Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for new blood vessel formation by splitting off existing ones.
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one. The identification of an angiogenic diffusible factor derived from tumors was made initially by Greenblatt and Shubik in 1968.
Cancer cells are cells that have lost their ability to
divide in a controlled fashion. A tumor consists of a population of
rapidly dividing and growing cancer cells.
Mutations rapidly accrue within the population. These
mutations (variation) allow the cancer cells (or sub-populations of
cancer cells within a tumor) to develop drug resistance and escape
therapy. Tumors cannot grow beyond a certain size, generally 1–2 mm³ ,
due to a lack of oxygen and other essential nutrients.
Tumors induce blood vessel growth (angiogenesis) by
secreting various growth factors (e.g. Vascular Endothelial Growth
Factor or VEGF).
Growth factors such as bFGF and VEGF can induce capillary
growth into the tumor, which some researchers suspect supply required
nutrients, allowing for tumor expansion.
On 18 July 2007 it was discovered that cancerous cells stop
producing the anti-VEGF enzyme PKG. In normal cells (but not in
cancerous ones), PKG apparently limits beta-catenin which solicits
Other clinicians believe that angiogenesis really serves as a
waste pathway, taking away the biological end products put out by
rapidly dividing cancer cells.
In either case, angiogenesis is a necessary and required
step for transition from a small harmless cluster of cells, often said
to be about the size of the metal ball at the end of a ball-point pen,
to a large tumor.
Angiogenesis is also required for the spread of a tumor, or
metastasis. Single cancer cells can break away from an established solid
tumor, enter the blood vessel, and be carried to a distant site, where
they can implant and begin the growth of a secondary tumor.
Evidence now suggests that the blood vessel in a given solid
tumor may in fact be mosaic vessels, composed of endothelial cells and
This mosaicity allows for substantial shedding of tumor
cells into the vasculature, possibly contributing to the appearance of
circulating tumor cells in the peripheral blood of patients with
The subsequent growth of such metastases will also require a
supply of nutrients and oxygen or a waste disposal pathway.
Endothelial cells have long been considered genetically more
stable than cancer cells. This genomic stability confers an advantage
to targeting endothelial cells using antiangiogenic therapy, compared to
chemotherapy directed at cancer cells, which rapidly mutate and acquire
'drug resistance' to treatment.
For this reason, endothelial cells are thought to be an
ideal target for therapies directed against them.
Recent studies by Klagsbrun, et al. have shown, however,
that endothelial cells growing within tumors do carry genetic
abnormalities. Thus, tumor vessels have the theoretical potential for
developing acquired resistance to drugs. This is a new area of
angiogenesis research being actively pursued.
Formation of tumor blood vessels
Tumour blood vessels have perivascular detachment, vessel
dilation, and irregular shape. It is believed that tumor blood vessels
are not smooth like normal tissues and are not ordered sufficiently to
give oxygen to all of the tissues.
Endothelial precursor cells are organized from bone marrow,
which are then integrated into the growing blood vessels. Then the
endothelial cells differentiate and migrate into perivascular space, to
form tumour cells.
Vascular endothelial growth factor (VEGF) plays a crucial
role in the formation of blood vessels that lead to tumor growth, which
allows the vessel to expand. It is called sprouting angiogenesis.
Angiogenesis research is a cutting edge field in cancer
research, and recent evidence also suggests that traditional therapies,
such as radiation therapy, may actually work in part by targeting the
genomically stable endothelial cell compartment, rather than the
genomically unstable tumor cell compartment.
New blood vessel formation is a relatively fragile process,
subject to disruptive interference at several levels. In short, the
therapy is the selection agent which is being used to kill a cell
Tumor cells evolve resistance rapidly due to rapid
generation time (days) and genomic instability (variation), whereas
endothelial cells are a good target because of a long generation time
(months) and genomic stability (low variation).
This is an example of selection in action at the cellular
level, using a selection pressure to target and differentiate between
varying populations of cells.
The end result is the extinction of one species or
population of cells (endothelial cells), followed by the collapse of the
ecosystem (the tumor) due either to nutrient deprivation or
self-pollution from the destruction of necessary waste pathways.
Angiogenesis-based tumour therapy relies on natural and
synthetic angiogenesis inhibitors like angiostatin, endostatin and
These are proteins that mainly originate as specific
fragments pre-existing structural proteins like collagen or plasminogen.
Recently, the 1st FDA-approved therapy targeted at
angiogenesis in cancer came on the market in the US. This is a
monoclonal antibody directed against an isoform of VEGF.
The commercial name of this antibody is Avastin, and the
therapy has been approved for use in colorectal cancer in combination
with established chemotherapy.
Angiogenesis for cardiovascular disease
Angiogenesis represents an excellent therapeutic target for
the treatment of cardiovascular disease. It is a potent, physiological
process that underlies the natural manner in which our bodies respond to
a diminution of blood supply to vital organs, namely the production of
new collateral vessels to overcome the ischemic insult.
Perhaps the greatest reason for these trials’ failure to
achieve success is the high occurrence of the “placebo effect” in
studies employing treadmill exercise test readout.
Thus, even though a majority of the treated patients in
these trials experience relief of such clinical symptoms such as chest
pain (angina), and generally performed better on most efficacy readouts,
there were enough “responders” in the blinded placebo groups to render
the trial inconclusive.
In addition to the placebo effect, more recent animal
studies have also highlighted various factors that may inhibit an
angiogenesis response including certain drugs, smoking, and
Although shown to be relatively safe therapies, not one
angiogenic therapeutic has yet made it through the gauntlet of clinical
testing required for drug approval.
By capitalizing on the large database of what did and did
not work in previous clinical trials, results from more recent studies
with redesigned clinical protocols give renewed hope that angiogenesis
therapy will be a treatment choice for sufferers of cardiovascular
disease resulting from occluded and/or stenotic vessels.
Early clinical studies with protein-based therapeutics
largely focused on the intravenous or intracoronary administration of a
particular growth factor to stimulate angiogenesis in the affected
tissue or organ.
Most of these trials did not achieve statistically
significant improvements in their clinical endpoints.
This ultimately led to an abandonment of this approach and a
widespread belief in the field that protein therapy, especially with a
single agent, was not a viable option to treat ischemic cardiovascular
However, the failure of gene- or cell-based therapy to
deliver, as of yet, a suitable treatment choice for diseases resulting
from poor blood flow, has led to a resurgence of interest in returning
to protein-based therapy to stimulate angiogenesis.
These failures suggested that either these are the wrong
molecular targets to induce neovascularization, that they can only be
effectively utilized if formulated and administered correctly, or that
their presentation in the context of the overall cellular
microenvironment may play a vital role in their utility.
It may be necessary to present these proteins in a way that
mimics natural signaling events, including the concentration, spatial
and temporal profiles, and their simultaneous or sequential presentation
with other appropriate factors.
Lessons learned from earlier protein-based studies, which
indicated that intravenous or intracoronary delivery of the protein was
not efficacious, have led to completed and ongoing clinical trials in
''which the angiogenic protein is injected directly into the beating
Such localized administration of the potent angiogenic
growth factor, human FGF-1, has recently given promising results in
clinical trials in no-option heart patients.
Angiogenesis is generally associated with aerobic exercise
and endurance exercise. While arteriogenesis produces network changes
that allow for a large increase in the amount of total flow in a
network, angiogenesis causes changes that allow for greater nutrient
delivery over a long period of time.
Capillaries are designed to provide maximum nutrient
delivery efficiency so an increase in the number of capillaries allows
the network to deliver more nutrients in the same amount of time.
A greater number of capillaries also allows for greater
oxygen exchange in the network.
This is vitally important to endurance training because it
allows a person to continue training for an extended period of time.
However, no experimental evidence exists to suggest that increased
capillarity is required in endurance exercise to increase the maximum
Overexpression of VEGF causes increased permeability in
blood vessels in addition to stimulating angiogenesis. In wet macular
degeneration VEGF causes proliferation of capillaries into the retina.
Since the increase in angiogenesis also causes edema, blood
and other retinal fluids leak into the retina causing loss of vision.
A novel treatment of this disease is to use a VEGF
inhibiting siRNA to stop the main signaling cascade for angiogenesis.
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