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 the production of more inhibitors than stimulators.

Known Angiogenic Growth Factors

Angiogenin

Angiopoietin-1

Del-1

Fibroblast growth factors: acidic (aFGF) and basic (bFGF)

Follistatin

Granulocyte colony-stimulating factor (G-CSF)

Hepatocyte growth factor (HGF) /scatter factor (SF)

Interleukin-8 (IL-8)

Leptin

Midkine

Placental growth factor

Platelet-derived endothelial cell growth factor (PD-ECGF)

Platelet-derived growth factor-BB (PDGF-BB)

Pleiotrophin (PTN)

Progranulin

Proliferin

Transforming growth factor-alpha (TGF-alpha)

Transforming growth factor-beta (TGF-beta)

Tumor necrosis factor-alpha (TNF-alpha)

Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF)

 

 

Known Angiogenesis Inhibitors

Angioarrestin

Angiostatin (plasminogen fragment)

Antiangiogenic antithrombin III

Cartilage-derived inhibitor (CDI)

CD59 complement fragment

Endostatin (collagen XVIII fragment)

Fibronectin fragment

Gro-beta

Heparinases

Heparin hexasaccharide fragment

Human chorionic gonadotropin (hCG)

Interferon alpha/beta/gamma

Interferon inducible protein (IP-10)

Interleukin-12

Kringle 5 (plasminogen fragment)

Metalloproteinase inhibitors (TIMPs)

2-Methoxyestradiol

Placental ribonuclease inhibitor

Plasminogen activator inhibitor

Platelet factor-4 (PF4)

Prolactin 16kD fragment

Proliferin-related protein (PRP)

Retinoids

Tetrahydrocortisol-S

Thrombospondin-1 (TSP-1)

Transforming growth factor-beta (TGF-b)

Vasculostatin

Vasostatin (calreticulin fragment)

Angiogenesis in Disease: The Big Picture
In many serious diseases states the body loses control over angiogenesis. Angiogenesis-dependent diseases result when new blood vessels either grow excessively or insufficiently.

Excessive angiogenesis:

• Occurs in diseases such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, and more than 70 other conditions.

• In these conditions, new blood vessels feed diseased tissues, destroy normal tissues, and in the case of cancer, the new vessels allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).

• Excessive angiogenesis occurs when diseased cells produce abnormal amounts of angiogenic growth factors, overwhelming the effects of natural angiogenesis inhibitors.

• Antiangiogenic therapies, aimed at halting new blood vessel growth, are used to treat these conditions.

Insufficient angiogenesis:

• Occurs in diseases such as coronary artery disease, stroke, and chronic wounds.
• In these conditions, blood vessel growth is inadequate, and circulation is not properly restored, leading to the risk of tissue death.
• Insufficient angiogenesis occurs when tissuse cannot produce adequate amounts of angiogenic growth factors.
• Therapeutic angiogenesis, aimed at stimulating new blood vessel growth with growth factors, is being developed to treat these conditions.

Angiogenesis is a disease common denominator
Angiogenesis, the growth of new blood vessels, is a “common denominator” shared by diseases affecting more than one billion people worldwide. This includes all cancers, cardiovascular disease, blindness, arthritis, complications of AIDS, diabetes, Alzheimer’s disease, and more than 70 other major health conditions affecting children and adults in developed and developing nations. Our vision is that angiogenesis-based therapies are a unifying approach to disease and will have the same impact in the 21st century that antibiotics had in the 20th century.

The Angiogenesis Process: How Do New Blood Vessels Grow?

The process of angiogenesis occurs as an orderly series of events:

1. Diseased or injured tissues produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues.
2. The angiogenic growth factors bind to specific receptors located on the endothelial cells (EC) of nearby preexisting blood vessels.
3. Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus.
4. The endothelial cell's machinery begins to produce new molecules including enzymes. These enzymes dissolve tiny holes in the sheath-like covering (basement membrane) surrounding all existing blood vessels.
5. The endothelial cells begin to divide (proliferate) and migrate out through the dissolved holes of the existing vessel towards the diseased tissue (tumor).
6. Specialized molecules called adhesion molecules called integrins (avb3, avb5) serve as grappling hooks to help pull the sprouting new blood vessel sprout forward.
7. 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.
8. Sprouting endothelial cells roll up to form a blood vessel tube.
9. Individual blood vessel tubes connect to form blood vessel loops that can circulate blood.
10. 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 vessels are comprised of cells called endothelial cells. The total surface area covered by these cells in an adult is 1000 m2 -- roughly the size of a tennis court.

• If all the blood vessels in the body were lined up end-to-end, they would form a line that could circle 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 different known angiogenic growth factors.

• Five angiogenic growth factors are being tested in humans for growing new blood vessels to heal wounds and to restore blood flow to the heart, limbs, and brain.

• Angiogenic gene therapy is also being developed as a method to deliver angiogenic growth factors to the heart, limbs, and wounds.

• There are at least 30 known natural angiogenesis inhibitors found in the body.

• The first angiogenesis inhibitor molecule was discovered in 1975 by Dr. Judah Folkman and Dr. Henry Brem in a study of cartilage.

• Angiogenesis inhibitors have been discovered from natural sources, including tree bark, fungi, shark muscle and cartilage, sea coral, green tea, and herbs (licorice, ginseng, cumin, garlic).

• In total, more than 300 angiogenesis inhibitors have been discovered to date.

• At least 184 million patients in Western nations could benefit from some form of antiangiogenic therapy.

• At least 314 million patients in Western nations would benefit from some form of angiogenesis-stimulating (pro-angiogenic) 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.

• Some cancer patients have experienced dramatic regression of their tumors from antiangiogenic therapy; others have experienced stabilization of their disease.

• More than 2,000 patients with heart disease have received some form of experimental angiogenic therapy.

• The first FDA-approved device to stimulate new blood vessels to grow in diseased hearts is a laser used in a technique called Direct Myocardial Revascularization, or DMR (sometimes called transmyocardial revascularization, TMR).

• The first FDA-approved blood vessel therapy for eye disease is a type of photodynamic therapy called Visudyne (QLT Therapeutics/CibaVision), which has shown effectiveness for treating macular degeneration.

• The first angiogenesis-stimulating medicine is a prescription gel called Regranex (recombinant human platelet-derived growth factor-BB, Ortho-McNeil Pharmaceuticals) that became FDA-approved to heal diabetic foot ulcers in December 1997.

• 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 medical research in human history.

Seminal Papers

First Description of Tumor Vascularization:
Goldman E. The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet 1907; ii: 1236-1240.

Seminal Hypothesis:
Folkman J. Tumor angiogenesis: therapeutic implications. New England Journal of Medicine 1971; 285: 1182-1186.

Early Discoveries:
Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. Journal of Experimental Medicine 1971; 133:(2): 275-288.

Gimbrone MA, Leapman S, Cotran RS, Folkman J. Tumor dormancy in vivo by prevention of neovascularization. Journal of Experimental Medicine 1972; 136 (2): 261-276.

Folkman J, Hochberg M. Self-regulation of growth in three dimensions. Journal of Experimental Medicine 1973; 138(4): 745-753.

Gimbrone MA, Cotran RS, Leapman SB, Folkman J. Tumor growth and neovascularization: an experimental model using the rabbit cornea. Journal of the National Cancer Institute 1974; 52(2): 413-427.

Orlidge A, D'Amore PA. Inhibition of capillary endothelial cells by pericytes and smooth muscle cells. Journal of Cell Biology 1987; 105: 1455-1462.

Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246(4935): 1306-1309.

Plouet J, Schilling J, Gospodarowicz D. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO Journal 1989; 8(12): 3801-3806.

First Angiogenesis Growth Factor:
Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M. Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 1984; 223 (4642): 1296-1299.

First Angiogenesis Inhibitor:
Brem H, Folkman J. Inhibition of tumor angiogenesis mediated by cartilage. Journal of Experimental Medicine 1975; 141:

First Clinical "Proof of Concept" of Antiangiogenic Therapy for Tumors:
White CW, Sondheimer HM, Crouch EC, Wilson H, Fan LL. Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. New England Journal of Medicine 1989; 320(18): 1197-1200.

Folkman J. Successful treatment of an angiogenic disease. New England Journal of Medicine 1989; 320(18): 1211-1212.

First Clinical "Proof of Concept" of Pro-angiogenic Therapy for the Ischemic Heart:
Schumacher B, Pecher P, von Specht BU, Stegmann T. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation 1998;97(7):645-650.

Historical Highlights of the Angiogenesis Field

1787 - British surgeon Dr. John Hunter first uses the term "angiogenesis" (new blood vessel growth) to describe blood vessels growing in the reindeer antler.

1935 - Boston pathologist Dr. Arthur Tremain Hertig describes angiogenesis in the placenta of pregnant monkeys.

1971 - Surgeon Judah Folkman hypothesizes that tumor growth is dependent upon angiogenesis. His theory, published in the New England Journal of Medicine, is initially regarded as heresy by leading physicians and scientists.

1975 - The first angiogenesis inhibitor is discovered in cartilage by Dr. Henry Brem and Dr. Judah Folkman.

1984 - The first angiogenic factor (basic fibroblast growth factor, bFGF) is purified by Yuen Shing and Michael Klagsbrun at Harvard Medical School.

1989 - One of the most important angiogenic factors, vascular endothelial growth factor (VEGF), is discovered Dr. Napoleone Ferrara. It turns out to be identical to a molecule called Vascular Permeability Factor (VPF) discovered in 1983 by Dr. Harold Dvorak.

1989 - The first successful treatment of an angiogenesis-dependent benign tumor (pulmonary hemangioma) using interferon alfa2a is reported by Dr. Carl White, a pediatric radiologist in Denver.

1992 - The first clinical trial of an antiangiogenic drug (TNP-470) begins in cancer patients.

1994 - The Angiogenesis Foundation is founded to improve global efforts by facilitating the development and application of angiogenesis-based medicines.

1997 - The first angiogenesis-stimulating drug (becaplermin, Regranex) is FDA-approved for treatment of diabetic foot ulcers.

1997 - Dr. Michael O'Reilly publishes research finding in the journal Nature showing complete regression of cancerous tumors following repeated cycles of antiangiogenic therapy using angiostatin and endostatin.

1998 - The first angiogenesis-stimulating laser is FDA-approved for the treatment of severe, end-stage coronary disease.

1999 - The first vascular targeting therapy is FDA-approved for treatment of age-related macular degeneration.

1999 - Massive wave of antiangiogenic drugs enter clinical trials: 46 antiangiogenic drugs for cancer patients; 5 drugs for macular degeneration; 1 drug for diabetic retinopathy; 4 drugs for psoriasis.

1999 - Massive wave of angiogenesis-stimulating drugs enter clinical trials: 5 drugs for coronary artery disease; 5 drugs for peripheral vascular disease; 1 drug for stroke; 10 drugs for wound healing.

1999 - Laboratory research led by Dr. Robert Kerbel and Dr. Judah Folkman shows that some traditional cytotoxic chemotherapies may inhibit tumor angiogenesis when given at low-doses.

1999 - Dr. Richard Klausner, Director of the U.S. National Cancer Institute, designates the development of antiangiogenic therapies for cancer as a national priority. 2003 - The monoclonal antibody drug Avastin (Bevacizumab) becomes the first antiangiogenic drug to demonstrate in large-scale clinical trials that inhibiting tumor blood vessel growth can prolong survival in cancer patients.

2004: A pivotal phase 3 trial published in the New England Journal of Medicine shows that the addition of bevacizumab (Avastin), an anti-VEGF monoclonal antibody, to chemotherapy significantly improves survival in patients with metastatic colorectal cancer.

2004: Bevacizumab is FDA approved for the treatment of advanced colorectal cancer. At the time of bevacizumab’s approval, FDA Commissioner Mark McClellan declares antiangiogenic therapy “the fourth modality for cancer treatment.”