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An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels ( angiogenesis). Some angiogenesis inhibitors are
endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...
and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet. While angiogenesis is a critical part of wound healing and other favorable processes, certain types of angiogenesis are associated with the growth of malignant tumors. 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" 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, so ...
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, 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 s ...
). These stimulate
endothelial cell The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...
proliferation, migration and invasion resulting in new vascular structures sprouting from nearby blood vessels. Cell adhesion molecules, such as integrins, 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 An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
directed against VEGF or VEGFR, soluble VEGFR/VEGFR hybrids, and
tyrosine kinase inhibitors A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a ph ...
. The most widely used VEGF pathway inhibitor on the market today is
Bevacizumab 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) and used for colon cancer, ...
. 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 The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...
formation and migration, endothelial tube morphogenesis, 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 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 ...
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 that are able to colonize solid tumors ''in vivo'', such as ''
Clostridium ''Clostridium'' is a genus of anaerobic, Gram-positive bacteria. Species of ''Clostridium'' inhabit soils and the intestinal tract of animals, including humans. This genus includes several significant human pathogens, including the causative a ...
'', ''
Bifidobacteria ''Bifidobacterium'' is a genus of gram-positive, nonmotile, often branched anaerobic bacteria. They are ubiquitous inhabitants of the gastrointestinal tract though strains have been isolated from the vagina and mouth ('' B. dentium'') of ma ...
'' and ''
Salmonella ''Salmonella'' is a genus of rod-shaped (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two species of ''Salmonella'' are '' Salmonella enterica'' and '' Salmonella bongori''. ''S. enterica'' is the type species and is ...
'' by adding genes for anti-angiogenic factors such as endostatin 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 additi ...
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, the ...
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 such as tofu 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, '' Rhizo ...
, (which contain the inhibitor " genistein") * '' Agaricus subrufescens'' mushrooms (contain the inhibitors sodium pyroglutamate and
ergosterol Ergosterol (ergosta-5,7,22-trien-3β-ol) is a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells. Because many fungi and protozoa cannot survive without ergosterol, t ...
) *
Black raspberry Black raspberry is a common name for three species of the genus ''Rubus'': *''Rubus leucodermis'', native to western North America *'' Rubus occidentalis'', native to eastern North America *''Rubus coreanus 300px, (left to right) ''R. corean ...
(''Rubus occidentalis'') extract * Lingzhi mushrooms (via inhibition of
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 ...
and TGF-beta) *'' Trametes versicolor'' mushrooms ( Polysaccharide-K) *'' Maitake'' mushrooms (via inhibition of
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 ...
) *''
Phellinus linteus ''Phellinus linteus'' (Japanese "meshimakobu", Chinese "song gen", Korean "sanghwang", English "mesima", American English "black hoof mushroom") is a mushroom. It is shaped like a hoof, has a bitter taste, and in the wild grows on mulberry trees ...
'' mushrooms (via active substance Interfungins A inhibition of
glycation Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proce ...
) * Green tea ( catechins) * Liquorice ( glycyrrhizic acid)Smith, Roderick
Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention.
''The Angiogenesis Foundation.'' 6 May 2009.
* Red wine (
resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sourc ...
) * Antiangiogenic phytochemicals and medicinal herbs * Royal Jelly (
Queen bee acid The queen bee acid (10-hydroxy-2-decenoic acid) or 10-HDA is a bio-active compound found in royal jelly. Royal jelly acid is being investigated for its pharmacological activities. Reports indicate that it promotes neurogenesis of neural stem/ ...
)


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. In addition to their use as anti-cancer drugs, angiogenesis inhibitors are being investigated for their use as anti-obesity agents, as blood vessels in adipose tissue 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 of the eye.


Overview


Bevacizumab

Through binding to
VEGFR VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing. Inhi ...
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 co ...
, 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 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 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, most notably phocomelia, 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 Cannabis, also known as marijuana among other names, is a psychoactive drug from the cannabis plant. Native to Central or South Asia, the cannabis plant has been used as a drug for both recreational and entheogenic purposes and in various t ...
, 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.


See also

*
Brain-specific angiogenesis inhibitor 1 Brain-specific angiogenesis inhibitor 1 is a protein that in humans is encoded by the ''BAI1'' gene. It is a member of the adhesion-GPCR family of receptors. Function Angiogenesis is controlled by a local balance between stimulators and inh ...
(and others)


References


Further reading

* Milosevic, V., Edelmann, R.J., Fosse, J.H., Östman, A., Akslen, L.A. (2022).
Molecular Phenotypes of Endothelial Cells in Malignant Tumors. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment
Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_3


External links

* The idea of antiangiogenesis was pioneered by Dr. Judah Folkman. Se

an


Angiogenesis Inhibitors for Cancer
- fro
The Angiogenesis Foundation
23 June 2009
Angiogenesis Inhibitors for Eye Disease
- fro
The Angiogenesis Foundation
23 June 2009
Angiogenesis Inhibitors in the Treatment of Cancer
- from the
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. T ...
* {{Antiangiogenics Angiology