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Summary SSA4 Tumor viruses and oncogenes
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Summary and WG answers of SSA4 Tumor viruses and oncogenes of the course MBO (molecular oncology and biology) at Leiden University.
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SSA4 Tumor viruses andoncogenes
Chapter 3 Weinberg
The cytopathic (cell-killing) and spreading ability of viruses makes it possible for them to
leave behind a lot of destruction. However, also the viral replication itself can do harm. Not
by killing the cell, but make it thrive more and thereby proliferate uncontrollably leading to
cancer.
3.1 Peyton Rous discovers a chicken sarcoma virus
The first oncogenic virus was discovered by Rous. He removed a sarcoma from chicken
breast and grinded it up. He collected a filtrate (that could not contains actual tumor cells)
and injected this in another chicken that also developed the sarcoma. This was because
there was a virus in the filtrate.
Individual virus particles are called virions. They have a protein coat (a capsid) that protects
the DNA or RNA that is in it. The virus can be virulent, meaning that the host cell is
destroyed, or temperate, meaning that the cell survival is increased to promote the viral
replication. Many viruses have dsDNA and they just use the host DNA polymerase for their
replication.
3.2 Rous sarcoma virus is discovered to transform cells in
culture
The RSV virus is a retrovirus. It thus also contains a reverse transcriptase. Within the protein
shell, there are two identical copies of the genome. The virus has glycoprotein spikes which
allows the virion to adsorb to cells and then inject its contents into the cell.
The RSV virus is used in cultures to transform cells. RSV-infected cells displayed many traits
that you also see in cancer. There were foci (clusters) of cells. The cells also looked like
sarcoma cells; they had a rounded morphology. Also an altered metabolism. This was the
first step to investigate individual cells and their transformation.
Normal cells stop growing after forming a confluent monolayer of cells. This is due to
contact/density/topoinhibition. This behavior is not seen in the transformants (the RSV
infected cells).
3.3 The continued presence of RSV is needed to maintain
transformation
This was discovered by an experiment in which they infected cells with a temperature
sensitive mutant. Denaturation leads to inactivation of the virus, but also made the cell go
back to its normal morphology. This thus
shows that the transformation by RSV is not
hit-and-run. The virus is thus necessary to
both initiate and maintain the transformed
phenotype.
, 3.4 Viruses containing DNA molecules are also able to induce
cancer
Papovaviruses are DNA virusus and it stands for papilloma, polyoma and the vacuoles. All
these viruses have circular dsDNA.
The adenoviruses and SV40 viruses can also lead to transformation in nonpermissive cells
as otherwise there is a lytic cycle. They can cause clones of transformants. The
herpesviruses type 1 and 2 are also dsDNA, but not tumorigenic. A distant relative, the EBV,
can provoke Burkitt's lymphomas.
3.5 Tumor viruses induce multiple changes in cell phenotype
including acquisition of tumorigenicity
Properties of transformed cells:
Altered morphology (rounded shape, refractile in phase-contrast microscope)
Loss of contact inhibition (ability to grow over one another)
Ability to grow without attachment to a solid substrate (anchorage independence)
Ability to proliferate indefinitely (immortalization)
Reduced requirement for mitogenic growth factors
High saturation density (ability to accumulate large numbers of cells in culture)
Inability to halt proliferation in response to deprivation of growth factors
Increased glucose transport
Tumorigenicity
The immune system dictate whether transformed cells can form tumors. The immune system
can spot these transformed cells and then kill them. Immunocompromised people have a
higher chance of cancer therefore. The immune system is also why there is tumor rejection
when you transplant a tumor from a non syngeneic host to another. When the immune
system is compromised, this is not the case anymore and injection of cancer cells can then
lead to cancer in the host.
3.6 Tumor virus genomes persist in virus-transformed cells
by becoming part of host-cell DNA
Display of the virus-induced tumor antigens correlates with the transformed state. This
correlation suggests that the gene sequence responsible for the transformation is associated
with the viral sequence encoding for the T antigen.
The cell-to-cell transmission of viral genomes over generations is only possible if it is
integrated into the host DNA. For retroviruses this is the standard. For the SV40 virus it can
happen when the circular DNA breaks and linearizes. It can then recombine with the host cell
chromosomes. Often, only the oncogenic genetic information can be found in the
chromosomes of the cancer cells. They thus insert oncogenes in the host genome. Some
viruses maintain their entire genome in the chromosomes by inserting in the telomeric
repeats. More common is for them to maintain the genomes in episomes (unintegrated
genetic elements).
3.7 Retroviral genomes become integrated into the
chromosomes of infected cells
The ssRNA of retroviruses is made into a cDNA by the reverse transcriptase. The resulting
dsDNA can integrate into the host chromosome with the enzyme integrase to form a
provirus. This provirus can then make new viral RNA with the host RNA polymerase II.
gag proteins that are part of the nucleoprotein core
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