by Elad Mashiach
Cancer is known as one of the most prevalent diseases around the world, affecting millions of people. One of the single hurdles that medical science needs to overcome to treat cancer is the idea that cancer is considered by many doctors and organizations to be a “noncommunicable” disease (Hanahan et al. 2011). That is, a chronic disease that is not passed from person to person and is of long duration. The root of this problem, and why cancer is so hard to treat, is that cancer infiltrates many of the body’s own defense mechanisms and uses them to its advantage. But what if we could fight cancer back naturally with our own bodies? The answer to that question lies in what is called angiogenesis. Angiogenesis is based on the process through which our bodies grow blood vessels by sending capillary “sprouts” to produce new vessels. The body has the remarkable ability to control blood vessels through an extensive range of stimulators and inhibitors, which are mainly different proteins that work like a system of checks and balances (Li et al. 2012). Pro-angiogenesis treatments can promote healing wounds while anti-angiogenesis drug treatments can help us fight with an array of diseases, from stroke to macular degeneration to thyroid and breast cancer. As a result of this elegant system, when we need new blood vessels quickly the body is able to meet this demand via delivery of stimulators that cause new blood vessels to sprout. When those vessels are no longer needed, the body can send inhibitors to prune back those vessels.
To understand why the use of angiogenesis bears a lot of potential, let’s dive into the core idea behind angiogenesis first, which is the development of blood vessels. The typical adult body is literally packed with blood vessels— 60,000 miles’ worth lined up end-to-end to form a line that would encircle the Earth twice! The larger blood vessels are known as arteries and veins, while the smallest ones are capillaries. These capillaries are the blood vessels that can reach single cells to deliver nutrients and oxygen, as well as remove waste. The remarkable aspect of blood vessels is that they can adapt to the environment in which they function. For instance, in the lungs they line the alveoli, the air sacs used for gas exchange. In the muscle tissue, they form corkscrew structures so that muscles can contract without cutting off circulation. In the liver, they form channels to detoxify blood (Li et al. 2012). In most adults, however, blood vessels do not continue to grow: most vessels develop while we are still in the womb. In spite of that, there are a few exceptions: women’s growth of blood vessels every month to build the lining of the uterus, the formation of a placenta during pregnancy, and the growth of blood vessels under a scab to heal a wound.
Angiogenesis is a primitive mechanism of the body and therefore closely regulated by the body. However, there are unfortunately a number of diseases that disrupt these mechanisms, preventing the body from growing enough new blood vessels or from pruning back unneeded blood vessels. These situations throw angiogenesis out of balance, which can lead to an array of serious medical problems, especially cancer, obesity, Alzheimer’s, stroke, Coronary Artery Diseases and many more (Cooke et al 2001). All of these medical problems together affect over a billion people worldwide, and although they all appear different from one another, they all share angiogenesis as their common denominator. Changes in the balance of angiogenesis in the body can cause an onset of these diseases. Let us focus on cancer. Angiogenesis has been a hallmark feature of cancer. That is, every type of cancer.
Cancer is a serious disease that poses a global health threat with considerable economic consequences, according to the United Nations. The cost of cancer care in the USA alone is projected to rise from $154 billion in 2015 to $207 billion by 2020 (National Cancer Institute). Although great strides have been made in reducing mortality from cardiovascular disease and other non-communicable diseases through preventive efforts, with the exception of breast cancer, cancer is still usually treated at advanced, often metastatic, disease stages. Although many types of cancers can be avoided by certain lifestyle changes, cancer prevention remains a difficult task. It is estimated that half of men and a third of women will be diagnosed with some form of cancer in their lifetime (Albini et al. 2012). Chemoprevention, which is the use of medication to lower the risk of cancer development, was proposed over three decades ago, but ever since little progress has been made to advance this life-saving approach, which should be inexpensive, non-toxic, and suitable for chronic administration. Angiogenesis and angioprevention, the prevention of angiogenesis in tumors, may hold the keys to solving the problem of finding cheaper and more efficient cancer treatment methods.
The reason angiogenesis is so promising is based on the fact that cancerous tumors start out as small nests of cells that can only grow to about 0.5mm. Once they reach this size, they cannot get any larger without a blood supply to feed off of. In fact, we are forming these nests of cancer all the time. Estimates show that by the time the average person reaches the age of seventy, the body has formed these growths of cancer in the thyroid gland. Thankfully, without a blood supply most of these cancers will never become dangerous. Dr. Judah Folkman, the pioneer of angiogenesis and angioprevention, once called these cancer nests “cancer without disease” (Folkman 1995). Therefore, the body’s ability to balance angiogenesis, that is to promote and inhibit vessel formation when it is working properly, is its best defense mechanism against cancer. It has been shown that if you prevent angiogenesis from ever reaching or supplying blood to a tumor, that tumor will wither and die. Conversely, if angiogenesis succeeds, cancer tumors can grow exponentially. Cancer cells mutate and can gain the ability to release angiogenic factors that will feed the tumor, causing cancerous cells to invade local tissue and enter the circulatory system as metastases. Therefore, the successful initiation of angiogenesis is the tipping point for a tumor. The use of antiangiogenic drugs selectively aims to counteract angiogenesis and the underlying inflammation. Antiangiogenic drugs, in general, all work on a similar principle: they prevent capillaries from invading local tissue, thereby blocking capillary migration to new tissues (Mousa 2001). The use of these drugs relies on the principle that to effectively combat a disease, early targeting is crucial.
Antiangiogenic drugs fall into different classes and subcategories. To better understand why they are helpful, we must first understand how they interact with tumor growth. Cancer tumors often have mechanisms to redirect blood supply through angiogenesis. They can achieve this through the use of numerous enzymes called proteases that are involved in digestion of long protein chains into shorter ones by the peptide bonds that join the proteins together. Among these proteases are matrix metalloproteases (MMPs). MMPs are capable of degrading all extracellular matrix (ECM) macromolecules and enable matrix remodeling of blood vessels, a crucial step in angiogenesis. Therefore, MMP inhibition is a role of many antioangiogenic drugs. Compounds such as phenethyl isothiocyanate are naturally present in dietary cruciferous vegetables, including broccoli and Brussels sprouts (Wilson et al. 2012). A key target of phenethyl isothiocyanate is protein kinase C, which leads to inhibition of MMP-2 and MMP-9 and thus inhibits angiogenesis from occurring (albini et al 2012). Cancer cell migration is a critical part for the tumor to grow. This is because once cancerous cells have migrated away from the original tumor and invaded local tissue, they can enter the blood stream or lymphatic system (Klagsbrun et al. 2012). Once a cancerous cell invades the blood stream, treatment of cancer becomes a lot harder as it can be carried to many parts of the body. Therefore, some angiopreventive compounds, including hyperforin, curcumin, resveratrol, and silibinin, affect metalloproteases and other matrix proteolytic enzymes, thereby interfering with the migration and invasion of surrounding tissue (albini et al. 2012).
Many angiogenesis inhibitors are endogenous to the body, meaning they reside within the host microenvironment. These include thrombospondin-1, platelet factor 4, angiostatin and other plasminogen fragments, endostatin, tumstatin, alphastatin, arresten, canstatin, pigment epithelium-derived factor (PEDF), TIMP-2, ADAM-TS 9 (albini et al. 2012). Therefore, a key promise of angiopreventive treatment is that upregulation of these inhibitors by drugs or diet can surge the body’s natural suppression mechanisms of angiogenesis. Endothelial cells are cells that play key roles in vessel formation and are sensitive to hormonal fluctuation, such as during the menstrual cycle (Folkman 1995). A diet high in phytoestrogens, which are a plant derivative and found most notably in soy, slows breast cancer progression by inhibition of pro-inflammatory cytokines IL-1α and IL-1β that promote angiogenesis (Li et al. 2012).
Another target of angioprevention is chronic inflammation. This is because it is linked to the development of 30% of all cancers and promotes angiogenesis. Cyclooxygenase-2 (COX-2) is a proinflammatory enzyme that is overexpressed in many cancers, including breast, lung, and prostate, but is not highly expressed in healthy tissues (Albini et al. 2012). When COX-2 is expressed, it catalyzes a reaction that induces MMP-2 and MMP-9 formation, which in turn enables angiogenesis to take place. Inhibition of COX-2 by drugs like aspirin in turn interferes with this pathway.
Angioprevention is a key player not only in cell biology, but also on a clinical treatment level. Angioprevention maintains transformed cells in a dormant state and keeps the microenvironment healthy so that transformation is hampered despite promoting stimuli. A hierarchal model of treatment based on the severity and stage of cancer was proposed and is made of four distinct levels of treatment that each aim at a different goal (Albini et al. 2012). Level I is aimed at cancer prevention in the general healthy population that is at the lowest risk of developing cancer. These individuals live generally healthy lifestyles and are not genetically predisposed for cancer. In these individuals, intervention must be safe with few, if any, adverse effects. Possible interventions include dietary factors and scientifically proven dietary supplements, caloric restriction, and aspirin, which is already used to prevent heart attack and stroke. Level II in angioprevention is aimed at individuals with moderate to high risk for cancer. These include healthy persons with genetic abnormalities that are associated with a higher cancer risk, family history of any cancer, lifestyle exposure such as asbestos, toxins, tobacco and heavy alcohol consumption, immunosuppression such as, transplantation or HIV (Albini et al. 2012). In this level, metformin is a well-tolerated drug suitable for angioprevention. Selected phytocompounds such as phytoestrogens we encountered earlier or curcumin, and black raspberry extract would also be appropriate. Level III angioprevention strategies are aimed at individuals with existing pre-neoplastic lesions, such as skin actinic keratosis, oral leukoplakia, colon adenomas, cervical dysplasia, prostatic hypertrophy, and Barrett’s esophagus. A number of prescription drugs with angiogenesis inhibitory properties are available, such as imiquimod for skin cancer, finasteride for prostate cancer, and celecoxib for colon cancer (Albini et al. 2012). Lastly, level IV angioprevention aims to prevent disease recurrence in patients in remission. In this level of treatment, an aggressive and sustained angiopreventive approach is necessary because tumor cell dissemination is likely. Angiopreventive interventions must potently suppress the microenvironment so that microscopic metastases will not thrive. Some of the drugs used to treat level IV individuals include tyrosine kinase inhibitors (axitinib, pazopanib, sorafenib, and sunitinib) and mTOR inhibitors (everolimus, and temsirolimus). mTOR is a protein that senses nutrients, oxygen and energy levels (Albini et al. 2012). It is involved in many key pathways on a cellular level such as cell proliferation, survival and cell motility. Therefore, it does not come as a surprise that mTOR is mutated in many cancers, thus leading to uncontrolled tumor cell growth. Therefore, inhibition of mTOR is essential in this stage of cancer treatment.
Although statistically half of the global population will be diagnosed with cancer at some point in our lives, most people that fall into level I and level II would rather use a simpler solution than antiangiogenic drugs to avoid reaching that stage. That solution is in dietary changes. In fact, poor diet accounts for 30 -35% of causes of cancer. A change in diet can prevent not only the onset of cancer, but also recurrence for those in remission (Wilson et al. 2012). The question is what can we add to our diet to prevent unwanted angiogenesis? This question intrigued Dr. William Li and his team at the American Angiogenesis Foundation. They decided to test certain dietary factors that are attainable by eating. Resveratrol, Ellagic acid and Genistein are extracts from grapes, strawberries and soybeans, respectively, which all potently inhibit angiogenesis formation in tumors. The team also found that a mix of Dragon Earl Jasmine and Sencha teas combined together is one of the most potent in combating angiogenesis in tumors (Li et al. 2012). These dietary factors do not simply compete with certain angiogenetic drugs, but go head-to-head with them, as Dr. Li explains. In some cases, soy extract, parsley, berries, grapes and garlic are even more potent than the actual drugs. A clinical study done by Harvard Medical School of 79,000 men over 20 years showed that “men who consumed 2-3 servings of cooked tomatoes per week have a reduced risk of developing prostate cancer by 40-50%”. This stems from the fact that tomatoes contain lycopene and lycopene, an antiangiogenic agent. In this same study, among the men that did develop prostate cancer, those that had eaten more servings of tomatoes had fewer blood vessels feeding their cancer.
It is, however, noteworthy to point out some of the hurdles that angiogenesis treatment faces. For some cancers, like breast cancer, antiangiogenic drugs are met with cell resistance, even in responsive patients. Bevacizumab, for instance, is an angiogenic inhibitor drug that inhibits the release of vascular endothelial growth factor A (VEGF-A), which, when released, promotes angiogenesis (Welti et al. 2013). The FDA revoked the approval use of Bevacizumab in antiangiogenic treatment against breast cancer because the drug has not been shown as effective. The reason a drug like Bevacizumab is met with a lot of cell resistance is that tumors usually produce multiple proangiogenic molecules, not just VEGF but many others with different molecular structures. Another major hurdle of antiangiogenic treatment is that cancer tumors switch between different modes of vessel formation, that is, they can also use vessel cooption in addition to sprouting angiogenesis. Vessel cooption is vessel growth around preexisting vessel structure (Welti et al. 2013). Melanoma and lung cancer are examples of such cancers that use vessel cooption.
Although antiangiogenic treatment is met with some obstacles along the way, vessel sprouting and VEGF nevertheless are still the preferred methods of angiogenesis in most cancers and the reason that angiogenesis is successful. Angioprevention has far greater implications, beyond cancer treatment. It has the potential to impact consumer education, insurance companies, food services, public health and many more industries. Additionally, dietary cancer prevention may be the only practical solution in developing countries due to lack of equipment and personnel for advanced-stage cancer treatment. Angiogenesis treatment also has the potential to combat and prevent many other diseases, like obesity. All in all, compared to classic chemoprevention directed at cancer cells, the inhibition of angiogenesis and inflammation boosts anticancer defense mechanisms and provides protection against a broad spectrum of neoplasms. Clinical trials are now underway to test the efficiency of certain angiopreventive molecules such resveratrol and genistein that are naturally found in soybeans and grapes in cancer level III and level IV and in other cardiovascular and neurological diseases. Angioprevention holds the promise to be the panacea we have sought to cure the world’s worst diseases.