Viruses and Cancer

Folder Title: CxVirus(NoTP)

Updated: April 19, 2016

See Chapter 3, Weinberg, 2nd Edition pages 71 to 102

 Turning Point Opening Slide
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 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?
What do those mechanisms of transformation
tell us about cancer biology?
What do those virally perturbed genes tell us about normal cell
biology?
The Discovery of Oncogenes
(Presented in Cancer Genetics Chapter 4)
 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 & 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
Hepatitis B Virus (HPV)
Human T-Cell Lymphotrophic Virus
(HTLV-1) 1980
(Bernie Poiesz and Robert Gallo)
Demonstration that a Non-Cellular Infectious Agent
Could Generate a Cancer:
Peyton Rous and the Rous Sarcoma Virus 1912

Later Found to be an RNA Genome (Retro-virus)

Named RSV = Rous Sarcoma Virus
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.
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?
 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
Can be naked or enveloped (See Adenoviruses)
DNA and RNA Tumor Viruses:
Have Potential to Alter Host DNA Structure or Expression
During Viral Infection of the Cell
 RNA Virus

DNA Virus

Naked Enveloped

DNA Virus

DNA Virus
p. 79
 Human Cancers

All others are

DNA Viruses
RNA Retro-virus

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

DNA Tumor Viruses
Structure of DNA Tumor Viruses: 1
Naked DNA Tumor Viruses
Double-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: 2
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)
 Families of DNA Tumor Viruses
Causing or Possibly-causing Naturally Occurring Neoplasms
or Able to Transform Mammalian Cells in Vitro
Hepadna 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 Unknown

SV40 Monkey
Human papova

Adenovirus Human Unknown

Ovine Sheep

Herpes Marek's Chicken Lymphosarcoma

Pig herpes Guinea pig Leukemia
Bovine Cattle Lymphoma
Epstein-Barr Human Burkitt's Lymphoma
Nasopharyngeal carcinoma
 Some DNA Tumor Viruses in Humans
(from Tannock & Hill)
Cancers and Related Diseases
Epstein-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)
Productive infection making new Aborted infection producing
infectious virus particles transformed cells
 Infection Cycle for DNA-
Virus

Productive Infection
producing virus particles

Figure 3.3 The Biology of Cancer ( Garland Science 2007) p. 60

Mechanism of Action of
Tumorigenic Viruses
 3 Turning Point Questions

Please clear desk of notes and devices other

than the TP Transmitter
Retro-viruses and
RNA-Tumor Viruses
 Structure of an RNA-
Virus (Retrovirus)

See Figure 3.4, Weinberg 2nd Edition, p. 75

p. 62
Figure 3.4a The Biology of Cancer ( Garland Science 2007)
Structure of Enveloped RNA Viruses
and RNA Tumor viruses
Retroviral Infection of DNA-Genome Cells:
Provirus Insertion
 RNA-Virus Infection of a Cell with DNA-Genome

Start
Here

Figure 3.17 The Biology of Cancer ( Garland Science 2007) p. 74

 Rous Sarcoma Virus Transformed Normal Chicken Embryo Fibroblasts

Normal Cells Virally

Transformed Cells

p. 77
p. 82
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-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

RNA Tumor Virus May carry additional genetic information (acutely

transforming) or may perturb host cell genetic information by virtue of
insertion (Sub-acute transforming virus)
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?

See Also Slide 5

 Examples of Oncogenic RNA Viruses
(from Ruddon, 3rd Ed, Table 6.2)
Acute Transforming Viruses (carry on oncogene)

Rous Sarcoma (non-defective) Chicken Sarcoma

Avian Erythroblastosis Chicken Leukemia
Avian Myeloblastosis Chicken Leukemia
Avian Myelocytomatosis Chicken
Abelson Leukemia Mouse Leukemia
Harvey Sarcoma Rat Sarcoma
Kirsten Sarcoma Rat Sarcoma
Feline Sarcoma Cat Sarcoma
Simian Sarcoma Monkey Sarcoma

See Table 3.3, p.81, Weinberg, for

comprehensive listing
 Examples of Oncogenic RNA Viruses
Acute Transforming Viruses
What Genetic Information Makes Them Oncogenic?

Virus Disease Extra Gene

Rous Sarcoma Chicken Sarcoma src
Avian Erythroblastosis Chicken Leukemia erb
Avian Myeloblastosis Chicken Leukemia myb
Avian Myelocytomatosis Chicken Myc
Leucoproliferation
Abelson Leukemia Mouse Leukemia abl
Harvey Sarcoma Rat Sarcoma Ha-ras
Kirsten Sarcoma Rat Sarcoma Ki-ras
Feline Sarcoma Cat Sarcoma fms
Simian Sarcoma Monkey Sarcoma sis
Where Do the Acutely Transforming RNA-Viruses get
their Oncogenes From?
 Acquisition by a sub-acutely transforming virus
of a c-onc Gene to produce a v-onc gene

p. 92 2nd Edition
Figure 3.22 The Biology of Cancer ( Garland Science 2007)
p. 95, Part 1
Part 2, Page 95
 Acutely Transforming vs Sub-Acutely Transforming
RNA Viruses

ALV: Sub-acutely transforming virus with no endogenous oncogene

RSV: Rous Sarcoma Virus carrying endogenous oncogene (src)

Figure 3.19 The Biology of Cancer ( Garland Science 2007)

 Examples of Oncogenic RNA Viruses
Sub-Acute Chronic Type
Do Not Transduce an Oncogene
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

If they dont carry on oncogene,

how do they transform cells?
 Insertional Mutagenesis:
Viral Promoter Control of Expression of Endogenous c-Oncogenes

C onc gene!

ALV = Avian Leucosis

Virus: (Sub-acutely
Transforming)

Figure 3.23b The Biology of Cancer ( Garland Science 2007) p. 83

Avian & Mammalian

p. 98
 3 Turning Point Question

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than the TP Transmitter
End Cancer Virology
Here
 2 Turning Point Questions

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than the TP Transmitter
HTLVI
Oncogenic Viruses Associated with Cancers in
Humans
(from Ruddon, 3rd Edition)