1. Viruses and Cancer Folder Title: CxVirus Updated: April 11, 2012 TtlVirus

2. Importance of Virology to Cancer 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? VirCxBio

3. 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)

4. 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 cells Viruses 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. VirusHid

5. 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 DNA From infection in times past Reactivated 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?

6. General Structural Features of Oncogenic Viruses DNA Viruses: DNA Genome Double Stranded Linear Double Stranded Closed Circular Single Stranded RNA Viruses ("Retro-Viruses") RNA Genome Two Copies of Single Stranded RNA Retroviral Genome replication by reverse transcription Makes a DNA "Provirus" Copy DNA and RNA Tumor Viruses: Have Potential to Alter Host DNA Structure or Expression During Viral Infection of the Cell GenVirus

7. Structure of DNA Tumor Viruses Naked DNA Tumor Viruses Double-stranded DNA & Capsid Proteins (No Envelop) Papova Viruses: Polyoma, Papilloma, Vacuolating Viruses Papova Viruses: Shope Papilloma, Simian Vacuolating Virus 40 : SV40 Polyoma Virus : Multiple Tumor Foci Adenoviruses DNANaked

8. Structure of DNA Tumor Viruses Enveloped 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) DNAEnvel

10. Figure 3.3 The Biology of Cancer (© Garland Science 2007) p. 60 Infection Cycle for DNA- Virus

12. If a virus has a no lipid bilayer membrane around it is called a (an) virus 0 of 94

13. Structure of RNA Tumor Viruses

14. Figure 3.4a The Biology of Cancer (© Garland Science 2007) p. 62 Structure of an RNA-Virus (Retrovirus)

15. Structure of Oncogenic RNA Viruses: Retroviruses or 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-derived RNA-Directed DNA Polymerase ("Reverse transcriptase) Transcribes RNA to complementary DNA: Provirus Virus coded protein spikes in envelop: Control host range Virus coded proteins in core membrane Nucleoid inside core with genome, some RNA's, and reverse transcriptase RetroStruct

17. Figure 3.17 The Biology of Cancer (© Garland Science 2007) p. 74 RNA-Virus Infection of a Cell with DNA-Genome Start Here

18. HIVInfect

19. HIVBud

20. HIVExit

21. 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 DNA From infection in times past Reactivated 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?

22. Examples of Oncogenic RNA Viruses (from Ruddon, 3rd Ed, Table 6.2) Acute Transforming Viruses Rous Sarcoma (non-defective)Chicken Sarcoma Avian ErythroblastosisChicken Leukemia Avian MyeloblastosisChicken Leukemia Avian MyelocytomatosisChicken Abelson LeukemiaMouse Leukemia Harvey SarcomaRat Sarcoma Kirsten SarcomaRat Sarcoma Feline SarcomaCat Sarcoma Simian SarcomaMonkey Sarcoma See Table 3.3, p.81, Weinberg, for comprehensive listing

23. Examples of Oncogenic RNA Viruses Acute Transforming Viruses What Genetic Information Makes Them Oncogenic? Rous Sarcoma Chicken Sarcoma Avian ErythroblastosisChicken Leukemia Avian MyeloblastosisChicken Leukemia Avian MyelocytomatosisChicken Abelson LeukemiaMouse Leukemia Harvey SarcomaRat Sarcoma Kirsten SarcomaRat Sarcoma Feline SarcomaCat Sarcoma Simian SarcomaMonkey Sarcoma Extra Gene src erb myb myc abl Ha-ras Ki-ras fms sis

26. 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

27. 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)

28. The Rous sarcoma virus transduces a viral oncogene called “v-src”. That makes the Rous sarcoma virus a or an _ _ _ _ _ _ _ transforming virus 0 of 94

29. 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)

30. 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!

31. p. 85

32. Acute transforming viruses carry and transduce an oncogene. That’s how they transform target cells. A sub-acute transforming virus does not carry an oncogene. How does a sub-acute transforming virus with no oncogene bring about neoplastic transformation? What does it do to cause transformation? 0 of 94

33. Table 4.6 The Biology of Cancer (© Garland Science 2007) p. 114

34. Some DNA Tumor Viruses in Humans (from Tannock & Hill) Cancers and Related Diseases Epstein-Barr VirusBurkitt's Lymphoma (C) Nasopharyngeal Carcinoma (A) Infectious Mononucleosis (C) Lymphoma in X-linked Lymphoproliferative Syndrome (C) Papilloma VirusesCervical Carcinoma (C) Papova VirusesMeningiomas (A) Progressive Leucencephalopathy (C) Hepatitis B (Hepadna)Hepatocellular Carcinoma (C) ("C" = Causative "A" = Associated) DNAManCx

35. Mechanism of Action of Tumorigenic Viruses

37. “V-src” is a v-onc gene, meaning it is viral oncogene. There is also a “c-src” and there are “c-onc” genes. What does the “c” stand for? 0 of 94

38. Using Viruses to Treat Cancers (See Scientific American, October 2003, pp 69 to 75 Virotherapy with Transductional Targeting: Adenovirus engineered to bind to an infect only cancer cells Does not infect normal cells Adenovirus multiplies in cancer c ells. Cancer cell burst and disperse virus to infect other cancer cells. Virotherapy with Transcriptional Targeting: Adenovirus engineered to replicate under control of tumor promoter genes. Virus replicates only in cancer cells that have the tumor-specific promoter. Cancer cell bursts and disperse virus particles to infect other cancer cells.

39. The four slides following on Cutaneous T-Cell Lymphoma (associated with HTLV - human T-cell lymphotropic virus, an RNA virus) and on other human cancers associated with DNA viruses will not be covered in class this year and will not appear in the second half-term exam.

40. HTLVI

42. Oncogenic Viruses Associated with Cancers in Humans (from Ruddon, 3rd Edition) ManVirCx

43. Families of DNA Tumor Viruses Causing or Possibly-causing Naturally Occurring Neoplasms or Able to Transform Mammalian Cells in Vitro HepadnaHepatitis B HumanHepatocellular Carcinoma Woodchuck, Duck, Squirrel PapillomaShope RabbitBenign Papilloma (Papova A)Canine, Equine, Human HumanCervical Carcinoma Papova BPolyomaMouseUnknown SV40Monkey Human papova AdenovirusHumanUnknown OvineSheep HerpesMarek'sChickenLymphosarcoma Pig herpesGuinea pigLeukemia Bovine CattleLymphoma Epstein-BarrHumanBurkitt's Lymphoma Nasopharyngeal carcinoma OncDNA

44. An acutely transforming virus can induce cancers that are polyclonal. Why is that? (there are at least two different responses that would work. Either one will be fine. The acutely transforming virus has a (an) _ _ _ _ _ _ _ _. Or The transforming process is ______________________ 0 of 94