Transcript Biology of Cancer

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
3.1 Peyton Rous discovered a
chicken sarcoma virus (1909)
Figure 3.1 The Biology of Cancer (© Garland Science 2007)
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
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.
Figure 3.4a The Biology of Cancer (© Garland Science 2007)
Transformation
- Process of converting a normal cell into a cell
having some or many of the attributes of a
cancer cell
3.5 Tumor viruses induce multiple changes in
cell phenotype including acquisition of
tumorigenicity
1.
2.
3.
4.
5.
6.
7.
8.
9.
Table 3.2 The Biology of Cancer (© Garland Science 2007)
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
3. Ability to grow without attachment to solid
substrate - anchorage independence
Anchorage-independent growth
Figure 3.12 The Biology of Cancer (© Garland Science 2007)
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
9. tumorigencity
Immunocomprimized
nude mice
- no thymus
(no T cell response)
- no hair
Figure 3.13 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?
Figure 3.17 The Biology of Cancer (© Garland Science 2007)
The virion of RSV (and other related viruses)
The life cycle of an RNA tumor virus (e.g., RSV)
Retrovirus
(RT)
Howard Temin
1. Propose provirus hypothesis
for retroviruses
2. Purification of reverse transcriptase
3. Focus assays
David Baltimore
1. Purification of reverse transcriptase
2. Virion polymerases
Renato Dulbecco
1. Study on oncogenic DNA tumor
virus
2. Interaction between polyoma virus
(and SV40) with host cells
The genome of retroviruses
3 retroviral genes for viral replication.
Which one is responsible for transformation?
Figure 3.19 The Biology of Cancer (© Garland Science 2007)
Structure of the Rous sarcoma virus genome
avian leukosis virus →
- very slowly transforming
Rous sarcoma virus →
- rapidly transforming
sarcoma
3.8 A version of the src gene carried by RSV
is also present in uninfected cells
genomic
DNA from
normal
chicken cells
Figure 3.20 (part 2 of 2) 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 3.21 The Biology of Cancer (© Garland Science 2007)
3.9 RSV exploits a kidnapped cellular gene to
transform cells
src
v-src : an oncogene
c-src : a proto-oncogene
Figure 3.22 The Biology of Cancer (© Garland Science 2007)
Michael Bishop
Harold Varmus
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)
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 3.23a The Biology of Cancer (© Garland Science 2007)
Insertional mutagenesis
transcription of myc gene is
controlled by viral promoters
excessive myc protein
Figure 3.23b The Biology of Cancer (© Garland Science 2007)
Table 3.4 The Biology of Cancer (© Garland Science 2007)
3.4 Viruses containing DNA molecules are also
able to induce cancer
Table 3.1 The Biology of Cancer (© Garland Science 2007)
3.6 DNA Tumor virus genomes
persist in virus-transformed
cells by becoming part of host
cell DNA
Life cycle of DNA viruses
Integration of SV40 genome