What is Angiogenesis in Cancer?

Angiogenesis is defined as the formation of new blood vessels to support the growth of tissues. It is necessary in the development of a baby, and "good" in the setting of tissue repair, but bad in the setting of cancer. Angiogenesis is, in fact, a hallmark of cancer, being necessary for both the growth (progression) and spread (metastasis) of cancer. Before a tumor can grow to larger than a few millimeters in size, new blood vessels are needed to ensure an adequate supply of oxygen and nutrients to the cells. Since tumors can't grow in the absence of angiogenesis, drugs referred to as angiogenesis are now used with several types of cancer.

Angiogenesis involves the sprouting or splitting of new vessels from blood vessels that are already present (existing vasculature), in contrast to the term vasculogenesis that means "origin" of new blood vessels. Due to its importance, angiogenesis is carefully regulated by both substances that stimulate and inhibit the process.

Definition and Basics

The term angiogenesis is derived from the root words angio, meaning blood, and genesis, meaning formation. The term lymphangiogenesis refers to the formation of both new blood vessels and lymphatic vessels.

History

The concept of angiogenesis was first hypothesized a few centuries ago, but the dependence of tumor growth on angiogenesis wasn't well understood until the early 1970s when Judah Folkman suspected that preventing new blood vessel formation in small cancers could prevent their growth. The first drug to inhibit angiogenesis was approved in 2004.

Good vs. Bad Angiogenesis (Normal vs. Abnormal)

Angiogenesis can be a normal and healthy bodily process when new blood vessels are needed. It occurs as part of growth in children, when the uterine lining is shed each month in menstruating women, and when new blood vessels are required in the process of wound healing. Researchers are actually looking for ways to boost angiogenesis in the setting of tissue damage, such as after a heart attack.

Angiogenesis means essentially the same thing as neovascularization, though neovascularization refers to any type of blood vessel (artery, vein, capillary, lymph vessel).

Angiogenesis vs. Vasculogenesis

There are a number of terms that describe the growth of blood vessels with some important differences. Angiogenesis refers to the use of pre-existing blood vessels. Vasculogenesis, in contrast, refers to the de novo (original) formation of blood vessels in the embryo. These de novo blood vessels arise from immature cells known as angioblasts that differentiate (become more mature) into endothelial cells. (There is some research, however, that suggests that vasculogenesis may play a role in some cancers.)

The Role of Angiogenesis in Cancer Growth

Angiogenesis is of interest in cancer because cancers require the formation of new blood vessels to grow and metastasize. In order for cancers to grow to be larger than roughly one millimeter (1 mm), angiogenesis needs to take place. Cancers do this by secreting substances that stimulate angiogenesis, and hence, the growth of cancer.

Role in Metastasis (Spread)

In addition to being a process needed for cancers to grow and invade neighboring tissues, angiogenesis is necessary for metastases to occur. In order for cancer cells to travel and set up a new home somewhere beyond their origin, these cells need to bring new blood vessels in to support their growth at their new locations.

The Process of Angiogenesis

The process of angiogenesis involves several steps involving endothelial cells (the cells that line the vessels). These include:

• Initiation: The process of angiogenesis must be activated by some signal (prior to this, it's thought that the blood vessels must dilate and become more permeable)
• Sprouting and growth (proliferation)
• Migration
• Tube formation
• Differentiation (maturation)

Cancers also recruit cells known as pericytes that are important in providing support for the new blood vessels.

The entire process is carefully regulated by proteins that can tip the balance in either way; either activating or inhibiting angiogenesis. At each of these steps, the tumor microenvironment, or normal tissue that surrounds a tumor, plays a crucial role.

When it Occurs

Ordinarily, angiogenesis can be thought of as being "switched off." When new blood vessels are needed for wound repair or after menstruation, the process may be "switched on" again, but usually for a very short period of time. Even when angiogenesis is "switched on", however, it is carefully regulated by signals in the surrounding environment.

It's thought that a lack of oxygen (hypoxia) in a tumor stimulates angiogenesis. This occurs when the surface area to volume ratio of a tumor is too low for diffusion alone to "feed" a tumor. In response to hypoxia, cancer cells send messages or "signals" to blood vessels that are nearby that stimulate the vessels to grow new extensions that will supply the tumor.

This is an example of the importance of the tumor microenvironment, as cancer cells actually "recruit" normal cells in their vicinity to assist in their growth.

(The details of this signaling are beyond the scope of this article, but it's thought that hypoxia in the cancer cells results in the production of hypoxia inducible factor. This factor, in turn, increases the expression of genes (leads to production of proteins coded for by the genes), that lead to angiogenesis. One of these genes is VEGF.)

How it Occurs

In response to hypoxia, cancer cells can either secrete signals themselves or influence other cells to secrete signals. An example of one of these messengers is VEGF or vascular enodothelial growth factor. VEGF, in turn, binds to VEGF receptors on normal endothelial cells (the cells that line blood vessels) signaling them to grow (and increasing their survival). With cancer, however, angiogenesis requires both activating factors and inhibition of inhibitory factors.

Regulation of Angiogenesis

We used the example of VEGF above, but there are actually dozens of proteins that both activate and inhibit angiogenesis. While the increased activity of activating factors is important, it's thought that activation alone is not enough for angiogenesis to occur in cancer. Factors that inhibit blood vessel growth also have to show less activity than they otherwise would.

Activation and Activating Factors

There are a number of different proteins that can stimulate (activate angiogenesis) through different signaling pathways. Some of these include

• Vascular endothelial growth factor (VEGF): VEGF is "expressed" in roughly 50% of cancers
• Platelet derived growth factor (PDGF)
• Basic fibroblast growth factor (bFGF)
• Transforming growth factor
• Tumor necrosis factor (TNF)
• Epidermal growth factor
• Hepatocyte growth factor
• Granulocyte colony stimulating factor
• Placental growth factor
• Interleukin-8
• Other substances including other cytokines, enzymes that break down blood vessels, and more

Activating factors often work together in tumor growth. For example, the endothelial cells that are activated by VEGF may secrete platelet derived growth factor. PDGF, in turn, bind to receptors on pericytes (the supporting cells noted above). This binding causes the pericytes to secrete more VEGF, hence enhancing the process.

Inhibition and Angiogenic Inhibitors

There are also a number of substances that play an inhibitory role to stop or prevent angiogenesis. Some of these include:

• Angiostatin
• Endostatin
• Interferon
• Platelet factor 4
• Thrombospondin-1 protein (this protein appears to inhibit the growth and migration of endothelial cells and activates enzymes that cause cell death)
• Prolactin
• Interleukin-12

As noted, angiogenesis in cancer requires both activation and reduced inhibition of angiogenesis factors. An example of how this occurs is in the presence of TP53 mutations (mutations found in roughly half of cancers). The p53 gene codes for a protein (tumor protein 53) that protects against the development of cancer. When the protein is abnormal (produced by a mutated gene), one of the effects is that there is decreased production of thrombospondin-1, an inhibitory factor.

Regulation of Angiogenesis and Metastases

The regulation (balance of activating and inhibitory factors) of angiogenesis can help to explain why cancers are more likely to spread to some tissues (such as the bones, liver, or lungs) than others. Some tissues produce more inhibitory factors than others.

Types of Angiogenesis

There are two main types of angiogenesis (there are also less common types not discussed here):

• Sprouting Angiogenesis: Sprouting angiogenesis is the best understood form of angiogenesis and describes how new blood vessels essentially sprout off of existing vessels, much like the growth of tree branches as a tree increases in size.
• Splitting Angiogenesis: Also called intususceptive angiogenesis, splitting angiogenesis was first described in 1986

It's important to note that when angiogenesis is triggered by hypoxia (as in cancer), the blood vessels that are produced aren't "normal" but rather structurally abnormal so that they are distributed unevenly in a tumor, and even then, blood flow can be uneven and inconsistent.

Angiogenesis and Cancer Treatment

Addressing angiogenesis can play a role in treatment through the use of angiogenesis inhibitors, but it's important to note that angiogenesis can affect other treatments as well. For example, the formation of new blood vessels (since they differ from normal blood vessels) can interfere with the ability of chemotherapy drugs to reach a tumor.

Angiogenesis Inhibitors

Angiogenesis inhibitors (anti-angiogenesis drugs) are drugs that block the ability of tumors to form new blood vessels, and hence, grow and spread. These medications can interfere with the process of angiogenesis at several different points. Some of these medications inhibit angiogenesis by binding directly to VEGF (vascular endothelial growth factor) so that it can no longer send the signals stimulating the process. Other medications work at different places in the process. Since they specifically target pathways involved in the growth of cancer, they are referred to as targeted therapies.

Unlike many cancer medications, these drugs can sometimes work across different cancer types. In addition, there may be less concern about resistance developing as it does with so many treatments currently available. That said, normal cells near a tumor (the tumor microenvironment) may interfere with their effect by producing proteins that allows angiogenesis to continue, and it's thought that this interference may be at least partly responsible for the lower effectiveness of the medications in humans compared with what has been seen in the lab.

Some currently available medications and cancers for which they are sometimes used include:

• Affinitor or Zortress (everolimus): Metastatic breast cancer, neuroendocrine tumors (of the pancreas or PNETs), kidney cancer, subependymal giant cell astrocytoma (a benign brain tumor)
• Avastin (bevacizumab): Lung cancer, kidney cancer, and colorectal cancer.
• Caprelsa (vandetanib): Thyroid cancer (medullary)
• Cometriq (cabozantinib): Kidney cancer, medullary thyroid cancer
• Cyramza (ramucirumab): Stomach cancer, colorectal cancer, lung cancer
• Inlyta (axitinib): Kidney cancer
• Lenvima (lenvatinib mesylate)
• Nexavar (sorafenib): Kidney cancer, liver cancer, thyroid cancer
• Revlimid (lenalidomide): Multiple myeloma, mantle cell lymphoma
• Stivarga (regorafenib): Gastrointestinal stromal tumors, colorectal cancer
• Sutent (sunitinib): Kidney cancer, neuroendocrine tumors of the pancreas, gastrointestinal stromal tumors
• Synovir or Thalomid (thalidomide): Multiple myeloma
• Votrient (pazopanib): Soft tissue sarcoma, kidney cancer
• Zaltrap (ziv-afibercept): Colrectal cancer

Angiogenesis in Combination with Other Cancer Treatments

Angiogenesis inhibitors are usually most effective when combined with other treatments such as chemotherapy. The reason this is done is easier to understand by looking at the mechanism by which angiogenesis inhibitors work. Angiogenesis inhibitors don't kill cancer cells, but simply work to prevent them from growing larger and spreading (metastasizing). Therefore, in order to get rid of a tumor, other treatments need to be combined with these medications.

Side Effects

Angiogenesis have common side effects such as fatigue, diarrhea, poor wound healing, and hypothyroidism, but can sometimes result in serious adverse reactions as well. Some of these include:

• Hemorrhage
• Blood clots
• High blood pressure
• Heart failure
• Perforation of the digestive tract
• Posterior reversible leukoencephalopathy syndrome, a brain condition that can lead to headaches, confusion, vision loss, and seizures

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.