An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels ( angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained

exogenously In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogen ...

through

pharmaceutical drugs A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and rel ...

diet Diet may refer to: Food * Diet (nutrition), the sum of the food consumed by an organism or group * Dieting, the deliberate selection of food to control body weight or nutrient intake ** Diet food, foods that aid in creating a diet for weight loss ...

. While angiogenesis is a critical part of

wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...

and other favorable processes, certain types of angiogenesis are associated with the growth of

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

. Thus angiogenesis inhibitors have been closely studied for possible

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

treatment. Angiogenesis inhibitors were once thought to have potential as a "

silver bullet In folklore, a bullet cast from silver is often one of the few weapons that are effective against a werewolf or witch. The term ''silver bullet'' is also a metaphor for a simple, seemingly magical, solution to a difficult problem: for example, pe ...

" treatment applicable to many types of cancer, but the limitations of anti-angiogenic therapy have been shown in practice. Nonetheless, inhibitors are used to effectively treat cancer,

macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...

in the eye, and other diseases that involve a proliferation of blood vessels.

Mechanism of action

When a tumor stimulates the growth of new vessels, it is said to have undergone an 'angiogenic switch'. The principal stimulus for this angiogenic switch appears to be oxygen deprivation, although other stimuli such as inflammation, oncogenic mutations and mechanical stress may also play a role. The angiogenic switch leads to tumor expression of pro-angiogenic factors and increased tumor vascularization. Specifically,

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

cells release various pro-angiogenic

paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...

factors (including

angiogenin Angiogenin (ANG) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ''ANG'' gene. Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular ...

, vascular endothelial growth factor (

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

), fibroblast growth factor ( FGF), and transforming growth factor-β (

TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

). These stimulate endothelial cell proliferation, migration and invasion resulting in new vascular structures sprouting from nearby blood vessels.

Cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...

s, such as

integrins Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

, are critical to the attachment and migration of endothelial cells to the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...

VEGF pathway inhibition

Inhibiting angiogenesis requires treatment with anti-angiogenic factors, or drugs which reduce the production of pro-angiogenic factors, prevent them binding to their receptors or block their actions. Inhibition of the VEGF pathway has become the focus of angiogenesis research, as approximately 60% of malignant tumors express high concentrations of VEGF. Strategies to inhibit the VEGF pathway include antibodies directed against VEGF or VEGFR, soluble VEGFR/VEGFR hybrids, and tyrosine kinase inhibitors. The most widely used VEGF pathway inhibitor on the market today is Bevacizumab. Bevacizumab binds to VEGF and inhibits it from binding to VEGF receptors.

Endogenous regulation

Angiogenesis is regulated by the activity of endogenous stimulators and inhibitors. Endogenous inhibitors, found in the body naturally, are involved in the day-to-day process of regulating blood vessel formation. Endogenous inhibitors are often derived from the extracellular matrix or basement membrane proteins and function by interfering with endothelial cell formation and migration, endothelial tube

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

, and down-regulation of genes expressed in endothelial cells. During tumor growth, the action of angiogenesis stimulators surpasses the control of angiogenesis inhibitors, allowing for unregulated or less regulated blood vessel growth and formation. Endogenous inhibitors are attractive targets for cancer therapy because they are less toxic and less likely to lead to drug resistance than some exogenous inhibitors. However, the therapeutic use of endogenous inhibitors has disadvantages. In animal studies, high doses of inhibitors were required to prevent tumor growth and the use of endogenous inhibitors would likely be long-term. A recent method for the delivery of anti-angiogenesis factors to tumor regions in cancer patients uses

genetically modified bacteria Genetically modified bacteria were the first organisms to be modified in the laboratory, due to their simple genetics. These organisms are now used for several purposes, and are particularly important in producing large amounts of pure human prot ...

that are able to colonize solid tumors ''in vivo'', such as '' Clostridium'', '' Bifidobacteria'' and '' Salmonella'' by adding genes for anti-angiogenic factors such as

endostatin Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin. Endostatin is a broad-spectrum angiogenesis inhibi ...

or IP10

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

and removing any harmful virulence genes. A target can also be added to the outside of the bacteria so that they are sent to the correct organ in the body. The bacteria can then be injected into the patient and they will locate themselves to the tumor site, where they release a continual supply of the desired drugs in the vicinity of a growing cancer mass, preventing it from being able to gain access to oxygen and ultimately starving the cancer cells. This method has been shown to work both in vitro and in vivo in mice models, with very promising results. It is expected that this method will become commonplace for treatment of various cancer types in humans in the future.

Exogenous regulation

Diet

Some common components of human diets also act as mild angiogenesis inhibitors and have therefore been proposed for angioprevention, the prevention of

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...

through the inhibition of angiogenesis. In particular, the following foods contain significant inhibitors and have been suggested as part of a healthy diet for this and other benefits: *

Soy products The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses. Traditional unfermented food uses of soybeans include soy milk, from which tofu a ...

such as

tofu Tofu (), also known as bean curd in English, is a food prepared by coagulating soy milk and then pressing the resulting curds into solid white blocks of varying softness; it can be ''silken'', ''soft'', ''firm'', ''extra firm'' or ''super f ...

and

tempeh Tempeh or tempe (; jv, ꦠꦺꦩ꧀ꦥꦺ, témpé, ) is a traditional Indonesian food made from fermented soybeans. It is made by a natural culturing and controlled fermentation process that binds soybeans into a cake form. A fungus, '' Rhiz ...

, (which contain the inhibitor "

genistein Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen. It was first isolated in 1899 from the dyer's bro ...

") * ''

Agaricus subrufescens ''Agaricus subrufescens'' (syn. ''Agaricus blazei'', ''Agaricus brasiliensis'' or ''Agaricus rufotegulis'') is a species of mushroom, commonly known as almond mushroom, mushroom of the sun, God's mushroom, mushroom of life, royal sun agaricus, '' ...

'' mushrooms (contain the inhibitors sodium pyroglutamate and ergosterol) *

Black raspberry Black raspberry is a common name for three species of the genus ''Rubus'': *''Rubus leucodermis ''Rubus leucodermis'', also called whitebark raspberry or blackcap raspberry, is a species of ''Rubus'' native to western North America. Descripti ...

(''Rubus occidentalis'') extract *

Lingzhi mushroom Lingzhi, ''Ganoderma lingzhi'', also known as reishi, is a polypore fungus ("bracket fungus") native to East Asia belonging to the genus ''Ganoderma''. Its reddish brown varnished kidney-shaped cap with bands and peripherally inserted stem giv ...

s (via inhibition of

and

TGF-beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

) *''

Trametes versicolor ''Trametes versicolor''also known as ''Coriolus versicolor'' and ''Polyporus versicolor''is a common polypore mushroom found throughout the world. Meaning 'of several colors', ''versicolor'' reliably describes this fungus that displays a varie ...

'' mushrooms (

Polysaccharide-K Polysaccharide-K (Krestin, PSK) is a protein-bound polysaccharide isolated from the fruitbody of ''Trametes versicolor''. Research summary PSK has been studied in patients with gastric cancer, breast cancer, colorectal cancer, and lung cancer. T ...

) *''

Maitake ''Grifola frondosa'' (also known as hen-of-the-woods, in Japanese, ram's head or sheep's head) is a polypore mushroom that grows at the base of trees, particularly old growth oaks or maples. It is typically found in late summer to early autu ...

'' mushrooms (via inhibition of

) *'' Phellinus linteus'' mushrooms (via active substance Interfungins A inhibition of glycation) * Green tea (

catechins Flavan-3-ols (sometimes referred to as flavanols) are a subgroup of flavonoids. They are derivatives of flavans that possess a 2-phenyl-3,4-dihydro-2''H''-chromen-3-ol skeleton. Flavan-3-ols are structurally diverse and include a range of comp ...

) * Liquorice (

glycyrrhizic acid Glycyrrhizin (or glycyrrhizic acid or glycyrrhizinic acid) is the chief sweet-tasting constituent of ''Glycyrrhiza glabra'' (liquorice) root. Structurally, it is a saponin used as an emulsifier and gel-forming agent in foodstuffs and cosmetics. ...

)Smith, Roderick
Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention.
''The Angiogenesis Foundation.'' 6 May 2009. * Red wine ( resveratrol) * Antiangiogenic phytochemicals and medicinal herbs *

Royal Jelly Royal jelly is a honey bee secretion that is used in the nutrition of larvae and adult queens. It is secreted from the glands in the hypopharynx of nurse bees, and fed to all larvae in the colony, regardless of sex or caste.Graham, J. (ed.) (199 ...

( Queen bee acid)

Drugs

Research and development in this field has been driven largely by the desire to find better cancer treatments. Tumors cannot grow larger than 2mm without angiogenesis. By stopping the growth of blood vessels, scientists hope to cut the means by which tumors can nourish themselves and thus

metastasize Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

. In addition to their use as anti-cancer drugs, angiogenesis inhibitors are being investigated for their use as

anti-obesity Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control weight. These medications alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absorp ...

agents, as blood vessels in

adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

never fully mature, and are thus destroyed by angiogenesis inhibitors. Angiogenesis inhibitors are also used as treatment for the wet form of macular degeneration. By blocking VEGF, inhibitors can cause regression of the abnormal blood vessels in the retina and improve vision when injected directly into the

vitreous humor The vitreous body (''vitreous'' meaning "glass-like"; , ) is the clear gel that fills the space between the lens and the retina of the eyeball (the vitreous chamber) in humans and other vertebrates. It is often referred to as the vitreous humor ...

of the eye.

Overview

Bevacizumab

Through binding to VEGFR and other VEGF receptors in endothelial cells, VEGF can trigger multiple cellular responses like promoting cell survival, preventing apoptosis, and remodeling

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...

, all of which promote angiogenesis. Bevacizumab (brand name Avastin) traps VEGF in the blood, lowering the binding of VEGF to its receptors. This results in reduced activation of the angiogenesis pathway, thus inhibiting new blood vessel formation in tumors. After a series of clinical trials in 2004,

Avastin Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (Intravenous therapy, intravenous) and use ...

was approved by the FDA, becoming the first commercially available anti-angiogenesis drug. FDA approval of Avastin for breast cancer treatment was later revoked on November 18, 2011.

Thalidomide

Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately.

Thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...

is one such antiangiogenic agent. Thalidomide was given to pregnant women to treat nausea. However, when pregnant women take an antiangiogenic agent, the developing fetus will not form blood vessels properly, thereby preventing the proper development of fetal limbs and circulatory systems. In the late 1950s and early 1960s, thousands of children were born with

deformities A deformity, dysmorphism, or dysmorphic feature is a major abnormality of an organism that makes a part of the body appear or function differently than how it is supposed to. Causes Deformity can be caused by a variety of factors: *Arthritis an ...

, most notably

phocomelia Phocomelia is a condition that involves malformations of human arms and legs. Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide scandal, thalidomide and from genes, genetic inheritance. Occu ...

, as a consequence of thalidomide use.

Cannabinoids

According to a study published in the August 15, 2004 issue of the journal ''Cancer Research'',

cannabinoids Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

, the active ingredients in marijuana, restrict the sprouting of blood vessels to gliomas (brain tumors) implanted under the skin of mice, by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).

General side effects of drugs

Bleeding

Bleeding is one of the most difficult side effects to manage; this complication is somewhat inherent to the effectiveness of the drug. Bevacizumab has been shown to be the drug most likely to cause bleeding complications. While the mechanisms of bleeding induced by anti-VEGF agents are complicated and not yet totally understood, the most accepted hypothesis is that VEGF could promote endothelial cell survival and integrity in the adult vasculature and its inhibition may decrease capacity for renewal of damaged endothelial cells.

Increased blood pressure

In a study done by ML Maitland, a mean blood pressure increase of 8.2 mm Hg systolic and 6.5 mm Hg diastolic was reported in the first 24 hours after the first treatment with sorafenib, a VEGF pathway inhibitor.

Less common side effects

Because these drugs act on parts of the blood and blood vessels, they tend to have side effects that affect these processes. Aside from problems with hemorrhage and hypertension, less common side effects of these drugs include dry, itchy skin, hand-foot syndrome (tender, thickened areas on the skin, sometimes with blisters on palms and soles), diarrhea, fatigue, and low blood counts. Angiogenesis inhibitors can also interfere with wound healing and cause cuts to re-open or bleed. Rarely, perforations (holes) in the intestines can occur.

References

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...

* {{Antiangiogenics Angiology