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Understanding
Angiogenesis
Angiogenesis
(angio'gen'esis) - the growth of new blood vessels - is an
important natural process occurring in the body, both in health and in
disease.
The Body's Control
of Angiogenesis
Angiogenesis occurs in the healthy body for healing wounds and for restoring
blood flow to tissues after injury. In females, angiogenesis also occurs
during the monthly reproductive cycle (to rebuild the uterus lining, to
mature the egg during ovulation) and during pregnancy (to build the placenta,
the circulation between mother and fetus).
The healthy body controls angiogenesis through a series of "on" and "off"
switches:
- The main "on switches" are known as angiogenesis-stimulating
growth factors
- The main "off switches" are
known as angiogenesis inhibitors
When angiogenic growth factors are produced in excess of angiogenesis
inhibitors, the balance is tipped in favor of blood vessel growth. When
inhibitors are present in excess of stimulators, angiogenesis is stopped.
The normal, healthy body maintains a perfect balance of angiogenesis modulators.
In general, angiogenesis is "turned off" by with more inhibitors being
produced than stimulators.
Tumors produce large amounts of angiogenic growth factors, overwhelming
natural inhibitors, to recruit their own blood supply.
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Known Angiogenic Growth Factors |
| Angiogenin |
Placental
growth factor |
| Angiopoietin-1
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Platelet-derived
endothelial cell growth factor (PD-ECGF) |
| Del-1
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Platelet-derived
growth factor-BB (PDGF-BB) |
| Fibroblast
growth factors: acidic (aFGF) and basic (bFGF) |
Pleiotrophin
(PTN) |
| Follistatin
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Proliferin
|
| Granulocyte
colony-stimulating factor (G-CSF) |
Transforming
growth factor-alpha (TGF-alpha) |
| Hepatocyte
growth factor (HGF) /scatter factor (SF) |
Transforming
growth factor-beta (TGF-beta) |
| Interleukin-8
(IL-8) |
Tumor
necrosis factor-alpha (TNF-alpha) |
| Leptin
|
Vascular endothelial
growth factor (VEGF)/vascular permeability factor (VPF)
|
| Midkine
|
Progranulin |
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| Known Angiogenesis Inhibitors |
| Angiostatin
(plasminogen fragment) |
Metalloproteinase
inhibitors (TIMPs) |
| Antiangiogenic
antithrombin III (aaATIII) |
Pigment
epithelial-derived factor (PEDF) |
| Canstatin
|
Placental
ribonuclease inhibitor |
|
Cartilage-derived
inhibitor (CDI) |
Plasminogen
activator inhibitor |
| CD59
complement fragment |
Platelet
factor-4 (PF4)
|
| Endostatin
(collagen XVIII fragment) |
Prolactin
16kD fragment |
| Fibronectin
fragment |
Proliferin-related
protein |
| Gro-beta |
Retinoids
|
| Heparinases
|
Tetrahydroco |
| Heparin
hexasaccharide fragment |
rtisol-S
|
| Human
chorionic gonadotropin (hCG) |
Thrombospondin-1 |
| Interferon
alpha/beta/gamma |
Transforming
growth factor-beta |
| Interferon
inducible protein (IP-10) |
Tumistatin |
| Interleukin-12
(IL-12) |
Vasculostatin |
| Kringle
5 (plasminogen fragment) |
Vasostatin
(calreticulin fragment) |
| 2-Methoxyestradiol
(2-d) |
Angioarrestin |
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The Angiogenesis
Process: How Do New Blood Vessels Grow?
 The
process of angiogenesis occurs as an orderly series of events:
- Diseased or injured tissues produce and release angiogenic growth factors
(proteins) that diffuse into the nearby tissues
- The angiogenic growth factors bind to specific receptors located on
the endothelial cells (EC) of nearby preexisting blood vessels
- Once growth factors bind to their receptors, the endothelial cells become
activated. Signals are sent from the cell's surface to the nucleus. The
endothelial cell's machinery begins to produce new molecules including
enzymes
- Enzymes dissolve tiny holes in the sheath-like covering (basement membrane)
surrounding all existing blood vessels
- The endothelial cells begin to divide (proliferate), and they migrate
out through the dissolved holes of the existing vessel towards the diseased
tissue (tumor)
- Specialized molecules called adhesion molecules, or integrins (αvß3,
αvß5)
serve as grappling hooks to help pull the sprouting new blood vessel sprout
forward
- Additional enzymes (matrix metalloproteinases, or MMP) are produced
to dissolve the tissue in front of the sprouting vessel tip in order to
accommodate it. As the vessel extends, the tissue is remolded around the
vessel
- Sprouting endothelial cells roll up to form a blood vessel tube
- Individual blood vessel tubes connect to form blood vessel loops that
can circulate blood
- Finally, newly formed blood vessel
tubes are stabilized by specialized muscle cells (smooth muscle
cells, pericytes) that provide structural support. Blood flow
then begins.
Angiogenesis Facts
& Figures
- Blood vessel cells do not normally grow in the healthy adult
- they are normally inactive, or quiescent.
- If all the blood vessels in the body were lined up end-to-end,
they would form a line that could encircle the earth twice.
- Blood vessel cells do not normally grow in the healthy adult
- they are normally inactive, or quiescent.
- There are at least 20 angiogenic growth factors.
- Five of the angiogenic growth factors are also being tested
in humans for growing new blood vessels to restore health to tissues
such as wounds, and to restore blood flow to the heart, limbs,
and brain.
- There are at least 30 known angiogenesis inhibitors found naturally
in the body.
- The first angiogenesis inhibitor molecule was discovered in
1975 by Dr. Judah Folkman and Dr. Henry Brem during their study
of cartilage, a tissue that resists blood vessel growth
- Angiogenesis inhibitors have also been discovered from many
sources in Nature, including: tree bark, fungi, mushrooms, shark
muscle and cartilage, sea coral, green tea, and herbs (licorice,
ginseng, cumin, garlic).
- More than 300 angiogenesis inhibitors have been discovered to
date.
- An estimated 14 million cancer patients could benefit from
an antiangiogenic therapy.
- The first successful treatment of an angiogenesis-dependent
disease occurred in 1989, when the drug interferon alfa2a, an
angiogenesis inhibitor, was used to regress the abnormal blood
vessels growing in the lungs of a boy with a benign disease called
pulmonary hemangiomatosis.
- At least 10,000 cancer patients have already received some
form of experimental antiangiogenic therapy.
- Some cancer patients have experienced stabilization of their
disease from antiangiogenic therapy; a few have experienced dramatic
shrinkage of their tumor.
- More than $4 billion has been invested in the research and
development angiogenesis-based medicines, making this one of the
most heavily funded areas of cancer research in human history
For More Information
If you are a patient and would like to learn more about angiogenesis, please
contact us at: patienthelp@angio.org
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