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12.8: Fighting Cancer with Inhibitors of Angiogenesis - Biology

12.8: Fighting Cancer with Inhibitors of Angiogenesis - Biology


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Once a nest of cancer cells reaches a certain size (1–2 mm in diameter), it must develop a blood supply in order to grow larger. Diffusion is no longer adequate to supply the cells with oxygen and nutrients and to take away wastes. Cancer cells (probably like all tissues) secrete substances that promote the formation of new blood vessels — a process called angiogenesis. Over a dozen substances have been identified that promote angiogenesis. A few examples are angiopoietin-1, the basic fibroblast growth factor (bFGF) and the vascular endothelial growth factor (VEGF).

Curiously, some tumors also secrete substances that inhibit angiogenesis. This explains a clinical phenomenon that has been known for decades:

  • A patient has a tumor, the so-called primary tumor.
  • There is no evidence that the primary tumor has metastasized.
  • A surgeon removes the primary tumor.
  • Some weeks later metastases of the tumor appear throughout the patient's body
  • The speed of their appearance indicates that they were present all along, but too small to be detected.

This phenomenon caused Dr. Judah Folkman of Children's Hospital and the Harvard Medical School in Boston to hypothesize that a large primary tumor secretes not only stimulators of its own angiogenesis but angiogenesis inhibitors that are released into the circulation and inhibit angiogenesis — and thus further growth — of any metastases of the primary tumor. A number of inhibitors of angiogenesis have been discovered.

Angiostatin

Angiostatin is a polypeptide of approximately 200 amino acids. It is produced by the cleavage of plasminogen, a plasma protein that is important for dissolving blood clots. Angiostatin binds to subunits of ATP synthase exposed at the surface of the cell embedded in the plasma membrane. (Before this recent discovery, ATP synthase was known only as a mitochondrial protein.)

Endostatin

Endostatin is a polypeptide of 184 amino acids. It is the globular domain found at the C-terminal of Type XVIII (18) collagen (a collagen found in blood vessels) cut off from the parent molecule.

Effects of angiostatin and endostatin in mice

Injections of angiostatin inhibit the metastasis of certain (mouse) primary tumors. Injections of endostatin (made by recombinant DNA technology) cause the primary tumor to regress. In time, the primary tumor reappears, but a repeat injection causes it to regress again. Each time it reappears, the tumor is just as susceptible to treatment as before. After a few cycles of growth, treatment, and regression, the primary tumor finally stops growing (at least in the cases examined) and remains dormant at a small size.

Some human tumors can be grown in immunodeficient mice. (Being immunodeficient, they cannot reject this foreign tissue). Treatment with endostatin caused these human tumor masses to shrink in their mouse host. Combined treatment with both angiostatin and endostatin has caused some primary mouse tumors to disappear entirely.

This is not seen with conventional chemotherapy. Repeated exposure to chemotherapeutic drugs selects for the appearance of drug-resistant tumor cells. Eventually, further drug treatment is worthless. Why the difference in response? Chemotherapy works directly on tumor cells which mutate easily. Angiogenesis inhibitors don't work on the tumor cells but on normal cells involved in the formation of blood vessels.

Other Angiogenesis Inhibitors

Epithelial cells express transmembrane proteins on their surface — called integrins — by which they anchor themselves to the extracellular matrix. It turns out that the new blood vessels in tumors express a vascular integrin — designated alpha-v/beta-3 — that is not found on the old blood vessels of normal tissues.

Vitaxin®, a humanized monoclonal antibody directed against the alpha-v/beta-3 vascular integrin, shrinks tumors in mice without harming them. In Phase II clinical trials in humans, Vitaxin has shown some promise in shrinking solid tumors without harmful side effects.

What does the future hold for angiogenesis inhibitors?

Clinical trials of endostatin (manufactured by recombinant DNA technology), in combination with standard chemotherapy have shown some benefit in one type of lung cancer.

Bevacizumab (Avastin®). This is a humanized monoclonal antibody that binds to VEGF thus keeping it from binding to its receptors. Approved by the US FDA in February 2004 for the treatment of colorectal cancers.

Ranibizumab (Lucentis®) is a modified version of Avastin® that is showing great promise in inhibiting the formation of new blood vessels in the retina — the cause "wet" macular degeneration.

Trials are also scheduled to begin on a synthetic ribozyme that blocks synthesis of the VEGF receptor. These are only a few examples of the ~50 antiangiogenesis drugs now in clinical trials.

But proceed with caution.

In animal studies, some cancers — notably pancreatic cancer — have turned out to resist chemotherapy because of their poor blood supply. Perhaps such cancers need to have angiogenesis promoted; inhibiting it could make a bad problem worse.


Understanding Cancer from a Systems Biology Point of View

Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back starts with a basic question, why do we sometimes observe accelerated metastatic growth after resection of primary tumors? Next, it helps readers understand the systemic nature of cancer and how it affects treatment approaches and decisions. The book puts together aspects of cancer that many readers have most likely never combined, using unfamiliar, novel methods. It is a valuable resource for cancer researchers, cancer biologists, mathematicians and members of the biomedical field who are interested in applying systems biology methodologies for understanding and treating cancer.

Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back starts with a basic question, why do we sometimes observe accelerated metastatic growth after resection of primary tumors? Next, it helps readers understand the systemic nature of cancer and how it affects treatment approaches and decisions. The book puts together aspects of cancer that many readers have most likely never combined, using unfamiliar, novel methods. It is a valuable resource for cancer researchers, cancer biologists, mathematicians and members of the biomedical field who are interested in applying systems biology methodologies for understanding and treating cancer.


12.8: Fighting Cancer with Inhibitors of Angiogenesis - Biology

The formation of new blood vessels is called angiogenesis. It is a normal part of growth and healing. But it plays a role in several diseases, including cancer.

A tumor needs nutrients and oxygen to grow and spread. Blood contains those ingredients. The tumor sends chemical signals that stimulate blood vessel growth. And the blood vessels carry blood to the tumor.

Angiogenesis inhibitors, also called anti-angiogenics, are drugs that block angiogenesis. Blocking nutrients and oxygen from a tumor “starves” it. These drugs are an important part of treatment for some types of cancer.

Cancer treatments that block angiogenesis

Certain drugs affect angiogenesis in one or more ways. Many angiogenesis inhibitors also affect other ways that tumors grow. People may receive these drugs with other types of treatment.

Examples of angiogenesis inhibitors are:

Axitinib (Inlyta). A treatment option for kidney cancer.

Bevacizumab (Avastin). A treatment option for colorectal, kidney, and lung cancers.

Cabozantinib (Cometriq). A treatment option for medullary thyroid cancer and kidney cancer.

Everolimus (Afinitor, Zortress). A treatment option for kidney cancer, advanced breast cancer, pancreatic neuroendocrine tumors (PNETs), and subependymal giant cell astrocytoma, which is a rare type of noncancerous brain tumor.

Lenalidomide (Revlimid). A treatment option for multiple myeloma, tumors involving cells that normally produce antibodies, and mantle cell lymphoma, which is a type of non-Hodgkin lymphoma.

Pazopanib (Votrient). A treatment option for kidney cancer and advanced soft tissue sarcoma.

Ramucirumab (Cyramza). A treatment option for advanced stomach cancer gastroesophageal junction adenocarcinoma, a cancer located where the stomach joins the esophagus colorectal cancers and non-small cell lung cancers.

Regorafenib (Stivarga). A treatment option for colorectal cancer and gastrointestinal stromal tumors (GIST).

Sorafenib (Nexavar). A treatment option for kidney, liver, and thyroid cancers.

Sunitinib (Sutent). A treatment option for kidney cancer, PNETs, and GIST.

Thalidomide (Synovir, Thalomid). A treatment option for multiple myeloma. Women who are pregnant should not take this drug. It harms fetuses.

Vandetanib (Caprelsa). A treatment option for medullary thyroid cancer.

Ziv-aflibercept (Zaltrap). A treatment option for colorectal cancer.

Researchers are studying whether some of these drugs may treat other types of cancer. Talk with your health care team about anti-angiogenic clinical trials.

Side effects of angiogenesis inhibitors

Many of the body's normal functions depend on angiogenesis. Therefore, angiogenesis inhibitors can cause a wide range of side effects including:

Hand-foot syndrome. This causes tender, thickened areas on the palms and soles. Sometimes, it causes blisters.

Problems with wound healing or cuts reopening

Although common, these side effects do not happen with every drug or every person. And medicines can help manage these side effects.

Holes in the intestines, called bowel perforations

Talk with your health care team about the risks and benefits of angiogenesis inhibitors. And ask about ways to prevent serious side effects.

Questions to ask your health care team

Consider asking these questions about angiogenesis inhibitors:

    Do you recommend an angiogenesis inhibitor as part of my treatment plan? Which one? Why?


A novel bisindole-PBD conjugate inhibits angiogenesis by regulating STAT3 and VEGF in breast cancer cells

Aims: Breast cancer is highly resistant to chemotherapeutic approach and hence, alternative strategies have been developed to fight against this heterogeneous group of disease. In particular, many studies have demonstrated about various drugs for the treatment of breast cancer. In our study, we assessed the anti-angiogenenic activities of Bisindole-PBD (5b) in MCF-7 and MDA-MB-231 cell lines.

Main methods: In vitro Endothelial Cell (HUVEC) Tube Formation Assay was performed to show inhibitory role of 5b along with its role upon wound healing process in breast cancer cells in vitro. Semi-quantitative reverse transcription PCR (RT-PCR) was also done to examine the expression of VEGF in response to 5b in breast cancer cells and in HUVEC cells. siRNA transfection study explored STAT3 mediated VEGF transcription in breast cancer cells MCF-7 and MDA-MB-231. CAM assay was performed to see the role of 5b on vessel formation in chicken embryo.

Key findings: From in vitro data we have demonstrated that 5b played a role in regulation of breast cancer cell proliferation by inhibiting angiogenesis. Test drug 5b suppressed the expression VEGF at both transcriptional and post transcriptional levels. Apart from this, there was significant down regulation in STAT3 level after drug treatment, which was found to be involved in the VEGF transcription. Metastasis related MMP-2 and MMP-9 expressions were also modulated by 5b. In vivo study by Chick Chorioallantoic Membrane (CAM) Assay also showed anti-angiogenesis role of the test drug which was consistent with the in vitro data.

Significance: Altogether, our data demonstrated 5b as potent small molecule with anti-angiogenic activities.

Keywords: Angiogenesis Bisindole-PBD (5b) Breast cancer CAM assay STAT3 VEGF.


Anti-Angiogenic Foods: Fight Cancer with Dietary Changes

In Greek, "angio" means vessels and "genesis" is birth - thus angiogenesis is the creation of new blood vessels. Blocking angiogenesis in cancerous tumors enables us to undercut the spread of the disease.

Cancers can hijack the process of angiogenesis to recruit their own private blood supply and feed themselves. Without these lifelines, cancers remain tiny and can't become dangerous. Many foods and beverages contain natural cancer-starving molecules that prevent tumors from acquiring blood vessels.

Quinoa: Many of the phenolic substances identified in quinoa, including genistein, quercetin, and kaempferol, have anti-angiogenic properties, or the ability to inhibit new blood vessel growth, and also suppress the proliferation of cancer cells.

The edible seeds of the quinoa plant are rich in protein, unsaturated fats, and essential vitamins and minerals. Quinoa also contains beneficial polyphenols that may help to reduce the risk of cardiovascular disease and cancer.

Flaxseed: Studies have shown that regular consumption of flaxseed, also known as linseed, increases levels of a natural angiogenesis inhibitor called endostatin. In the study, healthy premenopausal women who had 25 grams of freshly ground flaxseed added to their daily diets had significant increases in levels of endostatin in their breast tissue.

Endostatin is an endogenous (naturally occurring) substance in the body that inhibits angiogenesis. This is one of the first studies to show that a particular food can raise levels of an endogenous inhibitor of angiogenesis in the body.

Oolong Tea: Oolong tea is a partially fermented tea that is consumed heavily in Asian countries. Like green tea and black tea, oolong contains substances called polyphenols that have been shown to have chemopreventive (cancer-preventing) properties.

The major primary polyphenols in unfermented green tea leaves are catechins, with (-)-epigallocate- chin-gallate (EGCG) being the primary active component. EGCG has been shown in numerous studies to have antiangiogenic and anti-tumor activities.

Grapes: Grapes and red wine are high in polyphenols, powerful antioxidants that have been shown in numerous studies to have anti-cancer, anti-inflammatory and heart-protecting effects. Extracts from grapes and their seeds contain various polyphenols with anti-cancer and anti-inflammatory activity, including resveratrol, gallic acid, epigallocatechin-gallate (EGCG), epigallocatechin (ECG), epicatechin-3-gallate, epicatechin, and proanthocyanidins. The cancer-fighting properties of these compounds have been attributed to their ability to inhibit proliferation of tumors cells and to suppress the growth of tumor blood vessels (angiogenesis).

Chocolate and Cocoa: Chocolate, the fermented byproduct from processed cocoa, contains high levels of bioactive flavanoids (polyphenols) that are formed during the fermentation process. Two flavanoids in particular, catechins and procyanidins, are highly concentrated in dark chocolate and cocoa powder. Observational studies indicate that catechins and procyanidins may protect against a number of chronic diseases, notably cardiovascular disease and cancer.The cancer-protecting (chemoprotective) activity of catechins and procyanidins is likely related to their ability to inhibit proliferation of cancer cells, remove toxins from the body, reduce inflammation, and suppress angiogenesis.

Walnuts: Walnuts contain a number of compounds with anti-tumor effects. One of these, ellagic acid, has been shown to inhibit colon cancer cell proliferation and angiogenesis in a number of laboratory studies. Flaxseed oil has a similar effect as walnuts on tumor growth, but does not suppress angiogenesis to the same degree.

Tomato Sauce: Tomatoes and processed tomato products contain lycopene, a cartenoid antioxidant with potent antioxidant and anti-angiogenic activity. Regular consumption of foods containing lycopene has been found to reduce the risk for some cancers, making it intriguing as a dietary supplement for cancer prevention. In a recent study, researchers found that regular consumption of tomato paste can protect against skin damage caused by exposure to ultraviolet radiation (UVR), such as occurs with long-term sun exposure.

Papaya and other bright colored fruits: Recent studies have provided more evidence that foods high in carotenoids, natural organic pigments with anti-angiogenic properties, could lower the risk of certain cancers. Carotenoids such as lycopene, are found in many brightly colored fruits and vegetables. The tropical fruit papaya is a particularly good source.

One study found that consumption of high levels of carotenoids from papayas was associated with a 50% risk reduction of breast cancer. Papaya is high in the carotenoid beta-cryptoxanthin, and has also demonstrated a reduction in the risk of gallbladder cancer. These findings are illuminating because they suggest that the benefits of carotenoid circulation are most effective in women with a higher risk of breast cancer.

Avocados: Avocados contain anti-angiogenic compounds such as lutein that are being studied for their cancer-fighting abilities. In laboratory mice, lutein was shown to have a significant protective effect against colon cancer.

In other research, lutein was used to prevent the proliferation of blood vessels in the eyes of mice. This may eventually prove valuable in preventing eye diseases spurred by uncontrolled blood vessel growth, a process that can ultimately cause blindness. Finally, recent research has suggested that the content of carotenoids like lutein is highest in avocados that have been ripened for less than 10 days after harvesting.

Coffee: Epidemiological studies have shown that people who regularly drink coffee are at reduced risk for several types of cancer. In one pooled analysis of two prospective cohort studies, Japanese researchers found about a 40% decreased risk of primary liver cancer among people who drank at least one cup of coffee per day compared with those who didn't drink any.

Coffee contains hundreds of bioactive substances including chlorogenic acid, some of which are anti-inflammatory and antiangiogenic. Unfiltered coffee contains another substance called kahweol which was shown in a series of experiments to be a potent inhibitor of angiogenesis.

Anti-Angiogenic Compounds for Cancer Treatment

There is also aggressive on-going scientific research to identify compounds with anti-angiogenesis effects that could be used for the treatment of various cancers. AG Scientific has had broad success with a combination of fermentation and synthesis contracts, allowing us to build a catalog of over 150 antibiotics, many with promising anti-cancer potential.


Inhibitors of angiogenesis

Up-regulation of the activity of angiogenic factors is in itself not enough to initiate blood vessel growth, and the functions of negative regulators or inhibitors of vessel growth may need to be down-regulated. There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 ( Table 1 ). Angiostatin is composed of one or more fragments of plasminogen ( Stack et al 1999 ). It induces apoptosis in endothelial cells and tumor cells, and inhibits migration and the formation of tubules in endothelial cells ( Claesson-Welch et al 1998 Lucas et al 1998 ). Immunohistochemical examination of angiostatin-treated tumors indicated a decrease in the expression of mRNA for VEGF and bFGF ( Kirsch et al 1998 ). Endostatin is a 20 kDa C-terminal fragment of type XVIII collagen ( O'Reilly et al 1997 ), a component of the basement membrane. It binds to the 㬕㬡/αv㬣 integrin, the major fibronectin receptor in endothelial cells ( Rehn et al 2001 Wickstrom et al 2002 ) and may block endothelial cell focal adhesions ( Wickstrom et al 2002 ). Endostatin also inhibits the growth factor (eg, bFGF and VEGF-A), and induces proliferation and migration of endothelial cells in vitro and in vivo ( O'Reilly et al 1997 Dhanabal et al 1999 Olsson et al 2004 ).


4 DISCUSSION

In this study, we identified the previously undiscovered role of TARBP2 in the regulation of tumor angiogenesis, which was confirmed by both in vitro and in vivo experiments using multiple types of tumor cells. Several studies and our results demonstrated TARBP2 promoted the metastatic progression of human lung cancer and breast cancer. 36 To rule out the influence of tumor types, three types of human tumor cells were tested, including human lung cancer, breast cancer, and liver cancer cells. We showed that TARBP2 could significantly promote tumor angiogenesis in several types of human cancers in vitro. In contrast, this could be inhibited by knocking down TARBP2. In vivo studies also confirmed that TARBP2 was able to increase the number of microvessels in human lung tumor and breast tumor xenografts. These findings indicated for the first time that TARBP2 promoted tumor progression through tumor angiogenesis induction.

We used high-sensitive RNA-seq together with PCR array to detect angiogenesis-related gene expression precisely in tumor cells, confirming that TARBP2 specifically downregulates the mRNA expression of antiangiogenic factors. The preferential binding of TARBP2 to antiangiogenic mRNAs but not to proangiogenic mRNAs signified a selective targeting of TARBP2 in regulating tumor angiogenic mRNAs, resulting in an imbalance between antiangiogenic and proangiogenic genes. The upregulation of many proangiogenic mRNAs might be a secondary effect of TARBP2 overexpression because TARBP2 neither enriched the proangiogenic factor transcripts nor targeted their 3′UTRs. Furthermore, the expression of these genes is not affected by TARBP2 knockdown. The broad targets of TARBP2 in the tumor angiogenesis pathway suggested that TARBP2 induces tumor angiogenesis through targeting multiple molecules in tumor cells.

The 3′UTR plays an important role in the RBP-mediated post-transcriptional regulation of genes. 37-39 We confirmed that TARBP2 could suppress luciferase activity through the 3′UTRs of antiangiogenic genes and reduced their mRNA stability. It has been reported that the dsRBD1 and dsRBD2 domains are essential for TARBP2-mediated double-stranded RNA substrate recognition, binding, and processing. 34 In this study, we demonstrate that the dsRBD1/2 domains are required for the degradation of antiangiogenic genes and tumor angiogenesis induction by truncating the domains of TARBP2. Many elements, such as ARE, GRE, and the stem-loop structure, are localized in the 3′UTR and responsible for mRNA turnover. 40-42 Our results demonstrated that TARBP2 destabilized THBS1 by binding to the stem-loop structure in the 3′UTR. There are no consensus stem-loop sequences among the antiangiogenic genes, which further supports our hypothesis that TARBP2 mainly recognizes the RNA secondary structure in the 3′UTR. The direct binding of TARBP2 to THBS1 and TIMP1 were also confirmed by the high-throughput sequencing of RNAs isolated by a crosslinking immunoprecipitation experiment. 26

Finally, TARBP2 regulating tumor angiogenesis was further confirmed in human lung tumor samples. Our results demonstrated that TARBP2 is highly expressed in human lung cancer, breast cancer, and liver cancer, which was negatively related to the expression of antiangiogenic mRNAs. The strong association between high TARBP2 expression in tumor samples and poor survival of cancer patients further demonstrated its clinical significance. Collectively, our results identified a new tumor angiogenesis regulator and might lead to improved prognosis using TARBP2 as a target for antiangiogenic cancer therapy.


“I believe we have an answer to cancer. That answer lies within the grasp of the Angiogenesis Foundation.”

Dr. William Li presents at TED

Dr. William Li’s wildly popular TED Talk “Can We Eat to Starve Cancer” has been viewed by 11 million people. Join a community of 45,000 people passionate about using foods to fight cancer at the Foundation’s Eat to Beat website.

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Antiangiogenic Diet

The role of anti-angiogenic foods (foods that have components that inhibit angiogenesis) in cancer treatment is unknown in humans, though pre-clinical research (research in the lab and on animals) has suggested that diet could play a role. When talking about diet, however, it's important to stress that an antiangiogenic diet—even if it is found in the future to aid in treating cancer—is not a substitute for standard cancer treatments.

That said, many foods that could be classified as antiangiogenic are part of a healthy diet recommended by most oncologists. Some of these foods include:

  • Cruciferous vegetables: Broccoli, cauliflower, kale, brussels sprouts, radishes
  • Citrus foods: Oranges, lemons, grapefruit
  • Spices: Garlic, parsley, tumeric, nutmeg
  • Berries: Raspberries, blueberries, blackberries, strawberries

Studies looking at the role of specific foods in health and disease have been mixed and sometimes disappointing, and it appears that a diet rich in a wide variety of food containing different phytochemicals (plant based chemicals) is key. For this reason, the American Institute for Cancer Research recommends eating a "rainbow" of foods every day. The Mediterranean diet has been linked to a lower risk of death overall, and a 2019 study found that the Mediterranean diet is very rich in antiangiogenic foods.

Angiogenesis in Other Health Conditions

Angiogenesis plays a role not only in cancer, but in many health conditions. Dysregulated angiogenesis is important in:

  • Atherosclerosis
  • Diabetic retinopathy
  • Age-related macular degeneration
  • Some autoimmune conditions, such as rheumatoid arthritis and psoriasis

Just as treatments to stop or reduce angiogenesis have been found effective in treating some cancers and could help with some eye diseases and autoimmune conditions, finding ways to stimulate angiogenesis could prove helpful in ischemic heart disease (heart disease due to lack of blood flow in the coronary arteries), skin ulcers in people with diabetes, peripheral vascular disease, and in promoting the healing of wounds.

A Word From Verywell

Research into angiogenesis in cancer is critical as it plays a role in the growth and spread of all cancer types as well as other diseases. Since the process requires the recruitment of normal cells near a tumor, research that is now looking at the tissue microenvironment will hopefully cast more light on why inhibiting angiogenesis, to date, has led to less than optimal responses in cancer treatment.


New angiogenesis finding may help fight cancer growth

A researcher at the University of Wisconsin-Madison School of Medicine and Public Health has discovered a new part of the complicated mechanism that governs the formation of blood vessels, or angiogenesis.

The finding may help halt tumor growth in cancer patients, says Emery Bresnick, the senior author on the study, a professor of pharmacology and member of the UW-Madison Paul P. Carbone Comprehensive Cancer Center.

The research, published in the Journal of Cell Biology on Sept. 25, is the first to connect a particular nervous-system chemical to the regulation of blood vessels.

Normally, blood vessels form when wounds heal and during menstruation, pregnancy and fetal development. But impaired blood-vessel development and function are also a major cause of blindness, and tumors rely on new blood vessels as they develop.

Like most critical body processes, angiogenesis is tightly controlled by multiple balancing mechanisms. When Bresnick and colleagues, including postdoctoral fellow Soumen Paul, began the new study, they were not looking into angiogenesis. Instead, they were studying a protein that regulates the maturation of blood cells, and noticed that it turns on a gene that makes a compound called neurokinin-B, or NK-B.

Aware that NK-B affects cells in the nervous system, Bresnick wondered, "Why would a protein involved in blood-cell formation turn on the gene for a compound that is supposedly involved in regulating the nervous system?"

The researchers searched for NK-B receptors - molecules that can "recognize" and respond to NK-B - and found great numbers of them on endothelial cells, which line the inside of blood vessels.

Endothelial cells form the internal structure of a blood vessel, and during angiogenesis, they migrate, starting an extension of the blood-vessel network. When Paul added NK-B to endothelial cells, "They lost the capacity to organize in three dimensions, to form the tubes that are the precursors to new blood vessels," Bresnick says. "Then we got excited."

Further tests showed that NK-B could inhibit angiogenesis in four ways. It prevents the production of vascular endothelial growth factor (VEGF), a key stimulator of blood-vessel formation, and also reduces the number of receptor molecules that respond to VEGF. NK-B also slows the movement of endothelial cells, which is necessary to form new vessels, and raises the level of a newly discovered angiogenesis inhibitor.

"It's premature to call it a master switch, but intriguingly, it regulates at least four different processes, each of which individually would be anti-angiogenic," says Bresnick.

Angiogenesis inhibitors, Bresnick observes, are a fast-growing field of medicine. This June, the Food and Drug Administration approved an angiogenesis inhibitor as the first drug that can restore some vision in the more severe ("wet") form of age-related macular degeneration (AMD). Wet AMD occurs when leaky blood vessels form in the retina. Along with a similar growth of new blood vessels in diabetes, it is the major cause of blindness in older adults.

But the "holy grail" of angiogenesis inhibition concerns cancer treatment. Before solid tumors start to grow, they must create a new blood supply, and since adults need angiogenesis only during pregnancy and to heal wounds, blocking angiogenesis could be a promising way to halt tumor growth. Also in June, the FDA approved a compound that inhibits VEGF for treating colon cancer, the second-leading cause of cancer death in the United States. The VEGF-inhibitor reduces the formation of blood vessels, helping starve tumors.

But angiogenesis regulation is a two-way street, and there are some diseases in which it might be desirable to stimulate angiogenesis. The new research shows that the NK-B system can work both ways: Reducing inhibition seems to increase angiogenesis.

"Activating the NK-B receptor blocked angiogenesis, and blocking the receptor stimulated angiogenesis," Bresnick says. In theory, selectively stimulating angiogenesis could help treat heart attacks by restoring blood flow to the heart, increasing the blood supply to threatened heart muscle.

NK-B also plays a role in a mysterious but common syndrome called preeclampsia, in which soaring blood pressure and low blood oxygen levels harm or even kill pregnant women and their babies. Philip Lowry, at the University of Reading in the United Kingdom, has found that NK-B levels spike in preeclampsia, and the new understanding of NK-B's role in angiogenesis suggests that faulty blood-vessel formation may be to blame.

Because NK-B prevents endothelial cells from organizing into blood vessels, Bresnick says, "Maybe excess levels of NK-B are responsible for or contribute to impaired vascular development/function and certain symptoms of preeclampsia." According to the Preeclampsia Foundation, the condition affects about 200,000 American women each year.

Many angiogenesis inhibitors are under study at this point, but finding a regulatory molecule that affects four separate mechanisms "makes for an interesting package," Bresnick says.

The Wisconsin Alumni Research Foundation has applied for a patent on the discovery, which, says Bresnick, reflected the work of "outstanding collaborators at the University of Wisconsin-Madison, who facilitated this multidisciplinary study and co-authored this paper." Authors included Patricia Keely in the Department of Pharmacology John Fallon and Tim Gomez in the Department of Anatomy and Sam Gellman in the Department of Chemistry.

Bresnick and his collaborators are looking further into how the molecule works in human cells and in mouse models of angiogenesis.

Eventually, after years of basic research and drug development, the multitalented compound NK-B could wind up playing a major role in treating cancer and other diseases where blood vessel formation goes awry, Bresnick says. "We have discovered a new peptide that clearly suppresses angiogenesis via a novel multi-component mechanism," he says. "A key question is whether we can exploit it to develop therapeutics."


Watch the video: Καρκίνος προστάτη: παρακολούθηση ασθενών με βάση το PIRADS score. Δεληγιάννης Δημήτριος (September 2022).


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