Rakesh K. Jain is Andrew Werk Cook Professor of Tumor Biology and director of the Edwin L. Steele Laboratory for Tumor Biology in the radiation oncology department of Massachusetts General Hospital and Harvard Medical School. His research incorporates biology, imaging, engineering and mathematics in the study of blood and lymphatic vessels and their tissue environment, as well as the adaptation of basic findings to patient treatment. He would especially like to acknowledge the National Cancer Institute for contiuous support of his work since 1980 and more than 200 graduate students, postdoctoral fellows and collaborators worldwide who have shared his journey into the world of solid tumors. Jain also serves as an adviser to several pharmaceutical and biotechnology companies and is a member of both the National Academy of Engineering and the Institute of Medicine.
Tortuous Road
Tumors, which stimulate the growth of new vasculature of their own, tend to generate a tangle of vessels. These connect to one another randomly, with some oversize branches, many extraneous immature microvessels and areas of a tumor that will lack vessels altogether. Over the course of many years we managed to delineate the processes that govern the movement of fluids, drugs and cells within this tortuous vasculature and gained insight into the consequences of the abnormalities.
The picture that emerged was grim: the very first thing we realized was that tumor blood vessels are not just disorganized in their appearance but highly aberrant in every aspect of their structure and function. We found that blood flows quite briskly in some vessels within a tumor, whereas it is static in others. In a given vessel, blood may travel in one direction for a while and then reverse direction. These flow patterns alone create a major obstacle to uniform drug delivery.
Moreover, some parts of the vessel walls are overly leaky and others are unusually tight, that managed to penetrate the vasculature would be distributed into the surrounding tumor tissue unevenly.
When we began investigating the causes of this non-uniform porousness, we discovered that in some tumors the pores in blood vessel walls could be as large as one or two microns in diameter, which is more than 100 times the size of pores in healthy vessels. As a result, these vessels are unable to maintain normal pressure gradients across their walls. Fluid pressure inside healthy blood vessels is typically much higher than in the surrounding tissue. Because tumor vessels are so porous, escaping fluid raises the outside—or interstitial—pressure until it nearly equals that inside the blood vessels.
This unnatural pressure gradient is not just an impediment to the ability of drugs to reach tumor cells; the accumulation of interstitial fluid produces swelling in and around tumor tissues. In patients with brain cancers, where tissue expansion is limited by the skull, that swelling becomes a severe, often life-threatening problem in itself. In those with other types of cancer, the exuded fluid can also accumulate in body cavities. Wherever it goes, the fluid oozing from a tumor carries with it tumor cells as well as various tumor-generated proteins that promote the growth of new blood and lymphatic vessels in the surrounding normal tissue and lymph nodes—which can then serve as conduits for the metastatic spread of the cancer cells to other parts of the body.
Beyond the difficulty of delivering drugs through chaotic tumor vasculature and the dangerous fluid buildup caused by leaky vascular walls, the abnormalities of tumor vessels create a highly unnatural microenvironment inside a tumor as well. Because many areas of a tumor lack vasculature and existing vessels are unable to deliver sufficient oxygen to surrounding tissues, a general state of hypoxia (low oxygen) and high acidity prevails in the tumor. Hypoxia in turn makes tumor cells more aggressive and prone to metastasis. In addition, the body’s immune cells, which might help fight a tumor, are hampered by acidity and cannot function in low oxygen. Nor can radiation treatments and a subset of chemotherapy drugs that depend on chemical processes that require oxygen to kill cancer cells.
Thus, what began as an inquiry into seemingly simple aberrations in the flow of drugs inside tumors revealed that the abnormalities in tumor blood vessels are obstacles to treatment in even more ways than I had initially imagined. In 1994 I described our findings up to that point in-depth in this magazine [see “Barriers to Drug Delivery in Solid Tumors,” by Rakesh K. Jain; Scientific American, July 1994]. By that time, these observations were also beginning to suggest to my research collaborators and me that if we knew how to repair the structure and function of tumor-associated blood vessels, we would have a chance to normalize the tumor microenvironment and ultimately improve cancer treatment. To accomplish such a reversal, we first had to gain a better understanding of what makes tumor vessels abnormal and keeps them that way.
Restoring Balance
We began to look at the molecular factors involved in normal blood vessel formation, known as angiogenesis, including the single most potent one, vascular endothelial growth factor (VEGF). First discovered and named vascular permeability factor by my Harvard University colleague Harold Dvorak, VEGF promotes the survival and proliferation of endothelial cells, which form the inner lining of blood vessels.
Whether healthy or diseased, tissues that need new blood vessels increase their production of angiogenesis stimulators or reduce their production of inhibitors, or do both, tipping the balance in favor of angiogenesis. In healthy processes such as wound healing, a balance between growth and inhibitory factors is eventually reinstated once the new vessels are established. But in tumors and a number of other chronic diseases, an imbalance persists—and blood vessels grow increasingly abnormal.
BLOOD VESSELS in a normal mouse muscle’s capillary bed (far left) and inside a mouse tumor (left) differ distinctly. The tumor vessels branch erratically, vary in diameter along their lengths and are generally oversize—all features that contribute to irregular blood flow.
Vessel Repair: Beyond Cancer
Hundreds of millions of people around the world suffer from noncancerous conditions that involve abnormal vasculature. Modifying blood vessel growth and function might become a key component of the therapeutic arsenal for those diseases as well, so drugs that normalize blood vessels have the potential to vastly impact human health.
Among the most widespread of problems in this category, for example, is atherosclerosis, an artery disease whose features include an accumulation of fatty plaques within the inner walls of blood vessels. Inside such plaques, inflammation-inducing blood cells and other detritus accumulate, gradually enlarging the lesion. New blood vessels sprout within this growing mass to feed it, much like a tumor. These new vessels also share many abnormal features with tumor vessels, such as leakiness and disorganization. In principle, therefore, applying antiangiogenic agents should normalize intraplaque vessels, stabilizing the lesions, halting their expansion and reducing their potential for rupture.
Eye diseases such as diabetic retinopathy and the so-called wet form of age-related macular degeneration (AMD) are also characterized by vascular abnormalities similar to those seen in tumors. A hallmark of wet AMD is, in fact, the leakiness of blood vessels in the retina at the back of the eye. As a result, blood oozes into surrounding tissue, causing partial or total vision loss. More than nine million Americans are currently affected. Not surprisingly, the greatest progress outside the realm of cancer treatment in using antiangiogenesis to repair vascular abnormalities has been in wet AMD. Two drugs, Lucentis and Macugen—both inhibitors of VEGF—have already been approved for treating the condition and most likely work by normalizing the leaky vessels.
These same normalization principles may also be useful for controlling conditions that cause fluid buildup (edema) and for tissue engineering and regenerative medicine, which
require the creation and maintenance of normally functioning vasculature. —R.K.J. https://pdfs.semanticscholar.o
■ Abnormal and dysfunctional blood vessels are a hallmark of solid tumors, one that contributes directly to malignant properties of a cancer as well as preventing treatments from reaching and attacking tumor cells.
■ Normalizing tumor vessels allows cancer therapies to penetrate the mass and to function more effectively.
■ Unexpectedly, drugs originally designed to destroy tumor blood vessels act to repair them for a time, opening a new avenue for cancer treatment as well
as restoration of abnormal vasculature in other diseases.
A Formula for Healing Cancer: The Latest Research in Mind-Body Medicine
This book was written for anyone who has cancer, who has had cancer, or who cares for someone with cancer. It offers some profound insights into how and why your cancer may have begun and what steps you can take right now to begin to create real healing in your life. There are remarkable concepts, therapies and processes here that have achieved success in reversing even late-stage terminal cancer cases. This is a rare opportunity to explore in one place research from some of the world’s leading experts on the healing power of the mind and the emotions–and the newly emerging science of “Psychoneuroimmunology.”
This book is being offered free of charge because I want to make this vital information available to as many people as possible–no matter what their financial circumstances. If you find benefit in what you read here, please consider making a donation to our chosen non-profit cancer information, counseling and referral agency, The Center for Advancement in Cancer Education. (see Chapter 8 below for more information about this group and their excellent Executive Director, Dr. Susan Silberstein).
A WEAK BODY CAN’T DEFEND ITSELF !!!!
////////////////////////////////////////////////
Can Natural Nutrients Prevent Cancer and Its Recurrent? Taming the Volcano of Inflammation with Phytonutrients
Zhaoping Li, MD, PhD
There is a very simple and critically important piece of information for everyone to understand–a sedentary lifestyle contributes to increased inflammation; regular exercise helps reduce inflammation. Our ancestors spent many hours each day in active pursuit of food through hunting and gathering. There was a lot of physical activity, expenditure of calories and strength needed for these activities.
Interestingly, our DNA has changed very little over the last 50,000 years when our ancestors were hunter/gatherers. What has changed, however, is our diet. Diets used to be rich in fruits, nuts, seeds, root, tubers, flowers, leaves, stalks and beans. 50,000 years ago the human diet contained half the fat along with 2-3 times more protein. There was no dairy or refined flour, no processed foods, no alcohol and no tobacco.
What we eat today is lots of potatoes, refined pastas, cereals, white rice, flour and corn. Please remember that potatoes and corn are not vegetables, they are starches. Our diet has added fat, sugar and high fat proteins. In addition we eat ice cream, cheese and whole milk as well as many processed foods. Today the three most common “fruits and vegetables” consumed are potatoes (as French fries), iceberg lettuce (which is nothing but water) and tomatoes (in the form of ketchup). Needless to say, there is a lot of room for improvement. DRAMATIC NEWS FROM CHARLOTTE GERSON – YouTube https://www.pinterest.com/pin/
One of the key issues we have learned in recent research is the critical role that intra abdominal fat and obesity plays in a variety of medical conditions. The fat tissues create and contribute to the ongoing inflammation in the body. Obesity has been irrefutably linked to: hypertension, type-2 diabetes, heart disease, dyslpidemia, gallbladder disease, certain cancers, stroke, osteoarthritis, sleep apnea, esophageal reflux, depression and infertility. We now understand that fat tissue (adipocytes) function as a very active endocrine organ in the body, with as much importance as the adrenal and pituitary glands.
They are not just large cells that make people big and fat; rather, they play a significant role in how the body’s various systems function. Adipose tissues (fat) secrete adipokines which regulate energy homeostasis, glucose and lipid metabolism. They also regulate appetite, blood pressure, the reproductive system, the inflammatory response and angiogenesis (the development of blood vessels). Many readers may be aware angiogenesis is a primary area of cancer research in which drugs are being developed to keep cancer cells from establishing blood supplies which help feed them, thus depriving them of a necessary tool to grow.
Further, adipocytes also produce factors that participate in the body’s acute phase reaction, which is part of the immune system, and in immune surveillance. In other words, these adipokines, the chemical secreted by our fat cells, alter how our immune system responds. There are many hormones that are secreted by these adipocyte fat stores. In addition they have receptors on these as well that attract certain hormones. There is a complicated cycle that exists regarding fat tissue and the overall health of the organism that involves all aspects of functioning.
It is not just how much a person weighs relative to their height that matters, but whether the body is made up of lean muscle mass compared to fat tissues. It is essential to evaluate the total body fat mass, the amount of abdominal visceral fat, intramuscular lipid stores, non-alcoholic liver fat, pancreatic lipid infiltration, cardiac muscle lipid infiltration and abnormal fat tissue metabolism. The body mass index (a formula that is used that takes into consideration height and weight) has been a standard measure for evaluating whether people are obese. Recent research has shown a strong correlation in men between BMI and fat but not for women. The better measurement is actually how much muscle mass there is compared to fat cells. We have been studying this issue and found thateven thin people can have excess fat and this has been labeled as sarcopenia obesity. It is important to measure these variables and provide goals for improvement. Patients who go through treatment and are kept from doing their regular exercise or eating a balanced diet due to fatigue and/or side effects can experience a reduction in their muscle mass and will need reconditioning. Reconditioning requires both aerobic and strength (muscle) building exercises as well as the proper amounts of the right proteins (e.g., lean protein).
Phytonutrients
There are recent studies conducted here at UCLA and in other labs that illustrate the relationship between diet and our body’s inflammation levels. People who have a high intake of carotenoid -rich vegetables and fruits are able to reduce their blood levels of hs-CRP, a marker for inflammation. Carotenoid-rich fruits and vegetables are those that have many different colors. There is a growing consensus that individuals need to eat a diet that is rich in these various colors and that variety is important. These chemicals are called phytochemicals or phytonutrients. They are non-nutrient plant compounds that provide health benefits against certain chronic human illness such as cancer, heart disease and neurodegenerative diseases.
Research into phytonutrients is just beginning but what is known is positive. Some key things we have learned are that there are many phytochemicals and it is better to get them in whole foods when possible rather than extracting them into supplements, although there may be a few exceptions. Whole foods provide other benefits and the value of these phytonutrients may be related to the combination of other nutrients in those whole foods.
Some of the phytochemical classifications that have been studied include phenolics, flavonoids, tannins, and anthocyanidins as examples. Some of the foods that have been studied with attention to particular phytonutrients include turmeric (curcumin), chili peppers (capsaicin), ginger ([g]-gingerol), green tea (epigallocatechin-3-gallate), soy beans (genistein), tomatoes (lycopene), grapes (resveratrol), cabbage (indole-3-cartinol), broccoli (sulphoraphane) and others.
Pomegranate juice has been studied in patients with prostate cancer who have rising PSA levels. The substance being studied is ellagitannin (punicalagin). Men with rising PSA after surgery or radiotherapy who had Gleason scores of 7 were given 8 ounces of pomegranate juice daily. It is important to note that the pomegranate juice used in the study was real pomegranate juice and that is made from the entire pomegranate (hull and all) which is squashed to make the juice.
Many pomegranate juices are mixed with other juices and there is very little real pomegranate juice in these; also, much of the beneficial phytonutrients are in the hull or skin, not in the seeds. Juice which is kept in the refrigerated section of the grocery store is more likely to contain real pomegranate phytonutrients. The researchers looked at the effect on serum PSA and serum-induced proliferation and apoptosis of LNCaP cells (a kind of prostate cancer cells that grow in a dish). The data suggested that the men who drank the pomegranate juice had a slower rise in their PSA levels. There was a 12% average reduction in the growth of the LNCaP compared to baseline. This was one study and was not a randomized controlled study so it is suggestive and needs additional research.
Carotenoids have also been studied and found to have the ability to neutralize harmful byproducts of photo oxidation. These also include things like beta -carotene and lycopene. Beta-carotene is found in carrots. However, it should be noted that taking supplements of -carotene actually had the reverse effect in a study of patients with lung cancer and, thus, it underscores the importance of whole foods. Lycopene is found in many foods such as watermelon, grapefruit, and tomatoes. The best sources of lycopene are tomato sauce and juices.
For example, ½ a cup of tomato sauce contains 21.9 mg, ¾ of a cup of tomato juice contains 19.8 mg and 2 tbsp. of tomato paste contains 18.2mg. One half of a pink grapefruit contains 4mg. Studies at UCLA have found benefits to patients with prostate cancer who consume food rich in lycopene when they are in the watchful waiting period. There also appears to be some benefits related to breast cancer as well. The area closest to the skin in avocados have been shown to have higher amounts of a carotenoid called tocopherol and that has been shown in the lab to be effective against two cell lines of prostate cancer. Keep in mind these are cell lines in the lab, not people.
Cruciferous vegetables–cabbages, cauliflower, and broccoli–contain a phytonutrient called sulforaphane which is a prominent isothiocyanate. In the research lab, these have been shown to inhibit the growth of breast cancer cells. Similarly, berries such as blackberry, black raspberry, blueberry, cranberry, red raspberry and strawberry have been shown to inhibit human cancer cell growth in the lab. Berries contain flavanoids, hydrolyzable tannins and phenolic acids.
Tea is the second leading liquid consumed in the world after water. Tea is the brew made from the infusion of water and the leaves of a plant from the Camellia family. There are four major types of tea: White, Green, Oolong and Black. These teas come from the raw leaves of the same tea plant, Camellia sinensis. Tea is differentiated by how they are processed–steamed, dried and fermented (oxidized). White tea is unprocessed and steamed before drying. Green tea is not fermented, black tea is dried and fermented and oolong tea is only partially fermented.
Green tea is higher in polyphenols (about 16-30%) while black tea has 3-10% polyphenols but also has 2-6% theaflavins and 20% thearubigins. There have been some studies of case-control trials with green tea as a chemoprevention agent. A recent review found 2 of 6 positive studies for lung cancer, 7 of 15 for stomach cancer, 4 of 7 for colon cancer, 1 of 1 for prostate cancer and 3 of 3 for breast cancer. There is variability in these studies regarding the amounts of tea used but it appears individuals would need about 5 cups of tea per day to have benefits. Remember, tea contains caffeine.
Resveratrol is a phytonutrients found in grapes and, thus, in red wine. Individuals should not use wine to get resveratrol as one glass of wine has about 200 calories. It is a simple fatty acid. There are other relationships of alcohol to estrogen/estradiol that needs to be considered, especially for women and breast cancer.
Strategies for Increasing Phytonutrients and Health
It is easy to consume red-purple foods by eating fresh berries, cherries and grapes. Frozen are about as good as fresh and can be used a toppings to foods, eaten as snacks or desserts. From a nutritional standpoint, frozen whole berries and cherries are preferable over dried berries. Real bottled grape, pomegranate and cranberry juices are also goo, but avoid added sugar or high fructose corn syrups which are not good and add calories. And, for the record, despite what the commercials say about corn syrup being natural and from corn, they are NOT good for you and you should limit the amount of high fructose corn syrups to the extent possible. Some frozen juice concentrates may be better. Freeze-dried berries can be added to cereals yogurt or snacking. Pre-shredded red cabbage is also a handy snack.
There are over 100 phytonutrients in just one piece of fruit or vegetable. We are still learning about the interaction and relationship between phytonutrients but all our research indicates they may work together, so it is better to eat whole foods. Supplements are not the same as whole foods—if flavanoids are one of a hundred phytonutrients from a berry, we have no idea what other chemicals or interactions make eating that berry such a powerfully good food source.
Try to eat a wide variety of fruits and vegetables with lots of color. Do not eat the exact same fruit and vegetable each day and try to add different ones to your diet that are not part of your regular routine. Do a combination of raw and cooked. It is okay to microwave vegetables and less water is better. Try to consume no fewer than five servings per day of fruits and vegetables but 7 -9 are better and necessary to obtain the protective benefits of phytonutrients. A large apple is two servings.
Exercise regularly and include both aerobic and strength-based regimens that build muscle. Consider having your body fat assessed as well at looking at how much protein you consume. Protein from wild caught fish is one of the best protein sources. When eating chicken, eat the breast (white meat) as it has less fat and does not absorb as many toxins or harmful things as much as dark meat. Having less fat is also why white chicken meat is not as tasty for some as dark meat. During and after treatment get some help to improve your body’s ability to stay strong and recover.
https://articles.mercola.com/sites/articles/archive/2016/01/20/sugar-top-cause-cancer-surge.aspx
This talk was given at a local TEDx event, produced independently of the TED conferences.Because we want to understand what genes are required for blood vessel development, Courtney Griffin studies certain enzymes that help turn genes on and off. These enzymes are specifically involved in relaxing DNA that is normally tightly coiled up in our cells. https://www.youtube.com/watch?
