Angiogenesis Petronini Flashcards
importances and dangers of Formation of new blood vessels:
essential in physiological processes such as embryonic development, wound repair,
endometrial growth.
It is critical in pathological processes such as diabetes, arthritis, psoriasis, endometriosis,
tumor growth and metastases.
On the contrary, we can have a disease related to the deficiency of functional blood vessels
that contributes to a variety of ischemic symptoms in cardio and cerebrovascular diseases.
Examples related to angiogenesis:
- Angiogenesis by mobilisation of EPCs (endothelial precursor cells) from the bone marrow,
They move from the bone marrow and reach the site where vasculogenesis is important.
There is the formation of the capillary plexus. - Angiogenesis from pre-existing vessels.
The formation of blood vessels occurs through 2 processes:
1) VASCULOGENESIS - characteristic of embryonic development
2) ANGIOGENESIS - important during reparative processes, in connective reintegration and
in tumour growth.
Stages of the angiogenesis process:
5 stages are important:
1. Proteolytic degradation of the basal membrane and capillary bud formation
2. Migration of endothelial cells
3. These endothelial cells will undergo proliferation
4. Maturation
5. Recruitment of periendothelial cells
Here is represented the process of physiological angiogenesis during the repair of a wound
Tumour angiogenesis is very similar in its stages to a physiological angiogenesis but unlike
physiological angiogenesis, the tumour vessels are ___________________________
irregular, tortuous, less stable, and less
defined
In the normal case, the vessels, and the mature network is stable, and the structure and
the function of the wall are appropriate to the location.
In the case of tumor, the evolving network is unstable, has an abnormal structure and
function and is inappropriate for location.
While arterioles, capillaries, and venules are clearly distinguishable in the normal vascular
system, in a tumour the vessels are disorganized and unidentifiable
the tumour stops
growing when it reaches a diameter of 1mm. For a tumour to continue to grow, it must
develop onside the _____________________
network of blood vessels.
HIF target genes:
When a tumor has a high level of HIF-1α, that is not very good, on the contrary, it’s very
bad because you have chemoresistance. You have influenced metabolism, so you increase
glucose uptake and glycolytic enzymes.
The activation of β catenin induces cell proliferation. Β Catenin is degraded when an
oncosuppressor gene called APC is present.
When APC is absent you have a disease called familial polyposis of the colon.
HIF is also able to induce EMT, epithelial to mesenchymal transition (very important in
metastasis).
HIF induces angiogenesis, endothelial cells migration, proliferation, maturation so it induces
tumour vascularisation. (a very important factor in cancer)
Tumour cells release___________ and these factors
are able to induce the vascularisation of the tumour, so that the tumour starts to grow very
rapidly.
1 mm of capillaries can feed 10,000 neoplastic cells
TAF (tumor angiogenesis factors)
Many years ago, Judah Folkman studied this process in detail. These experiments were
performed on the rabbit cornea.
A small piece of tumour was placed in the anterior chamber of the rabbit but the tumour did
not grow, it was alive though, until a signal ________ produced by the tumour induced the iris to
produce new vessels. Then what happens is that the tumour grows so fast. (So, tumors release tumour angiogenetic factors)
tumour angiogenesis is actually controlled by an imbalance between __________________
factors of angiogenesis.
(TAF), promoter and inhibitory
Growth factors and receptors involved in angiogenesis:
VEGF, vascular endothelial growth factor, is also called VPF, vascular permeability factor
because new vessels have a higher permeability than all the other vessels.
VEGFR2: VEGF (growth factor) binds to these tyrosine kinase receptors (VEGFR2) auto
phosphorylation of the receptor happens and then activation of the signal transduction
pathway, which culminates with the activation of transcription factors.
HIF: hypoxia inducible factor
Hypoxia activates HIF-1 or HIF-2
Just for a reminder: this factor is composed of 2 subunits α and β and in normoxia the α
subunit is hydroxylated and degraded by proteasomes.
In hypoxia the α subunit isn’t hydroxylated, it’s stable as it’s bound to the β subunit and it induces
the transcription of different genes whose products are related to angiogenesis, so VEGF is
related to glucose metabolism (glucose transporter and enzymes involved in glycolytic
processes) and induces cell proliferation
When HIF-1 is activated, it induces the synthesis of erythropoietin. Erythropoietin binds
onto CFU cells and induces the survival and proliferation of CFU, colony forming unit.
These cells have the receptors with the highest affinity for erythropoietin
Inhibitors of angiogenesis:
these can inhibit this process
Angiostatin (fragment of the plasminogen)
Endostatin and Tumstatin (collagen fragments)
MUTATIONS OF ONCOGENES OR ONCOSUPPRESSORS ALSO
REGULATE THE BALANCE OF ANGIOGENESIS:
RAS MAPK, mitogen-activated protein kinase - important in the transduction pathway
MYC, transcription factor - this gene is amplified in certain tumors, translocated in other
tumors
ex: in the Burkitt lymphoma (chromosome 8 in humans)
P53, the most important onco-suppressor, it’s the garden of the genome
Bevacizumab:
a very important drug! the monoclonal antibody that binds VEGF (binds to the
factor, not the receptor). VEGF blockage induces tumor regression.
* Bevacizumab binds to VEGF by blocking interaction with receptors and activation of
downstream signal transduction
* VEGF blockage induces regression of tumor vascularity
It can block neoangiogenesis, but it’s also able to induce a normalization to these
vessels so that the drugs can reach the tumor and the component of the immune system
(ex. Lymphocytes) can also reach the tumor. Therefore, it improves both the effect of the
immune system on tumor cells and the action of therapeutic drugs.
In vitro, transfection studies have shown since the 1980s that no single oncogene can
completely transform undamaged cells in vitro. It is usually necessary to alter an oncogene
whose product is _________ and an oncogene whose product is __________. So if you want to
obtain a tumor cell from a normal cell, one oncogene is not enough, you need to use 2
oncogenes. 1 localized in the nucleus and the other in the cytoplasm
nuclear, cytoplasmic
For example: myc nuclear oncogene and src cytoplasmic oncogene. (src is present in Rous sarcoma virus)
Myc and ras: the oncogenic versions of myc and ras are easily obtained. You can use a
mutated 1 or, better, you can put these genes under the control of a promoter (this is a better
solution)
Promoters are present in the LTR sequence (long terminal repeats)
Other ways of blocking neoangiogenesis:
There’s another possibility to block this process.
VEGFR is a tyrosine kinase receptor.
Sunitinib
Sorafenib
-Nib endings (different from -mab) are tyrosine kinase inhibitors.
So, these 2 are used as drugs in kidney cancer because they block the angiogenesis
Carcinogenicity is a multi-step process:
A clear example of the multi-facility of carcinogenesis in human pathology is colon cancer
associated with the alteration of the oncosuppressor gene APC.
You have a normal tissue (mucosa, submucosa, muscularis propria) and an inherited
mutation at the germ-line “first hit” (most of the onco-suppressor genes must be inactivated
by “2 hits”, but there is an oncosuppressor that has a dominant behavior which is p53).
P53 is a tetramer, 1 mutated subunit of the tetramer is enough to make p53 not work correctly. APC is located on chromosome 5 (long arm, position 2 1)
“2nd hit”: eg. Methylation of the promoter, inactivating APC.
B catenin is free, it’s a transcription factor that induces the proliferation of these epithelial cells.
The signal transduction pathway is called wnt beta-catenin.
Then we have a proto-oncogene mutation. A typical example is K-ras (this version of ras is
present in the Kirsten virus). The protooncogene ras becomes an oncogene by a point mutation.
Then there’s loss of additional cancer suppressor genes and overexpression of COX-2 (a
chemical mediator of inflammation and it’s produced starting from arachidonic acid. 2
enzymes are involved cox-1 and cox-2, cox 2 produces prostaglandin)
Remember the link between inflammation and cancer, inflammation is an evolved mark of
cancer.
P53 is mutated or lost, SMAD2 and SMAD4 are molecules involved in the transduction
signal starting from TGF beta (transforming growth factor beta) which is a growth factor that
doesn’t stimulate the proliferation of epithelial cells but it’s able to inhibit the proliferation of
epithelial cells.
Additional mutations, for example, gross alteration in chromosomal number and structure,
activation of telomerase and many other genes.
We start from a normal colon, we move to a mucosa at risk, then to adenomas, and end in
carcinoma in situ and invasive carcinoma.
In this additional mutation, we can introduce receptor MET that induces motility of the cells.
So, we can associate a molecular alteration to the histology of the tumor.
