Turning Point Question
Please clear desk of notes and devices other than the TP Transmitter
Oncogenic Viruses Associated with Cancers in Humans
(from Ruddon, 3rd Edition)
ManVirCx