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Chapter 3
Tumor Viruses
3.1, 3.2, 3.5
3.7 - 3.11
3.4
Mar 15, 2007
What is a virus ? - A virus is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the cells of a biological organism. Viruses can replicate themselves only by infecting a host cell and, therefore, cannot reproduce on their own.
Virion: virus particle including a capsid (coat) and the viral genome
Figure 3.1 The Biology of Cancer (© Garland Science 2007)
3.1 Peyton Rous discovered a chicken sarcoma virus (1909)
Peyton Rous
1. Discovered a virus that causes
cancers in chickens (Rous
sarcoma virus, 1911)
2. His findings:
(1) established a precedent
that some viruses can
cause cancers
(2) cancer viruses provide a
genetic simplification for the
study of cancer
Figure 3.4a The Biology of Cancer (© Garland Science 2007)
3.2 Rous sarcoma virus is discovered to transform infected cells in culture
A focus of Rous sarcoma virus (RSV) -transformed chicken embryo fibroblasts surrounded by a monolayer of uninfected cells.
Transformation
- Process of converting a normal cell into a cell having some or many of the attributes of a cancer cell
Table 3.2 The Biology of Cancer (© Garland Science 2007)
3.5 Tumor viruses induce multiple changes in cell phenotype including acquisition of tumorigenicity
1.2.3.4.5.6.
7.8.9.
1.Altered morphology – rounded, refractile
2. Loss of contact inhibition - ability to grow over one another (pile up)
6. High saturation density - ability to accumulate large numbers of cells in culture dish
Figure 3.12 The Biology of Cancer (© Garland Science 2007)
Anchorage-independent growth
3. Ability to grow without attachment to solid substrate - anchorage independence
4. Ability to proliferate indefinitely - immortalization (Chapter 10)
5. Reduced requirement for mitogenic growth factors
7. Inability to halt proliferation in response to deprivation of growth factors
8. Increased transport of glucose
Figure 3.13 The Biology of Cancer (© Garland Science 2007)
9. tumorigencity
Immunocomprimizednude mice
- no thymus (no T cell response)
- no hair
Figure 3.17 The Biology of Cancer (© Garland Science 2007)
3.7 Retroviral genomes become integrated into the chromosomes of infected cells
- Tumor viruses consist of DNA tumor viruses and RNA tumor viruses
- Rous sarcoma virus (RSV) is an RNA virus. How could the genomic RNA integrate into the chromosomal DNA of an infected cell?
The virion of RSV (and other related viruses)
The life cycle of an RNA tumor virus (e.g., RSV)
Retrovirus
(RT)
Howard Temin
David Baltimore
Renato Dulbecco
1. Propose provirus hypothesis
for retroviruses
2. Purification of reverse transcriptase
3. Focus assays
1. Purification of reverse transcriptase
2. Virion polymerases
1. Study on oncogenic DNA tumor
virus
2. Interaction between polyoma virus
(and SV40) with host cells
Figure 3.19 The Biology of Cancer (© Garland Science 2007)
3 retroviral genes for viral replication.
Which one is responsible for transformation?
The genome of retroviruses
Structure of the Rous sarcoma virus genome
avian leukosis virus → - very slowly transforming
Rous sarcoma virus → - rapidly transforming
sarcoma
Figure 3.20 (part 2 of 2) The Biology of Cancer (© Garland Science 2007)
genomic DNA from normal chicken cells
3.8 A version of the src gene carried by RSV is also present in uninfected cells
Figure 3.21 The Biology of Cancer (© Garland Science 2007)
Evolutionary tree of the src gene
The presence of src sequences was later found in Drosophila and even a sponge.
Figure 3.22 The Biology of Cancer (© Garland Science 2007)
3.9 RSV exploits a kidnapped cellular gene to transform cells
srcv-src : an oncogenec-src : a proto-oncogene
Harold Varmus
Michael Bishop
1. Cellular origin of retroviral
oncogenes
2. Retroviral transduction
3. Roles of proto-oncogenes
Extended ideas from these findings:
1. If retroviruses could activate c-src proto-oncogene into a potent oncogene, perhaps other carcinogens might operate in a similar way.
2. All of the transforming powers of RSV derived from the presence of a single gene – v-src. Thus, a single oncogene can change the shape, metabolism, and growth behavior of a cell.
3. Other retroviruses may acquire oncogenes from other proto-oncogenes.
3.10 The vertebrate genome carries a large group of proto-oncogenes
Table 3.3 The Biology of Cancer (© Garland Science 2007)
Figure 3.23a The Biology of Cancer (© Garland Science 2007)
3.11 Slowly transforming retroviruses activate proto-oncogenes by inserting their genomes adjacent to these cellular genes
Can RNA viruses which do not carry oncogenes cause cancers?
Figure 3.23b The Biology of Cancer (© Garland Science 2007)
transcription of myc gene is controlled by viral promoters
excessive myc protein
Insertional mutagenesis
Table 3.4 The Biology of Cancer (© Garland Science 2007)
Table 3.1 The Biology of Cancer (© Garland Science 2007)
3.4 Viruses containing DNA molecules are also able to induce cancer
Life cycle of DNA viruses Integration of SV40 genome
3.6 DNA Tumor virus genomes persist in virus-transformed cells by becoming part of host cell DNA