The term
Angiogenesis was first used by Dr. John Hunter, a
British surgeon in 1787 to describe the growth of new blood vessels in
Reindeer antlers. It occurs in healthly
tissue, where it is used by the body to repair
damage caused by
wounds. In
women it also occurs during the
reproductive cycle, (to rebuild the lining of the
uterus), also during
pregnancy to make the
placenta and (of course!) in the
baby itself.
The body naturally produces chemicals which both
stimulate and
inhibit this process, and disease can occur when the balance between
growth and inhibition is upset.
Excessive angiogenisis can occur when
diseased cells, (such as
cancer cells) release angiogenic growth factors, which tips the balance in favour of rapid new blood vessel production. These new blood vessels can rip though healthy
organs and tissues, impairing their function. Also in cancerous tissues this influx of new blood not only helps a
tumour grow, but provides it with the means to
sow the seeds of new tumours, by spreading cancerous cells throughout the body. (
Metastases)
More than 70 other conditions have been linked to excessive angiogenis, such as
psoriasis,
diabetic blindness and diabetic
ulcers,
rheumatoid arthritis, even the
degeneration of our
eyes as we
age.
If you can't produce enough angiogenetic growth factors,
wound healing may be greatly slowed, which can cause
necrosis of the affected area.
Coronary heart disease and
stroke have also been linked to insuffiecent AGF.
Needless to say, these are
important targets for
drug companies, and a huge amount of ongoing research is targeting angiogenesis. Indeed in 1999 Dr. Richard Klausner, the director of the
USA National Cancer Institute targeted angiogenenic therapies as a
national priority. It's easy to see why, cancer is one of the biggest killers, and trials have shown
regression or even complete
remision of cancers in many patients.
The Process of Angiogenesis
- Angeniogenic growth factor production. (AGF)Damaged (or diseased) tissues release angiogenic growth factors, that diffuse out into surrounding tissue.
- Receptor binding. Once the AGF's reach existing blood vessels, they bind to receptors on endothelial cells
- Endothelial cell activation. The binding of the AGF stimulates the cell to produce enzymes. These enzymes dissolve holes into the porous basement membrane that surrounds the blood vessels, until the holes are large enough for cells to pass through.
- Endothelial cell proliferation. The EC's undergo rapid cell division and diffuse out into the extra cellular matrix (ECM).
- Directional migration. The damaged tissues leak chemicals that allow the migrating cells to move toward the affected area, by moving from low to high concentration. Also integrin (fibrin) molecules are released from the affected area, which also provide a path, as well as supporting the nascent bloodvessel.
- ECM remodelling. A path is cleared through the matrix by metalloproteinases(MMP's), these enzymes literally dissolve the tissue in front of the advancing endothelial cells. Some of the breakdown products of the ECM can in fact promote the angiogenic response, helping the growth of the tip of the new blood vessel.
- Tube formation. Once the process is mature enough, the endothelial cells roll up to form a tube, strong enough to carry blood vessels.
- Loop formation. During this stage the loops needed to carry blood to and from the damaged tissue are formed.
- Vascular stabilisation. Finally the vessel is made strong enough to cope with blood flow by smooth muscle cells providing structural support. Only then does blood flow begin.
Anti-
cancer treatments can work inhibiting any of the above stages.