Antiangiogenesis..., the new alternative therapy for cancer?

Dear Friends,

It has been ever so long since I have sat down to write to you. My world has become incredibly busy, since the last time I wrote to you. I am at a crucial point of my life, with one year of school remaining and another six years of University life to look forward to. Many of you may be in such a position, in which case, I wish you all the best of luck for the future (not that you're going to need it). I will try desperately hard not to make this post very long, but I can't make any definite promises.

So, I guess I'll introduce the background behind this seemingly strange title. Fairly recently, I have being doing some super-curricular research and reading into various topics in medicine that interest me. Whilst browsing through a list of TED Talks, I came across one given by a Dr William Li (who in fact heads the Angiogenesis Foundation). His concise and coherent explanation of the role of angiogenesis in tumour growth sparked some curiosity in me. Why hadn't I heard about this before? I mean Chemotherapy, Radiation Therapy and Surgery were fairly well known conventional treatments. We had already learnt about these various approaches in Biology lessons and through our general reading. Maybe I have been behind in my knowledge of advancements in cancer treatment, but the use of antiangiogenic drugs was completely new to me. So, I decided to investigate. (It has been a bit of a learning curve for me, so I will share exactly what I have learnt with you, as well. That way, it helps to solidify my knowledge and will probably make sense to you.)

I think we should start by understanding what the process of angiogenesis entails. According to Wikipedia (http://en.wikipedia.org/wiki/Angiogenesis), angiogenesis is defined as the "physiological process through which new blood vessels form from pre-existing vessels". Blood vessels come in three distinct varieties, arteries, veins and capillaries. They are comprised of cells called endothelial cells. In fact, the total surface area covered by these cells amasses to a total of 1000m² (in adults). If all the blood vessels in the body were to be lined up, end-to-end, they would form a line that could potentially circle the Earth twice. The three types of blood vessels have their own unique role in the body. Arteries are blood vessels that carry blood away from the heart, whereas veins carry blood to the heart. Capillaries connect these two major blood vessels; they are much smaller in size and enable the actual exchange of water and other chemicals between the bloodstream and neighbouring tissues. There are an estimated 19 billion capillaries in the body and they are in essence the vessels of life. Overall, blood vessels have developed the invaluable ability to adapt to the environment that they’re growing in. For an example: in the liver these vessels form channels to enable the detoxification of the blood, in the lungs they line the alveoli to promote efficient gas exchange and in muscles they form a corkscrew shape which allows the muscles to contract without the risk of cutting off any vital circulation. Angiogenesis surrounds the growth of new capillary blood vessels in the body, which is an extremely important natural process for healing and reproduction. 

Diagram showing the basic structure of arteries, veins and capillaries

Diagram of blood vessels in the liver

Blood vessels surrounding the alveoli in the lungs

Blood vessel network in a healthy heart muscle

In actuality, we develop most of these blood vessels when we’re still in the womb. As adults, the growth of new blood vessels is fairly rare, apart from in a few special scenarios. In women, blood vessels grow every month to build the lining of the uterus (endometrium), during pregnancy they help to form the placenta (an organ that connects the developing foetus to the uterine wall, which then allows the foetus to absorb nutrients, get rid of waste, exchange gases via the mother’s blood supply etc.), after injury they also grow under the scab in order to heal the wound.

Diagram of endometrium

Human embryo attached to placenta

The body itself can control angiogenesis with the use of specific growth and inhibitory factors found in healthy tissues. However, disturbing this balance can result in abnormal blood vessel growth. It has been found that both the excessive and the insufficient growth of blood vessels can act as the underlying factor, or the 'common denominator' for over 70 deadly and debilitating conditions. This includes cancer, skin diseases, age-related blindness, diabetic ulcers (a major complication of diabetes mellitus), cardiovascular disease and stroke amongst many other illnesses. As I have already mentioned, for a number of diseases there are defects in the homeostatic build up and breakdown of blood vessels, whereby the body is unable to prune back extra blood vessels or can’t grow new branches. Here I have presented a list of the illnesses caused by insufficient angiogenesis and excessive angiogenesis.

As you might be able to guess from the title, I am going to be focusing on the link between cancer and excessive angiogenesis. As many of you probably know already, cancer is defined as “a condition where cells in a specific part of the body grow and reproduce uncontrollably”, according to the NHS (http://www.nhs.uk/conditions/Cancer/Pages/Introduction.aspx). The danger is that these cells may spread, invade and destroy surrounding healthy tissue and thus conquer the entire organ, or spread to other organs in other parts of the body. But it must be acknowledged that cancers don’t begin as huge clusters of cells with an active blood supply. They are initiated as small microscopic nests of cells that only grow to approximately 0.5mm³ (i.e. the size of the tip of a ballpoint pen). They cannot expand in size, without a blood supply that provides the necessary oxygen and nutrients to the rapidly dividing cells. Moreover, we are probably forming these microscopic cancers all the time in our body. Autopsy studies that have been carried out on those who have passed away in car accidents show that around 40% of women between the ages of 40 and 50 have microscopic cancers in their breasts, and 50% of men between the ages of 50 and 60 have micro-cancers in their prostate. In all honesty, by the time we reach our 70s, virtually 100% of us will have micro-cancers in our thyroid gland (one of the largest endocrine glands).

A diagram of the progression of cancer

Properly functioning angiogenesis will prevent blood vessels from feeding the cancers, which is considered one of the most important defence mechanisms against cancer. But, once angiogenesis to cancerous cells occur, the cancers can theoretically grow exponentially (which is how cancer changes from harmless to deadly). Essentially, cancer cells mutate and gain the ability to release several angiogenic factors that act as a form of ‘natural fertiliser’ that can favour the cancers by allowing the blood vessels to invade and supply the necessary nutrients and oxygen. Once blood vessels succeed in invading, the cancer can expand and invade local tissue. The same vessels that are nourishing the tumour will also allow cancer cells to enter into the circulation as metastases. Unfortunately, cancers are generally diagnosed at this late stage, where the cancer is no longer localised and cannot simply be removed surgically from one place.

Process of metastasis

Angiogenesis-based medicine aims to restore the body’s natural control over the growth and decay of blood vessels by using innovative medical treatments. Thus, doctors are able to prolong the lives of cancer patients, avoid the need for limb amputations, overcome vision loss and improve their patients’ general health. As mentioned earlier, cancerous tumours release ‘angiogenic growth factors’ that encourage blood vessels to grow into the tumour. A key mechanism of the proposed antiangiogenic therapy is to interfere with the process of blood vessel growth by attempting to deny the tumour of the blood supply that it has recruited. According to the organisation ‘The Angiogenesis Foundation’ (http://www.angio.org/learn/angiogenesis/), some cancer patients have experienced positive and dramatic changes to the rate of growth of their tumours due to the antiangiogenic therapy they have received. In total, more than $4 billion have been invested in the research and development of these medicinal drugs, making this project one of the most heavily funded areas of medical research in history.

Looking back, Dr. Judah Folkman and Dr. Henry Brem discovered the very first angiogenesis inhibitor molecule in 1975. Following this ground-breaking finding, the first successful treatment of an angiogenic-dependent disease took place in 1989. This involved the drug interferon alfa2a (an inhibitor) and was used to revert growth of abnormal blood vessels in the lungs of a boy with a benign disease called pulmonary hemangiomatosis.

Dr. Judah Folkman

Dr. Henry Brem

I think it’s important to realise that antiangiogenic therapy is completely different from conventional chemotherapy, because it ‘selectively aims’ at the blood vessels that are feeding the growing cancer. This is possible because the abnormalities that are presented in these blood vessels decrease the quality of their construction and make them highly vulnerable to treatments that target them directly. The following table contains a list of the current FDA approved antiangiogenic drugs, their year of discovery and the list of cancers that they claim to treat.

Green tea	Red grapes	Lavender
Strawberries	Red wine	Pumpkin
Blackberries	Bok Choy	Sea cucumber
Raspberries	Kale	Tuna
Blueberries	Soy beans	Parsley
Oranges	Ginseng	Garlic
Grapefruit	Maitake mushrooms	Tomato
Lemons	Liquorice	Olive oil
Apples	Turmeric	Grapeseed oil
Pineapple	Nutmeg	Dark chocolate
Cherries	Artichokes	Others

Chemical structure of lycopene