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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
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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
Papilloma
(Papova A)
Shope
Rabbit
Canine, Equine, Human
Human
Benign Papilloma
Papova B
Polyoma
SV40
Human papova
Unknown
Adenovirus
Human
Ovine
Sheep
Marek's
Pig herpes
Bovine
Epstein-Barr
Chicken
Guinea pig
Cattle
Human
Herpes
Human
Hepatocellular Carcinoma
Woodchuck, Duck, Squirrel
Mouse
Monkey
Cervical Carcinoma
Unknown
Lymphosarcoma
Leukemia
Lymphoma
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
infectious virus particles
Aborted infection producing
transformed cells
Infection Cycle for DNAVirus
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 RNAVirus (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
p. 77
Virally
Transformed Cells
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)
Avian Erythroblastosis
Avian Myeloblastosis
Avian Myelocytomatosis
Abelson Leukemia
Harvey Sarcoma
Kirsten Sarcoma
Feline Sarcoma
Simian Sarcoma
See Table 3.3, p.81, Weinberg, for
comprehensive listing
Chicken Sarcoma
Chicken Leukemia
Chicken Leukemia
Chicken
Mouse Leukemia
Rat Sarcoma
Rat Sarcoma
Cat Sarcoma
Monkey Sarcoma
Examples of Oncogenic RNA Viruses
Acute Transforming Viruses
What Genetic Information Makes Them Oncogenic?
Virus
Rous Sarcoma
Avian Erythroblastosis
Avian Myeloblastosis
Avian Myelocytomatosis
Abelson Leukemia
Harvey Sarcoma
Kirsten Sarcoma
Feline Sarcoma
Simian Sarcoma
Disease
Chicken Sarcoma
Chicken Leukemia
Chicken Leukemia
Chicken
Leucoproliferation
Mouse Leukemia
Rat Sarcoma
Rat Sarcoma
Cat Sarcoma
Monkey Sarcoma
Extra Gene
src
erb
myb
Myc
abl
Ha-ras
Ki-ras
fms
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
Murine Leukemia
Feline Leukemia
Friend Murine Leukemia
Mouse Mammary Tumor
Human T Lymphotropic
Transforms Hematopoietic Cells
Mouse Leukemia
Cat Leukemia
Reticulum Cell Sarcoma &
Erythroleukemia
Mammary Cancers (Vertical
transmission)
Cutaneous T-Cell Lymphoma
If they don’t 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
Please clear desk of notes and devices other
than the TP Transmitter
End Cancer Virology
Here
2 Turning Point Questions
Please clear desk of notes and devices other
than the TP Transmitter
HTLVI
Oncogenic Viruses Associated with Cancers in
Humans
(from Ruddon, 3rd Edition)