Oncology 2 petronini Flashcards
- 1910: discovery of the first oncogenic virus called?
“Rous sarcoma virus
it is able to induce sarcoma when inoculated in a chicken leg
- 1960: identification of a gene present in the genome of the Rous sarcoma virus responsible for
the sarcoma induction
This oncogene is called v-Src (Src is the abbreviation of “sarcoma”)
- 1974: demonstration that in the genome of normal cells (even in that of cells that have never
been in contact with the virus) there’s a gene called Src which is a ______________, the normal
version of an oncogene.
proto-oncogene
These genes are really useful during embryogenesis and differentiation due to their cell proliferation control abilities, which is why they show high evolutionary conservation and are expressed by
normal cells.
We have called the product of these genes “accelerators” since they stimulate proliferation in cells.
what are slow transforming retroviruses or chronic retroviruses?
These viruses don’t transform the cells in culture and are able to induce tumors but in a
very long time span. In fact these viruses to induce the tumor need to integrate their genome near
a proto-oncogene.
Why when the genoma of retroviruses is inserted into host DNA near a proto-oncogene induces a
tumor? Because these viruses have two sequences called “long terminal repeats”, that contain
promoter and enhancer sequences which are really strong, so they can modulate the expression of
the proto-oncogene. In this situation the proto-oncogene is expressed at very high level.
A proto-oncogene can become an oncogene by two modalities:
- Qualitative: the oncogene is mutated, the sequence is mutated from the normal one (the proto-oncogene);
- Quantitative: the product is expressed at really high levels.
Right now we know a lot of viral oncogenes. Here are some examples:
-The v-onc present in the “ Rous sarcoma virus” was called: v-src
-The v-onc present in the “feline sarcoma virus” was called: v-fes
-The v-onc present in the “simian sarcoma virus” was called: v-sis
The difference between an acute virus and a chronic one is the presence of __________ in the acute one,
absent in the chronic one.
v-onc
Both contain:
-Gene gag: encoding for internal structural proteins
-Gene pol: encoding for reverse transcriptase, integrase and protease
-Gene env: coding for outer viral envelope proteins. In the case of HIV in that region of the virus we
have gp120 and gp41 (glycoproteins).
-LTR: regulatory sequences (contain transcriptional promoters and enhancers)
Src is the oncogene src.
These enzymes are very important for the replication of the virus.
Steps of the retroviral replication cycle:
- binding to the cell membrane receptor (CD4 is the receptor for Hiv and binds with very high affinity gp120);
- release of genetic material into the cytoplasm (the genome of a retrovirus is composed by two
molecules of single filaments of RNA); - the RNA filament is retro-transcribed into DNA filament, so you obtain a DNA double strand
called provirus, then integrated in the cell genome; - when the DNA of the cell is transcribed also the viral one is transcribed, this RNA will be the
virus genetic material, the mRNA will codify for viral proteins and will translate into viral proteins.
At the end we have the budding of the virus, when a piece of cell membrane is taken up by the
virus and, together with envelope proteins, constitute its new envelope.
In this case the information is not from DNA to protein, but from RNA to DNA to RNA protein.
Temin and Baltimore described this replication process.
________are not present in all oncogenic viruses, for example in chronic retroviruses they are absent.
To induce the formation of a tumor the viral genome has to be integrated near a proto-oncogene.
[Src for example]
V-onc
Typical characteristics of transformed cells:
A transformed cell has specific characteristics:
* Changes in cell morphology
* Changes in growth (no contact inhibition)
* Growth capacity independent of growth factors, they are also able to grow in medium without
serum (fetal calf serum able to induce the proliferation of fibroblast or epithelial cells). In serum
are present pdgf, egf, insulin growth factors, fibroblast growth factors. Most of these growth factors are released into the serum during platelets clotting.
* Unlimited growth capacity (immortalization), autocrine stimulation growth. (One of the 3 ways of
Communication between cells, the others are paracrine and endocrine)
* Alterations in the differentiation
* Anchor-independent growth capacity, transformed cells are able also to grow in soft agar, normal
cells don’t because in this situation interaction to the extracellular cell matrix is lacking. A proliferation of a normal cell depends on two signals: soluble factors (pdgf) and extracellular matrix.
* Transformed cells don’t need serum, they can grow even without it
In the course of evolution RNA viruses acquired the cellular oncogene from animal genomes by
_________________
genetic recombination
characteristics of Acute transforming retroviruses?
- Contain oncogenes (v-onc)
- Are defective in the replication
- Induce polyclonal tumors (100% efficiency) in a few days
The v-onc originates from a proto-oncogene that is embedded in the genome of a retrovirus that
has replicative capability.
The v-onc differs from the proto-oncogene by: - Lack of introns
- Truncated gene (e.g. v-Src)
- Presence of point mutations (ex. v-ras)
- Frequent fusion between viral and oncogene gene (e.g. gagonc or env-onc)
- Very high expression under LTR control
Here some examples // no need to remember all of these, just v-src //
V-src is a cytoplasmic tyrosine kinase
characteristics of Chronic transforming retroviruses?
They do not have v-onc. Remember this example : Avian leukosis virus (ALV), that induces
leukemia in birds.
The provirus is ALWAYS integrated in the same position of the cellular genome, this is important
because only in this condition you have the appearance of the tumor that is monoclonal. In ALV-induced tumors, provirus is always integrated near the v-myc gene, expressed at very high level.
The effect can be related to the promoter but also to the enhancer activity of specific viral sequences.
During the insertion there’s the possibility of insertional mutagenesis, retroviruses are able to transform the cells because they have the viral oncogene or they integrate the genome near a protooncogene that is over expressed or mutated by insertional mutagenesis.
Crucial event for transformation is therefore rare and cells forming a tumor are a clone (monoclonal
tumors).
Retrovirus insertion near the proto-oncogene v-myc increases cell protein expression and makes it
independent of normal control systems.
Even if they do not have a v-onc the end result is the same as if the virus encodes a v-onc.
Leukemia lymphoma is one of the few tumors we can get from these viruses, since they are not
that harmful for humans, but they are really important because thanks to them we discovered
oncogenes.
normal proto-oncogenes can, independently from viruses, undergo such
modifications that they become real cellular oncogenes which, in this case, take the name of _________
c-onc.
A proto-oncogene is therefore a normal gene, essential for cell growth, that can however become
oncogene due to mutations or increased expression.
Why a proto-oncogene becomes mutated?
There are physical, chemical (UV radiations, ionizing radiations…) and biological causes.
The gene changes (mutations) that transform proto-oncogenes into oncogenes are mainly of two
functional types:
- Changes in the structure of the gene (point mutations) resulting in the synthesis of a qualitatively
abnormal gene product with ‘aberrant and/or resistant to down-regulation mechanisms of
activity’.
- Changes in the regulation of gene expression that cause an increased synthesis of normal protein but no longer quantitatively adjustable.
The main types of mutations responsible for both conditions are: point mutations, chromosomal
rearrangements (inversions, translocations), deletions, gene amplification.
