Lecture notes
TUMOURGENESIS
- Module
- Mechanisms of pathology
- Institution
- Aston University, Birmingham (Aston)
Lecture notes of 8 pages for the course Mechanisms of pathology at Aston (IMMUNOLOGY NOTES)
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Tumorigenesis: oncogenes and tumour suppressor genes.Tumorigenesis.
Formation of a tumour is a very long-lasting event.
Cell proliferation is going to take a very long time.
Tumours form in decades 30,40, 50 years.
The steps towards tumorigenesis.
It is a long-lasting process as there are many different requirements that are
important for the cancer to form.
There are 6 different processes/pathways that are needed to be hijacked and
affected so that a normal cell can become a tumour cell:
Tumorigenesis is the formation of a primary tumour the pathways that are important
for this are: they have to have insensitivity to anti-growth signal because the tumour
cells are going to be forcing that cell to not divide anymore because they know
something is wrong and they are going to be ordering them to fall back in ranks.
they need to grow sufficiently and have a self-sufficiency in growth signal so they will
have to stimulate themselves because no one else will want to do so.
lots of processes will be activated to make sure that the cells are dying so apoptosis
will be triggered, so they have to protect themselves and make sure that they do not
die so they will have to evade apoptosis.
When all of this is taken care of, one of the effects that they are going to have to
deal with is potential limitless replication. This is because most cells in our body, only
have a very small amount of replication within themselves, they cannot grow
forever, tumour cells we need to do so if they want to become a true potential
cancer. They will have to find a way to give themselves limitless replicative potential.
The first best way would be to become hyperplastic and start growing, growing and
forming a neoplasm and finding ways to proliferate.
Self-sufficiency in growth signals.
We are going to have to increase the cell-division and allow for pathways to be
activated so that they can grow.
Protooncogene would have to be activated, and on the process of activation it will
become an oncogene.
What are oncogenes?
Oncogenes are activated genes, they are constitutively activated/gain of functioning,
which allows them to induce cell proliferation.
For example, there is an experiment done where you can find out what an oncogene
is:
If you have a fibroblast, which is not a cancer or tumour, they have an ability to
proliferate extensively. This is because something in their DNA has been affected
which allows them to do that.
If you take the DNA of the transformed fibroblast, and you transfect the DNA, so you
introduce the DNA into new cells that are not transformed and not highly
proliferative, you will be able to form a proliferative form of cells. This means that
, some information that was found in the DNA has been changed in some way that the
protooncogene has become an oncogene and has allowed for the cells to proliferate.
This proliferating fibroblast can be used and eventually may become a tumour.
These are the molecules that have the ability to drive cells into proliferation.
It is due to a gain of function.
Mechanisms for converting proto-oncogenes into oncogenes.
There are different ways in how the proto-oncogene can become an oncogene.
There are mutagenic events, this means that there is a mutation taking place.
It can be a single point mutation, where you have a single change of the DNA.
It can be gene amplification, or it can be something as severe as chromosomal
translocation, where pieces of chromosome are moved from one chromosome to
the other.
There can be insertional mutations, so certain parts of DNA are going to integrate
themselves into chromosomes any mobile element can do that.
Sometimes you can have deletion or insertion of pieces of DNA, in a local region of
your genes.
We are looking at how the protooncogene would be affected, and in all cases, this is
where mutation will take place, and this will basically lead to changes in the DNA.
This is what you get to see when you get initiation.
It is believed that the initiation/formation of the neoplasm, the first stage is a
mutagenetic event and the protooncogene is more likely to be affected there.
How do you achieve growth factor independence?
In the context of cells in general, cells are told when to proliferate.
Cells do not make decisions on their own.
There are always growth factors that are being synthesised and released either in
the blood stream or neighbouring tissues, or neighbouring cells, they will wait for
promotion of proliferation.
They do not make the decision on their own and they will usually wait for growth
factors to be released.
The growth factors will eventually lead to a pathway.
Growth factor pathway that can lead to cellular proliferation:
Growth factor is released, it is binds to receptors (RTKs), the receptor gets
phosphorylated, adaptor proteins get affected, usually GTP exchange factors are
being activated, this will lead to the GDP GTP recycling onto a RAS protein potentially
or a G protein. Then there is a subsequent advancement of kinase activation which is
induced, this will lead to the transcription factor activation. Transcription factor will
lead to the activation of certain proteins, then the cell may or may not proliferate
depending on the pathway.
Growth factor independence means that the growth factor is not coming in, it is not
coming in from neighbouring cells and the blood stream and other things.
So this pathway should be fulfilled and activated potentially without the presence of
growth factors coming from neighbouring cells.
All components of this pathway could potentially be seen as protooncogene to
become an oncogene.
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