How Tumor Cells Work Overtime to Restore Vascular Health

Young or old, every person with a troubling health condition who has turned to the conventional medical system for answers, braces himself for the moment when the diagnosis might come back with the dreaded “C” word. And we have all been conditioned to believe that, following such a dire diagnosis, not a moment is to be wasted: immediate action is needed to surgically remove the tumor.

Of course the prevailing view says that the operation should be followed with radiation therapy and chemotherapy to assure that every last tumor cell has been destroyed. Then we must patiently wait out the five-year “proving” interval in hopes that the cancer doesn’t return, or, worse, metastasize to some other tissue such as the brain or the bone marrow. Following cancer treatment, one is forevermore a “cancer survivor.” One is never cured.

If you peruse the research literature on cancer, you will find that investigators are frustrated and puzzled by much of what they find. Well-motivated logic and reason typically lead to the development of a new drug that seems like a dynamite idea for disrupting the tumor in some critical way, such as suppressing its blood supply or depriving it of an essential molecule for growth. Yet again and again the clinical trials turn up unexpected dangerous side effects that prevent the drug from going to market. A virulent tumor seems like a cat with nine lives or a phoenix ever arising””it always finds a way to come back to life in a much more deadly form than what it was before it was tampered with.

Cancer is usually portrayed as a disease that befalls us due to “bad luck” or perhaps “susceptible genes.” We are not led to believe that lifestyle choices might protect us from cancer. In fact, however, 90 to 95 percent of cancer cases have their roots in environmental and lifestyle factors.2 We are exposed in our daily lives to a host of chemical carcinogens, only some of which are formally acknowledged. These include toxic fumes from automobile exhaust, toxic pesticides applied to our foods, toxic agents in the vaccines our children are subjected to, various pharmaceutical drugs with carcinogenic potential, and a variety of chemicals like benzene, polychlorinated biphenyls (PCBs) and formaldehyde, to name a few.

Ironically, sunlight is one of the best protective agents against cancer. Although we are encouraged to stay out of the sun or to lather on the sunscreen for fear of getting skin cancer should we venture outside on a sunny day, the truth is that incidence rates of skin cancer have been rising steadily by 2 percent per year for the last thirty years, while sunscreen usage has increased thirty-fold.34 Sunscreens interfere with vitamin D3 synthesis in the skin24 and this effect may more than negatively compensate for any protection they afford from UV exposure.

Furthermore, places nearer the equator and places with less annual rainfall have lower rates of a multitude of different cancers, including esophageal, gastric, colon, pancreatic, breast, ovarian, rectal, prostate, renal, bladder, cervical, gallbladder, laryngeal, oral and Hodgkins lymphoma.14 A cancer diagnosed in the summer has a better prognosis than one diagnosed in the winter.30 And sunlight is also excellent treatment therapy following a cancer diagnosis.29

Breast cancer is the number one cancer for women, and one in eight women born today in America is expected to have to confront the disease at some time in life. We are just now questioning an era of active campaigns to insure that every woman get a mammogram every year for “early detection,” with the hope that this would surely save lives. Those hopes have now been dashed. A study conducted in Norway showed that aggressive use of mammograms resulted in a substantial rise in the rate of breast cancer, followed by no improvement whatsoever in the death rate from breast cancer.44 The conclusion was that either the radiation exposure from the mammogram increased risk, or tiny tumors that would usually be missed without mammograms were resolving on their own without treatment. Both of these hypotheses are remarkable for their role in changing the mindset towards this disease. Now those in the know are starting to recommend a “watchful waiting” policy towards both breast cancer and prostate cancer, something that most people find very hard to accept after all the years of brainwashing towards the concepts of early detection and immediate aggressive surgery.

These two types of cancer””breast cancer and prostate cancer””are interesting for several reasons, not the least of which is that they are respectively the most common cancers for women and men in the U.S. Breast cancer in particular can be viewed as affecting a “vestigial organ” if it occurs in a postmenopausal woman. A diagnosis of breast cancer is so much better than a diagnosis of pancreatic cancer or brain cancer or liver cancer, because the cancer is not disrupting the normal function of a critical organ.

HOW DOES A TUMOR KILL YOU?

At this point it is appropriate to ask the rather naive question: what is it exactly that a tumor does that causes harm? A woman often first notices she may have breast cancer by discovering a lump in her breast. She does not actually feel ill in any way. On the other hand, a person with cancer being treated with radiation therapy and chemotherapy suffers from a large number of symptoms that are due to the treatment rather than the cancer itself. Chemotherapy to treat breast cancer leads to cognitive impairment in a dose-response relationship.43 Cognitive decline appears to be even more strongly related to antihormone therapy (such as Tamoxifen) than to chemotherapy.31,27 One in four cancer survivors is left suffering from long-term debilitating health conditions, and 20 percent of those diagnosed with breast, colorectal or prostate cancer experience pain up to five years following diagnosis.10 Women with breast cancer are almost twice as likely to succumb to heart failure, and men with prostate cancer have double the risk of osteoporosis. Prostate cancer is also associated with a high risk of incontinence and impotence. Radiation therapy to treat early stage breast cancer on the left side has been shown to increase the patient’s risk to heart disease, presumably due to radiation damage to the heart itself.8 Even surgical removal of the tumor is dangerous. For example, deep vein thrombosis (which can cause a fatal pulmonary embolism) is far more common following cancer surgery than following other surgeries.12 Why is this?

SULFUR DEFICIENCY IN BLOOD VESSELS

A problem that frequently shows up in terminal cancer is something called “cancer cachexia.” This is a muscle wasting disease where the person has little or no appetite and the muscles are broken down to provide fuel to maintain basic minimal function of the vital organs.20

Why is there no appetite? How can a lump in a breast cause such a profound effect? While the argument is that the cancer is releasing signals called cytokines that induce a loss of appetite or an inability for the cells to utilize food as an energy source, one has to ponder why it is that these cytokines are released. Is there a reason why the sheer act of eating itself might be dangerous to the cancer patient?

I believe that the inability to metabolize food is due to the sorry state of the vasculature, which, in turn, is due to global, systemic deficiency in sulfate supplies to the vascular walls, to the cells and particles coursing through the blood, and in the tissues. The blood, particularly the hepatic portal vein which delivers digested food from the gut to the liver, is in such a fragile state that it can no longer support nutrient transport. In a 2012 article,36 my colleagues and I argue that the ability of the heart and skeletal muscles to metabolize glucose depends critically on the bioavailability of cholesterol sulfate, which is supplied through sunlight exposure to the skin. When sulfate supplies are depleted, sugar piles up in the blood, and this can be very destructive to the blood proteins. The result of an overload of nutrients to a fragile vasculature is the formation of blood clots, for example, thrombosis, a life-threatening condition.

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THE STRANGE METABOLISM OF A TUMOR CELL
A normal cell (left) uses its mitochondria to break down glucose (Glc) to carbon dioxide and water, producing ATP, the cell’s energy currency. A tumor cell usually has functional mitochondria but chooses not to use them. Instead, it converts glucose to lactate (Lac) which it releases into the medium, and it produces only a tiny amount of energy from each glucose molecule. It therefore requires 18 times as much glucose for the cell to obtain an equivalent amount of ATP, which it produces in the cytoplasm rather than in the mitochondria. It can use this ATP to energize sulfate so that it can be conjugated to a sterol such as estrone (breast cancer) or cholesterol (prostate cancer).

The answer I propose, therefore, is simple, but it’s extremely provocative. The tumor is not the problem! Furthermore, the tumor represents a valiant attempt to solve the real problem, and destroying the tumor’s ability to do its job is going to lead to a deterioration in overall health. Indeed, treated cancer patients are placing a huge burden on healthcare systems due to the many health problems that they acquire following cancer treatment, such as chronic pain, mental confusion, deep vein thrombosis and increased heart disease risk, as I discussed above.

Cancer cells have a very unusual metabolic policy which has been called the “Warburg effect,” named after the researcher who first characterized this feature in the 1920s.21 Ordinarily, when a cell is, for whatever reason, deprived of oxygen, it is capable of reverting to glycolysis as a way of extracting a small amount of energy from glucose by converting it to lactate, and this process does not depend on oxygen. It gets only one-eighteenth as much energy as you would derive if you broke glucose down all the way to carbon dioxide and water using oxidative phosphorylation in the mitochondria. Cancer cells are extraordinary, however, because, even in the presence of abundant oxygen, they refuse to use their mitochondria to produce energy. Instead, they are a powerhouse for taking in glucose””eighteen times as much as a normal cell to obtain equivalent energy””and shipping out lactate. This is the Warburg effect.

Why would cancer cells do this? I have a very simple explanation: the tumor is clearing the excess glucose from the blood and replacing it with an abundance of lactate to provide usable fuel for the critical organs like the heart and the brain. This is one reason why the tumor is part of the solution instead of part of the problem. The service it performs is essential to allow the heart and the brain, in their compromised state of severe cholesterol and sulfate deficiency, to continue to function by utilizing lactate as a source of fuel instead of glucose. But the tumor suffers from glycation damage and acidification as a consequence, so it struggles to survive under such harsh conditions.

The tumor has another more practical reason not to run its mitochondrial engines. Because it is severely deficient in sulfate, it needs to somehow produce sulfate from an available substrate. A promising candidate is homocysteine thiolactone. But, unfortunately, superoxide is required as a source of reactive oxygen to oxidize the sulfur atom in the homocysteine thiolactone. Furthermore, nitrate is needed to offset the kosmotropic effects of sulfate (otherwise, the blood will become too viscous). But the precursor to nitrate, nitric oxide, reacts with the precursor to sulfate, superoxide, to produce a nasty, highly reactive oxidizing agent called peroxynitrite,26 which will destroy the iron-sulfur containing proteins such as aconitase in the mitochondria.5 It’s really hard to avoid peroxynitrite exposure if a cell is producing both nitric oxide and superoxide. However, it has to produce both of these in order to be able to synthesize sulfate and not gel the blood in the process. A tumor cell is a very good candidate for the job, precisely because it’s not performing other essential duties, so it can “take the heat.”

This is probably the right place to bring up the critical issue about sulfate””it is vitally important as a component of the complex sugar molecules called glycosaminoglycans (GAGs), which decorate the exterior of just about all the cells in the body.9 However, it is both difficult to synthesize and difficult to transport. It plays a powerful role in forming an “exclusion zone” around every cell, to keep out unwanted molecules and protect the cell from ion leaks. It does this by inducing the surrounding water to form a crystalline structure that can almost be described as “liquid ice,28” something that is very similar to the gelled water in gelatin desserts. This special water-structuring effect of sulfate, while affording protection for the cell when a sulfate anion is attached to its matrix, presents a problem when the sulfate anion is in solution in the blood, because the free-flowing blood cannot afford to be gelled. This is why any free sulfate above about 0.3 mM concentration is immediately excreted through the kidneys. And it also explains why the body can be severely depleted in sulfate even while it is excreting sulfate in the urine. I believe the observation that sulfate is routinely excreted in the urine has misled both researchers and medical practitioners into thinking that sulfate can’t possibly be deficient.

Mitochondria are especially susceptible to damage by peroxynitrite, so a cell trying to synthesize sulfate is much better off if it suppresses mitochondrial activities. This means getting by on oxidative glycolysis to supply its ATP energy needs. Plus, ATP needs to be in the cytoplasm, not in the mitochondria, in order to produce PAPS, an activated, energized form of sulfate that can now be attached to complex sugar molecules being constructed in the cytoplasm in order to refurbish the barren extracellular matrix with heparan sulfate proteoglycans and restore the tumor cell to a healthy state.

HEPARIN SULFATE FROM TUMOR CELLS

Heparan sulfate is a remarkable molecule which is present in abundance just outside most of the cells of the body, attached to membranebound proteins called syndecans. It plays an extremely important role in regulating nutrient uptake, signal transduction and ion exchange across the membrane.4 Sulfate depletion in heparan sulfate is associated with a large number of disease states, including diabetes,36,38 autism,37 hypertension,15 digestive disorders25 and kidney disease.40 My colleagues and I have argued that sulfate deficiency, rather than excess cholesterol, is the major factor in heart disease, and that the cardiovascular plaque can be viewed as a factory where cholesterol sulfate is synthesized from precursors derived from LDL and homocysteine.36

Breast cancer cells will respond to exposure to estrogen by multiplying, which is why estrogen receptor antagonists such as Tamoxifen have been used as a hormone therapy option to impede their growth.1,13 Cancer cells use estrogen to produce estrone sulfate, which they release into the surrounding medium (thereby distributing sulfate to other cells). They also produce lots and lots of heparan sulfate, and, since they produce a sulfatase that detaches sulfate from estrone sulfate,22 I suspect that estrone sulfate becomes a source of sulfate for the synthesis of heparan sulfate.

Prostate cancer has a story similar to breast cancer with regard to sterol sulfate synthesis, except that the tumor makes cholesterol sulfate instead of estrone sulfate.11 Both estrone and cholesterol are sterols (estrone, testosterone, and vitamin D3 are all synthesized from cholesterol). Cholesterol sulfate is the same molecule that is synthesized in the skin upon sunlight exposure. Thus, a plausible way in which sunlight exposure might protect from cancer is by leading to the production of a molecule””cholesterol sulfate”” that is sorely needed to maintain the stability of the blood and the general health of the body.

While the tumor cell produces excessive amounts of heparan sulfate, it also produces excessive amounts of heparanase, an enzyme that breaks down heparan sulfate! Tumors that are more aggressive and more likely to metastasize (spread to other tissues) produce more heparanase than more benign tumors.18,3 Tumors, in fact, produce a continual stream of small vesicles called exosomes, which are pinched off from their plasma membrane and distributed via the vasculature.41 These contain syndecans bound to heparan sulfate in their membranes, so the tumor cell is delivering heparan sulfate to other cells on the backs of these exosomes! It appears that the tumor is involved in a program of obsessively making and shipping out heparan sulfate chains.

Why would it do this? As astonishing as this may sound, one is tempted to conclude that a tumor cell is altruistic””it is providing a continual stream of fragments of heparan sulfate to the vasculature with the explicit goal of fixing a severe pathology that would otherwise lead to the death of the organism. Or maybe this is not altruism but rather self-preservation. After all, if the blood supply to the tumor fails, the tumor itself will die.

It was at least thirty years ago when researchers first became aware that tumor tissues have a propensity to break down their extracellular matrix.33 This is not just due to the fact that the cancer cells release heparan-sulfate-containing exosomes as well as enzymes that degrade their surrounding matrix. They are also attacked by enzymes released by the healthy infiltrating stromal cells and by the invasive immune cells. Fragments of the heparan sulfate proteoglycans are broken off, or the protein, syndecan, that the sugar complex is attached to is attacked, or individual sulfate anions are snipped off of the sugar complex.33 All of these different methods of attack take place. The tumor is basically under siege, and it devotes considerable effort to replenishing the matrix that is constantly being degraded by enzymatic attack.

Careful examination of the evidence leads to the inevitable conclusion that the tumor is not the problem. In fact, it is the solution! Sugar is piling up in the blood because the cells are unable to utilize it as fuel. This is a direct consequence of insufficient sulfate in the pancreas, leading to an inability to manufacture insulin,39 and insufficient sulfate in the extracellular matrix of all the cells, leading to insulin resistance.36 The tumor cell can perform a wonderful service by sucking all that sugar out of the blood and replacing it with lactate. Lactate is a beautiful fuel””its negative charge helps to alleviate blood acidification, and it does not glycate blood proteins, such as hemoglobin and ApoB in LDL, a huge problem with glucose and other blood sugars. And the tumor is producing estrone sulfate and heparan sulfate and releasing them into the blood, supplying the essential nutrients that can restore the blood’s stability to prevent blood clots and hemorrhages.

TREATMENT STRATEGIES TARGETING THE CONNECTIVE TISSUES

Researchers argue that the tumor’s ability to break down the surrounding connective tissue that holds the cells in place, a process referred to as “matrix remodeling,” is a key factor in allowing a tumor cell to “break free,” and therefore migrate to some other place in the body. This often has catastrophic consequences, as metastasizing cells can then colonize other organs, and when this occurs the prognosis of death as an outcome is much higher.

Cancers metastasize when the primary tumor sheds cells into the blood, and one way to monitor this is to detect these wandering tumor cells in blood samples.19 Metastasis is the cause of 90 percent of cancer deaths, and about 25 percent of women diagnosed with breast cancer will go on to develop metastasized cancer. In studies in Europe, some cancer patients have been found to already have disseminated primary tumor cells in their bone marrow even before metastasis has occurred.19 These cells clearly break away from the main tumor (became dislodged from the matrix of supporting tissues), and their presence in the bone marrow indicates a poorer prognosis.

The breakdown of the matrix metalloproteins is carried out by specific enzymes called “metalloproteinases” (MMPs). There was initially considerable excitement about the possibility of developing drugs to inhibit these MMPs, called MPIs (metalloprotein inhibitors).6 In fact, new drugs were rushed to phase II trials without adequate prior study. However, the results were so disappointing that the pharmaceutical industry has now more or less given up on this line of attack.

What went wrong? The main problem was an unexpected side effect of severe muscle pain and weakness. This is remarkably similar to the most common side effect of statin drugs. I have previously described how statin drugs force the skeletal muscle cells to take up excessive amounts of fructose that can no longer be metabolized by the liver due to its inability to produce sufficient cholesterol in the presence of statin drugs.35 The muscle cells also use glycolysis to convert fructose and other sugars into lactate, just like the tumor cells. To the extent that the MPIs interfere with the tumor’s function, the muscle cells have to pick up the slack. Only, unlike a tumor, they have another very important role to play, which is to provide mobility. Their intense exposure to glycating agents like fructose causes damage to their proteins, particularly myoglobin, which, like hemoglobin in RBCs, is highly susceptible to glycation damage. This is what leads to muscle pain and weakness, and it can lead to even more dangerous outcomes like rhabdomyolysis””kidney failure due to the exposure of the kidney glomeruli to toxic debris in the form of damaged myoglobin released by dead and dying muscle cells.16 Indeed, patients with cancer often experience aching muscles and flu-like symptoms in response to cancer treatment programs, and they are at high risk of kidney failure.17

Curiously, a novel treatment for cancer has recently been proposed where the “drug” is a sulfated polysaccharide mimetic: essentially imitating the sulfated fragments that are released from tumor tissues through the activity of heparanase and syndecan shedding.23 The authors conclude with the idea that additional sulfation of this synthetic sugar might further improve its observed effects in reducing angiogenesis (blood vessel growth) and reducing mechanisms that are essential for metastasis.

A huge question that was left unanswered in the paper is whether these synthetic forms are actually accessible to the endothelial cells lining the vasculature such that they can repair the problem of severe sulfate deficiency that likely necessitated the development of a tumor. If not, then patients treated with these new drugs can expect to suffer from the same side effect profile as that experienced following MPI treatment: severe muscle pain and weakness.

HOW TO PROTECT YOURSELF FROM CANCER

What I conclude from my studies of cancer and its connection to sulfate deficiency is that “watchful waiting” is an excellent policy for breast cancer management, that mammograms are never a good idea, and that the best way to protect yourself from cancer is to optimize for the supply of sulfate to the blood and to the tissues. This means, first and foremost, getting as much sun exposure to the skin as you can manage. In today’s lifestyle, it’s difficult to allocate enough time to be outside in the sun, and I think a simple conscientious effort to spend more time outdoors would yield high payoff in terms of protection not only from cancer but also from many other modern diseases.

The second cancer-preventative strategy is to choose a diet that will support both sulfate synthesis and sulfate transport. The first part of this is to eat foods that are rich in sulfur. This includes meat, seafood, eggs, milk and milk products, as well as garlic, onions, and cruciferous vegetables.

A second step is to eat foods that contain “sulfate transporters.” These include polyphenols and flavonoids, as well as vitamin C and cholesterol. All of these molecules have in common a six-carbon ring and at least one hydroxyl group that can get swapped for a sulfate anion. The carbon ring disperses the negative charge on the sulfate anion and makes it safer for transport without risk of gelling the blood. I believe that the health benefits of buckwheat, ginger, virgin coconut oil, brightly colored fruits and vegetables, resveratrol (in wine) and curcumin (such as turmeric in curry powder) have more to do with the fact that they transport sulfate than the fact that they have antioxidant properties.

Another component of healthy eating is to choose only organic foods to the extent that this is practical. I recently published a paper together with Anthony Samsel which explains how glyphosate, the active ingredient in the most common weedkiller, Roundup, likely disrupts both sulfate transport and sulfate synthesis.32 I also published an article about glyphosate in connection with autism in the Fall 2013 issue of this journal. Glyphosate has been shown in in vitro experiments to induce proliferation of human cancer cells even when it is present in a concentration of mere parts per trillion.42

Obviously, it is imperative to minimize exposure to toxic chemicals. The aluminum in many sunscreens and antiperspirants is a good example. Women who use antiperspirants on a regular basis are at increased risk of breast cancer.7 Conscious restriction in the use of cosmetics, hair dyes, and pharmaceutical drugs will probably reduce risk to cancer. And it’s worth avoiding spending time in places where the air is highly polluted with automobile exhaust, while at the same time optimizing time spent on the seashore, where the air is fresh and sulfur-rich.

Another strategy that would likely be helpful is to soak periodically in Epsom salts baths. Epsom salts are magnesium sulfate crystals, and most people believe that their value lies mainly in their supply of magnesium. But I suspect it’s the sulfate that is providing most of the benefit from these baths. If you have access to a natural sulfur hot springs so much the better!

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