Cells in the body need a constant supply of oxygen and nutrients, which are supplied via the blood circulatory system. The body’s tissues are full of tiny blood vessels called capillaries, which carry blood very close to the cells of the tissues to exchange dissolved gases, nutrients, and waste products.
When new blood vessels are needed, for example for wound healing, a normal bodily process, called angiogenesis, takes place by which new capillary blood vessels grow from pre-existing blood vessels, to supply the affected area with oxygen and nutrient rich blood.
What is angiogenesis?
The growth of new blood vessels from pre-existing blood vessels is a normal process that takes place throughout life. It starts in utero (the vascular system is the first organ system to develop in the embryo) and continues into old age. Angiogenesis, the process by which new blood vessels are formed from pre-existing blood vessels, is a vital function for growth and development, for the healing of wounds, and for a few days in every month in the female reproductive tract in the ovary and the uterus, when the uterine lining is shed during the menstrual cycle. However, angiogenesis can also play a role in several diseases, such as cancer and macular degeneration.
The term angiogenesis stems from the Greek words angio, which means blood, and genesis, which means beginning. Angiogenesis is normally not active, but get switched on, usually short term, when new blood vessels are needed for the healing of wounds, or after menstruation.
The formation of capillary tube is a complex process, which is controlled by chemical signals. Various proteins can activate angiogenesis, such as vascular endothelial growth factor (VEGF), which binds to receptors on the surface of endothelial cells in the lining of blood vessels. This signals endothelial cells to initiate the sprouting and growth of new blood vessels, followed by migration towards the designated area and tube formation, which ends with maturation of the new blood vessel. Many of the new capillary blood vessels will either regress or become established capillaries.
Other chemical signals, on the other hand, can interfere with blood vessel formation and are aptly called angiogenesis inhibitors. There are dozens of proteins that can activate or inhibit angiogenesis.
These initiating or inhibiting signals are normally well balanced, for new blood vessels to only form when and where they are needed. These signals, however, can become unbalanced and result in increased blood vessel growth, which can lead to disease and other abnormal conditions, for example by playing a role in the growth of cancer tumors.
Types of angiogenesis:
There are two main types of angiogenesis, which involves the forming of new blood vessels by either sprouting new vessels from pre-existing vessels (like the growth of new branches on a tree) or by splitting pre-existing vessels. Splitting angiogenesis is also known as intussusceptive angiogenesis.
- Sprouting angiogenesis is characterized by the growth of sprouts (composed of endothelial cells) towards an angiogenic stimulus, such as vascular endothelial growth factor (VEGF). When oxygen sensing mechanisms detect a decrease in oxygen levels (a condition called hypoxia) due to poor delivery of blood through the capillaries in certain tissues, VEGF is released and sprouting angiogenesis is initiated. Once the affected tissues receive adequate amounts of oxygen again, VEGF returns to normal levels.
- Splitting angiogenesis is characterized by the vessel wall extending into the lumen, which causes a single vessel to split in two. This type of angiogenesis works faster and more efficient than sprouting as it reorganizes existing endothelial cells, causing new capillaries to develop in areas with existing capillaries. The mechanism of splitting angiogenesis is not as well-known as that of sprouting angiogenesis.
The role of angiogenesis in cancer growth:
Angiogenesis plays a critical role in the growth of cancer, as solid tumors need a constant supply of blood to grow and divide. Microscopically small cancers are formed in our bodies all the time, but remain dormant and small, unless they develop a blood supply. Some tumors can produce angiogenesis activating growth factors that stimulate the formation of new blood vessels or cause nearby normal cells to release the growth factors. When these new blood vessels are formed, the oxygen and nutrients they supply are used to feed the tumors, which results in the tumor growing and cancer cells invading nearby tissue. The blood vessels created in this way are often less organized and leakier than normal blood vessels.
Research done in the early 1970’s found that the formation of cancer depends on angiogenesis. This finding has since led to the development of cancer fighting drugs, called angiogenesis inhibitors, to slow or prevent the growth of tumors by starving the tumors of its blood supply. Most angiogenesis inhibitors target VEGF or its receptors to block its growth-related activities, while others work on the immune system to inhibit angiogenesis. As angiogenesis inhibitors don’t kill cancer cells, but work by slowing or stopping tumor growth, they are given over a long period of time to patients. In some cancers, angiogenesis inhibitors are more effective in combination with other cancer fighting therapies.
While the idea of choking the blood supply to starve cancers has resulted in the development of many different angiogenesis inhibitors, in practice these drugs have showed some benefit, but have not worked as well as expected. Some experts in this field believe that some kinds of white blood cells (the “soldiers” of the immune system) in the tumor’s microenvironment allows tumors to form new blood vessels without needing VEGF. Some other experts believe that the extracellular matrix, the non-cellular portion of tissue which provides structural and biochemical support to the surrounding cells, is somehow blocking the access of antiangiogenic drugs.
These drugs come with side effects, as they inadvertently also target normal blood vessels. Side effects can include high blood pressure, problems with wound healing, low blood counts, and in rare cases side effects such as serious bleeding, blood clots, or even heart failure or heart attacks may occur.
Conclusions:
More research into angiogenesis in cancer is crucial, seeing that it plays a role in the growth and spread of all cancer types, while efforts to inhibit angiogenesis did not show the expected results so far. Current research is also looking at the tissue microenvironment, as the cancer cells “recruit” the normal cells near a tumor to assist with the process of angiogenesis.
References:
Angiogenesis inhibitors. Published online and reviewed 2 April 2018. National Cancer Institute. National Institutes of Health. USA. (www.cancer.gov)
Angiogenesis. Book by authors Adair TH & Montani JP, published by Morgan & Claypool Publishers. 2010.
What is Angiogenesis? Published 13 March 2014. Memorial Sloan Kettering Cancer Center. (www.mskcc.org)
Angiogenesis and angiogenesis inhibitors to treat cancer. Published November 2018. Cancer.Net. American Society of Clinical Oncology. (www.cancer.net)
Angiogenesis inhibitors. Published online. Johns Hopkins Medicine, Johns Hopkins University. USA). (www.hopkinsmedicine.org
Angiogenesis. Published online. CancerQuest. (A cancer education and outreach program.) Winship Cancer Institute, Emery University. USA. (www.cancerquest.org)
What is angiogenesis in cancer? Published online and updated 1 December 2019. Verywellhealth. (www.verywellhealth.com)
Angiogenesis. Published online. Dr. D Ribatti & others. ScienceDirect. (www.sciencedirectcom)
HEALTH INSIGHT.
February 2022.