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

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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

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End Cancer Virology Here

HTLVI

Turning Point Question

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Oncogenic Viruses Associated with Cancers in Humans

(from Ruddon, 3rd Edition)

ManVirCx