Angiogenesis

By

Eng. Nashat M. Dahiyat

Seminar Title : Angiogenesis Content

 

Objectives

Introduction “ understanding of angiogenesis “

The Angiogenic Process

Growth Factors & Inhibitors & Anti –Angiogenesis

Angiogenesis in Disease 

Tumor Angiogenesis

Therapeutic Angiogenesis

Diet, Lifestyle & Angiogenesis

Conclusion

Recommendation

References

 

summary

Understanding Angiogenesiso Angiogenesis is defined as the

growth of blood vessels and is an important natural process used by the body for reproduction and for

healing injured tissues o Blood vessels bring oxygen and

nutrients via the circulation to nourish all tissues in the body

o The cells comprising blood vessels are called endothelial cells o The endothelial cells of a blood

vessel also produce molecules that support the growth of tissues o Cancer cells take over the

body's control of angiogenesis in order to recruit their own private

blood supply

vascular endothelial growth factor. J Biol Chem 272, 24203-24209 (1997

Angiogenesis andVascular Endothelial Cells

Vascular endothelial cells

Blood vessel

What Is Metastasis?

Blood vessel

2 .Cancer cellsare transported by the circulatorysystem to distant sites

3 .Cancer cells reinvade and grow at new location

1 .Cancer cells invade surrounding tissues and vessels

Metastasis Requires Angiogenesis

Angiogenesis

The Angiogenesis Process

The Angiogenesis Process: How Do New Blood Vessels Grow?

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

I. Diseased or injured tissues produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues.

II. The angiogenic growth factors bind to specific receptors located on the endothelial cells (EC) of nearby preexisting blood vessels.

III. Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus.

IV. 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.

Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell 1996;87:1153-1155 .

I. The endothelial cells begin to divide (proliferate) and migrate out through the dissolved holes of the existing vessel towards the diseased tissue (tumor).

II. Specialized molecules called adhesion molecules called integrins (avb3, avb5) serve as grappling hooks to help pull the sprouting new blood vessel sprout forward.

III. 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.

IV. Sprouting endothelial cells roll up to form a blood vessel tube.

V. Individual blood vessel tubes connect to form blood vessel loops that can circulate blood.

VI. Finally, newly formed blood vessel tubes are stabilized by specialized muscle cells (smooth muscle cells) that provide structural support. Blood flow then begins.

The Angiogenesis Process continued

Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell 1996;87:1153-1155 .

The Angiogenesis Process continued

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.

Angiogenic Growth Factors

Basic fibroblast growth

factor (bFGF)

Acidic fibroblast growth

factor (aFGF)

Angiogenin

Angiotropin

Insulin-like growth factor

Interleukin-8

Platelet activating factor

(PAF)

Platelet-derived growth factor (PDGF)

Proliferin

Transforming growth factor-

Transforming growth factor-

Tumor necrosis factor-

Vascular endothelial growth factor (VEGF)

J. Battegay: J. Mol Med; 1995J. Battegay: J. Mol Med; 1995

Angiogenesis InhibitorsOther angiogenesis inhibitors have

been found in nature - in green tea, soy products, fungi, mushrooms, Chinese cabbage, tree bark, shark tissues, snake venom, red wine, and many other substances.

Still other angiogenesis inhibitors have been manufactured synthetically in the laboratory.

Some FDA-approved medicines have also been "re-discovered" to have anti-angiogenic properties.

Inhibition of vascular vo. Nature 362, 841-844 (1993)

To date more than 300 angiogenesis inhibitor molecules have been discovered:Some angiogenesis inhibitors are naturally present in the human body because healthy tissues appear to resist cancer growth by containing these anti-angiogenic compounds.

List of 32 Known Angiogenesis Inhibitors in the Body

Angiostatin (plasminogen fragment) Metalloproteinase inhibitors (TIMPs)

Anti-angiogenic 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-betaRetinoids

Heparinases Tetrahydroco

Heparin hexasaccharide fragmentrtisol-S

Human chorionic gonadotropin (hCG)Thrombospondin-1

Interferon alpha/beta/gammaTransforming 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

What Is Tumor Angiogenesis?

Small localized tumor Tumor that can grow and spread

Angiogenesis

Signaling molecule

Blood vessel

Without Angiogenesis,Tumor Growth Stops

Injected cancer cells stop growing as mass reaches 1–2 mm in diameter

Isolated organ (e.g., thyroid gland)

Infuse nutrient solution

Definition of Angiogenic Therapy

A new form of cancer treatment using drugs called 'angiogenesis inhibitors' that specifically halt new blood vessel growth and starve a tumor by cutting off its blood supply.

A substance in the body called Vascular Endothelial Growth Factor (VEGF) is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues.

Anti-Angiogenic drugs prevent the VEGF from binding with the receptors on the surface of the endothelial cells.

Three Major Types of Anti-angiogenic Therapies for Cancer

1. Drugs that stop new blood vessels from sprouting (true angiogenesis inhibitors)

2. Drugs that attack a tumor's established blood supply (vascular targeting agents)

3. Drugs that attack both the cancer cells as well as blood vessel cells (the double-barreled approach).

Anti-Angiogenic Drugs in Clinical Trial for Cancer

A6Alpha5Beta1 Integrin AntibodyABT-510ActimidAngiocolAngiostatinAngiozymeAplidineAptosynATN-161Avastin (bevacizumab)AVE8062ABenefinBMS275291CarboxymidotriazoleCC4047CC7085CDC801Celebrex (Celecoxib)CEP-7055CGP-41251/PKC412Cilengitide

Combretastatin A4PCP-547, 632CP-564, 959DexrazoxaneDidemnin BDMXAAEMD 121974EndostatinFlavopiridolGBC-100Genistein Concentrated PolysaccharideGreen Tea ExtractInterleukin-12INGN 201Interferon alfaIressaLY317615Mab huJ591-DOTA-90 Yttrium (90Y)Medi-522Metaret (suramin)Metastat (Col-3)

NeovastatNM-3NPe6OctreotideOltiprazPaclitaxelPanzem (2ME2)PenicillaminePI-88PSKRevimidRo317453SqualamineSU11248SU6668TemptostatinTetrathiomolThalidomideUCN-01VEGF TrapZD6126

rate Proc. Natl. Acad. Sci.USA 95, 8875-8800 (1998)

Thalidomide

Anti-angiogenesis, the starving of cancers by cutting off its blood supply . Many healthy foods contain bioactive compounds – specific substances that affect the body in certain ways, such as lowering blood pressure or cholesterol or inhibiting angiogenesis.

some other good examples of cancer fighting, anti-angiogenesis foods include :  

Green tea

Strawberries

Red Meeker raspberries

Soybeans

Chocolate

Cinnamon

Lavender

Olive Oil

Nutmeg

Artichokes

Sea Cucumber

Tuna

Parsleay

Garlic

Tomatoes

Grape See Oil

We now know that all fruits and vegetables are not created equal – some are much more potent than others, based on their anti-angiogenesis profiles.

 Eat to Defeat: A New Way to Fight Cancer

At the Angiogenesis Foundation, we are launching an ambitious new initiative, called Eat to Defeat Cancer, to help people take advantage of foods that fight cancer. Using published data and the Foundation’s own anti-angiogenesis food research, we are identifying and telling the world about the most potent cancer-fighting foods.  

Diet, Lifestyle & Angiogenesis How You Can Eat (and Drink) to Defeat Cancer

Eating to defeat cancer can be accomplished simply by adding a few anti-angiogenic foods to your meals each day, like those listed above. Like life itself, one’s diet is all about making choices. Since we all eat every day, why not choose foods that can reduce your risk of disease? Listed below are some food facts, supported by scientific research, to help you get the most cancer fighting benefits from your diet. 

Be picky. Red Delicious and Granny Smith apples have twice as many cancer fighters as Fuji or Golden Delicious apples. The San Marzano tomato contains more cancer fighters than any other variety. Wine grapes grown in cooler climates have more cancer fighters than grapes grown in warmer climates.

Eat Your Sprouts. Broccoli sprouts can contain more cancer-fighting properties than regular broccoli.

Dunk Your Teabag. Dunking a tea bag up and down releases more cancer-fighting molecules than letting the bag just sit in the cup.

Cook Your Vegetables. Raw tomatoes are good, but cooking them in olive oil is better.

Chew Your Greens. Chewing leafy greens helps to release enzymes that activate cancer-fighting molecules embedded deep in the leaves.

Go Soy. Fermented soy, like the kind used in miso soup, contains four times more cancer fighters than regular soybeans.

Choose one cancer fighting food for each meal. At 3 meals each day, that adds up to more than a thousand of cancer fighting food choices each year

Summary

Angiogenesis inhibitors specifically halt new blood vessel growth and starve a tumor by cutting off its blood supply. VEGF is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. Angiogenesis inhibitors prevent the VEGF from binding with the receptors on the surface of the endothelial cells. There are 3 major types of anti-angiogenic therapies Angiogenesis is the growth of blood vessels and is an important natural process used by the body for reproduction and for healing injured tissues

references1. O’Reilly, M.S., et al., Cell, 79, 315 (1994). Folkman, J., Nat. Med., 1, 27 (1995). Wu, Z., et al.,

Biochem. Biophys. Res. Commun., 236, 651 (1997). 2. Boehm, T. Folkman, J. Browder, T. & M. O’Reilly : Anti-angiogenic therapy of experimental

cancer does not induce acquired drug resistance. Nature 390, 404-407 (1997) 3. Kim, K.J. Li, B. Winer, J. Armanini, M. Gillett, N. Phillips, H.S. & N. Ferrara : Inhibition of

vascular endothelial growth factor-induced angiogenesis suppresses ttumor growth in vivo. Nature 362, 841-844 (1993)

4. Aiello, L.P. Pierce, E.A. Foley, E.D. Takagi, H. Chen, H. Riddle, L. Ferrara, N. King, G.L. & L.E. Smith: Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 92, 10457-10461 (1995)

5. Jonca, F. Ortéga, N. Gleizes, P.E. Bertrand, N. & J. Plouët: Cell release of bioactive fibroblast growth factor by exon 6 encoded sequence of vascular endothelial growth factor. J Biol Chem 272, 24203-24209 (1997)

6. M. Tsujii, S. Kawano, S. Tsuji, H. Sawaoka, M. Hori, R.N. DuBois, Cyclooxygenase regulates angiogenesis induced by colon cancer cells [published erratum appears in Cell 1998 Jul 24;94(2):following 271], Cell 93 (1998) 705-716.

7. P. Pradono, R. Tazawa, M. Maemondo, M. Tanaka, K. Usui, Y. Saijo, K. Hagiwara, T. Nukiwa, Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth, Cancer Res. 62 (2002) 63-66.

8. Y. Takahashi, F. Kawahara, M. Noguchi, K. Miwa, H. Sato, M. Seiki, H. Inoue, T. Tanabe, T. Yoshimoto, Activation of matrix metalloproteinase-2 in human breast cancer cells overexpressing cyclooxygenase-1 or -2, FEBS Lett. 460 (1999) 145-148.

9. ^ Perhaps an inhibitor of angiogenesis: Sheppard D (October 2002). "Endothelial integrins and angiogenesis: not so simple anymore". The Journal of Clinical Investigation 110 (7): 913–4. doi:10.1172/JCI16713. PMC 151161. PMID 12370267. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=151161. Retrieved 2009-06-18.

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