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ISIS Report 04/04/12

Cancer an Epigenetic Disease

Cancers are overwhelmingly caused by environmental factors and hence largely preventable; the focus on therapy based on genetic mutations is misplaced Dr. Mae-Wan Ho

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“We Fought Cancer…And Cancer Won”

The headline of an article in Newsweek Magazine said it all [1]. Richard Nixon declared war on cancer in 1971. Since then, the federal government, private foundations and companies have spent at least $200 billion in the quest for cures that resulted in an estimated 1.5 million or more scientific papers. But we are on the losing side of the cancer war.

Cancer was projected to kill about 230 000 more Americans in 2008, a 69 % increase over 1971. The raw number is misleading as the population has become older and 50 % larger. Death rates have fallen, especially for breast cancer in women. Between 1975 and 2005, the death rate from all cancers dropped by 7.5 %, though this compares unfavourably with the cardiovascular death rate, which has fallen by 70 % in the same period, thanks largely to less smoking.  New discoveries on cancer pathways, new drugs, new treatments, and new ways to reduce side effects and suffering and prolong lives have all been achieved, except for the cure of cancer itself.

 The main reason for losing the cancer war is that basic understanding of the disease continues to elude the army of cancer researchers who can think of nothing better to do than looking for yet more genes to attack as cancers develop resistance to new drugs. The National Cancer Institute admitted that “the biology of more than 100 types of cancers has proven far more complex than imagined.” Otis Brawley of the American Cancer Society was quoted saying: “one tumour is smarter than 100 brilliant cancer scientists.”

The issue has come to a head as the promise of ‘personalized medicine’ in cancer therapy based on genetic profile of individual patients suffered a serious setback when researchers found that tumours have more than a hundred gene mutations in coding regions alone, and not only do individual patients differ from one another, but different regions within a single tumour also have distinctly different genetic profiles (see [2] Personalized Medicine in Cancer Therapy Fact or Fiction? SiS 54).

That is precisely the picture one would expect if gene mutations are the effects rather than the causes of cancer; tumour cells simply mutate their genes to enable them to survive, all too often at the expense of the patient, thanks to the fluidity of the genome, first discovered in the late 1970s and abundantly corroborated since the human genome has been sequenced (see [3]  Living with the Fluid Genome, ISIS publication).

Cancer an epigenetic disease

I raised the possibility that cancer is an epigenetic disease in the final chapter of my book [4] Genetic Engineering Dream or Nightmare, ISIS publication), first published in 1998. ‘Epigenetic’ implies a change of the cell or gene expression state in response to the environment that is not immediately due to alteration in genomic DNA. I cited a paper published in 1992 [5] by Harry Rubin, Professor Emeritus of cell and developmental biology at University of California, Berkeley, in the United States, who was among the first to suggest that cancer is an epigenetic disease when almost everybody else was assuming cancer was a genetic disease due to mutations in several key ‘oncogenes’.           

Rubin described experiments carried out in two laboratories, one using X-rays to induce malignant transformation, the other using the carcinogen methyl-cholanthrene. Both studies found that most, if not all exposed cells were altered in some way, so that their progeny had a higher probability of transformation than untreated cells. In other words, the entire population of exposed cells showed an increased probability of transformation to the cancer state, and this increased probability was inherited in subsequent cell generations.  So, if one divided up the exposed population into several subpopulations, each of them would show essentially the same frequency of transformation. Moreover, if these were further subdivided and propagated, the same frequency of transformed cells arose in all of them. Such high frequencies of transformation are also characteristics of spontaneous transformations induced by metabolic and other stress on cells in culture, and are not due to correspondingly high frequencies of mutations.

Still more suggestive was the observation that clones of cells transformed by X-rays or by metabolic stress revert to normal when placed under optimal growth conditions. These results are reminiscent of high rates of reversion in the early stages of malignancy development.

A team of Russian scientists had been studying spontaneous transformations of cell lines derived from inbred mice and rats. The cells produced sarcomas in the mice and rats from which the lines were established. The researchers found that on culturing cells from the tumours, they were able to obtain colonies that were fully transformed, partly transformed or not transformed at all. On six successive recloning of transformed colonies, the cells persisted in giving rise to all three kinds of colonies. The non-transformed cells, which have lost their ability to give rise to tumours in the animals, arose at high frequencies. Commenting on the results, Rubin wrote [5]: “The question arises…whether the underlying process in all tumors is fundamentally epigenetic in character. I know of no experiment that rules out this possibility.”

The strong implication is that mutations are not the primary cause of transformation. Instead, they may arise after the crucial transformation of the cellular state, which is the result of response to physiological stress.  It also indicated the possibility that the transformed state can be reversed (again, thanks to the fluid genome!)

Indeed, long periods of starvation in bacteria have been known to result in ‘adaptive’ or ‘directed’ non-random mutations that enable bacteria to survive on new substrates or ones that they could not metabolize (see [3, 4, 6] To Mutate or Not to Mutate, SiS 24). British biochemist John Cairns, who made significant contributions to defining adaptive mutations, had drawn the parallel between conditions that give rise to adaptive mutations in bacteria and cancer in mammalian cells [7].

Recent evidence on epigenetic origin of cancer

More recently, Tatiana Karpinets and Brent Roy at Wright State University, Dayton, Ohio, in the United States proposed that cells exposed to stressful environments respond by epigenetic adaptive changes that result in ‘matched’ mutations arising in the longer term [8]. It is of interest that the phenomenon parallels a hypothesis of epigenetic evolution Peter Saunders and I proposed in 1979 [9] (see [10] Development and Evolution Revisited, ISIS scientific publication, for a recent review and evaluation of the hypothesis).

Specifically, Karpinets and Roy proposed that cells respond to stress by epigenetic changes that hypermethylate  (turning off) tumour-suppressor genes involved in cell cycle arrest, apoptosis (programmed cell suicide) and DNA repair; hypomethylate (thereby activating) proto-oncogenes associated with persistent proliferative activity; and globally demethylate the genome, activating DNA repeats and promoting genome instability. (Methylation involves adding a methyl-group  -CH3 to any cytosine base directly before a guanine base in the same DNA chain, and has the effect of turning genes off; conversely, removing the methyl group, or under methylation turns genes on.) As a result of these epigenetic changes, the cells continue to replicate, activating the processes related to promotion of replication, and suppressing processes related to inhibition of proliferation, cell cycle arrest, apoptosis, and DNA repair. Most of the well-known oncogenes are key regulators in these processes.  The generation of mutations by error-prone DNA replication is not random. Instead the mutations match the epigenetic alterations [8].

Hypermethylated genes are known to be predisposed to all kinds of mutations: point, frameshift, missense, and deletions, resulting in loss of function. Hypomethylation, on the other hand, predisposes to chromosomal mutations, rearrangements and aneuploidy, conferring usually a gain of function. In addition, global demethylation leads to a variety of mutations through the activation of DNA repeats. In sum, the epigenetic changes predispose cells to generate adaptive mutations characteristic of tumour cells.

Among the evidence cited in support of their hypothesis is that the epigenetic changes in cells exposed to stress are indeed similar to those indicated in premalignant and early stages of cancer development. For example, many studies have shown early epigenetic silencing of genes involved in cell cycle arrest and apoptosis, including cyclin-dependent kinase inhibitors p16, p14, p14, p73, APC, and DAP-kinase. Early hypomethylation is found for transcription factors involved in activation of proliferation such as c-myc and c-fos, and transduction of proliferative and survival signals such as EGFR, and Ras.

Karpinets and Roy also pointed out that rodent cells in culture readily undergo ‘spontaneous’ neoplastic transformations (abnormal growth that may not may not be malignant).  In a primary culture of mouse embryo cells, a small number of cells survive after apoptosis crisis by forming immortal cell lines that can overgrow the culture. These cells are primed for malignant modifications.

The hypothesis may explain the delayed effects of environmental factors on cancer development, the latent period corresponding to epigenetic adaptation (though it does not explain why different latent periods exist).

A major question raised is what mechanisms are responsible for the epigenetic ‘reprogramming’ of cells under stress.

Evolution of tumours and adaptive mutations

Chen Ding-Shinn and Wu Chung-I at the Beijing Institute of Genomics, Chinese Academy of Sciences in China are lead authors in a report from a team of 44 researchers who analysed the evolution of tumours in a single case of hepatocellular carcinoma exhaustively [11]. They wanted to know how many adaptive mutations drive the tumour growth, how strongly each mutation drives the growth, and what kinds of mutations they are.  Cancer mutations are often divided into drivers - those that contribute directly to tumour formation - and others that are merely passengers. The team decided to look for answers in the dynamics of tumour cell proliferation in the patient. They used Next Generation Sequencing techniques that can generate huge amounts of sequence data rapidly, with each sequence repeated many times so the frequency of different variants can be determined and rare variants detected.

The female patient had chronic hepatitis B virus infection, and was diagnosed with hepatocellular carcinoma at age 35. A primary tumour removed in the first surgery was grade II to III (IV being the most advanced). Fifteen months later a recurrent tumour was removed in the regenerated liver at the site of the first resection, plus a smaller recurrent tumour identified at a second site nearby. The team sampled nine different sections from the three tumours and seven more sections from the adjacent non-tumour tissues.

Selected sections were subjected to exon (coding sequence) as well as whole-genome sequencing. (Exon or exome sequencing selectively sequences the coding regions or exons that are translated into proteins. In the human genome there are some 180 000 exons, constituting about 1 % of the genome [12]). Among the mutations validated, 24 were amino acid changes, and 22 were large (> 1 Mb) insertion/deletion copy number variants. These somatic mutations defined four evolutionary lineages among tumour cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation.  Thus three coding changes: CCNG1, P62, and an insertion/deletion fusion gene were found to be tumour-driver mutations. These three mutations affect cell cycle control and apoptosis, and are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. The early ‘background’ mutations are believed to predispose cells to the tumour-driving mutations.

However, the researchers warned that the results cannot be generalized to other tumours, as each tumour may have its own repertoire of driving mutations that could be the target of cancer therapy.

Thus, the available evidence suggest that chronic stress and inflammation may predispose cells epigenetically to mutations in the stress related genes; but additional changes of mutations in cell cycle control/cell suicide genes are involved in triggering tumour formation. This is borne out by the latest research results on cancer prevention.

New studies [13, 14] confirm that a daily intake of low doses (75 mg) aspirin was sufficient to significantly reduce risk to a range of cancers, especially colorectal cancer, as well as oesophageal, gastric, biliary (gall bladder) and breast cancer. It also prevents the distant metastasis of existing cancers. Aspirin is well-known for its anti-inflammatory properties [15].

How cancer can be prevented

The root causes of cancer are overwhelmingly environmental, as generally recognized [16, 17], and hence largely preventable. Yet very little investment has gone into cancer prevention compared with the hundreds of billions spent on treatment or potential cures.

In a comprehensive review, Bharat Aggarwal and his team at University of Texas Houston in the United States documented that only 5 to 10 % of all cancer cases can be attributed to pre-existing genetic defects; the remaining 90-95 % of cases are environmental [17].

Of all cancer-related deaths, some  25-30 % are due to tobacco, 30-35 %  linked to diet (fried foods, red meat, alcohol), 15-20 % due to infections (especially viral infections), and the remaining due to radiation (both ionizing and non-ionizing), stress,  physical inactivity, environmental pollutants, etc.  Aggarwal’s team suggest that tissue inflammation is the link between the agents that cause cancer, which can be addressed by anti-inflammatory agents. They recommend, among other things, to stop smoking, eat less meat, and drink less alcohol; and instead to eat more fruits, vegetables and whole grain cereals, all of which are rich in anti-oxidants that neutralize reactive oxygen species (ROS), pro-inflammatory agents produced by cells under stress. (The role of ROS will be further examined in a later report [18] Cancer a Redox Disease, SiS 54).

Aggarwal and colleagues highlight cancer prevention through diet, and provided long mouth-watering lists (with illustrations) of fruits, vegetables, spices, condiments and cereals from around the world with the potential to prevent cancer [17].

The fruits include apple, apricot, banana, blackberry, cherry, citrus fruits, dessert date, durian, grapes, guava, Indian gooseberry, mango, Malay apple, mangosteen, pineapple, and pomegranate.

The vegetables include artichoke, avocado, Brussels sprouts, broccoli, cabbage, cauliflower, carrot, daikon (Chinese/Japanese white radish) kohlrabi, onion, tomato, turnip, ulluco (a root crop in the Andean region of South America), watercress, okra,  potato, fiddle head (the tender new leaves of the ostrich fern found along fresh waterways in the Maritime Provinces of Canada and the United States) , radicchio (Italian red cabbage), komatsuna (Chinese green leafy vegetable, a variety of Brassica rapa), salt bush (a salt tolerant plant Atriplex hortensis used as food since the stone age), winter squash, zucchini, lettuce, spinach.

The spices and condiments are a treasure trove of turmeric, cardamom, coriander,  black pepper, clove, fennel, rosemary, sesame seed, mustard, licorice, garlic, ginger, parsley, cinnamon, curry leaves, kalonji, fenugreek, camphor, pecan, star anise, flax seed, black mustard, pistachio, walnut, peanut, cashew nut.

Whole grain cereals include  rice, wheat, oats, rye, barley, maize, jowar (sorghum), pearl millet, proso millet,  foxtail millet,  little millet, barnyard millet, kidney bean, soybean,

mung bean, black bean, pigeon pea, green pea, scarlet runner bean, black beluga, and all the varieties of Spanish pardina (lentil), brown, green, green eston, ivory white, multicolored blend, petite crimson,  petite golden,  and red chief.

And don’t forget to drink green tea, with proven anti-cancer properties [19] (Green Tea Against Cancers, SiS 33) and benefits to health [20] (Green Tea, The Elixir of Life? SiS 33).

What Aggarwal and colleagues failed to mention is the importance of eating organically produced food, which are known to contain more cancer-fighting antioxidants as well as other beneficial nutrients while being free of cancer-causing pesticides and polluting chemical fertilizers, and are also what we need for mitigating and adapting to climate change ([21] Food Futures Now: *Organic *Sustainable *Fossil Fuel Free , ISIS publication).

There are 8 comments on this article so far. Add your comment
dr.ravindra. Comment left 4th April 2012 15:03:59
enlightened article...
Dr. Michael Godfrey Comment left 4th April 2012 19:07:37
The biologist Bruce Lipton was teaching epigenetics before the word was coined. He famously stated that the nucleus was merely a gonad for cell reproduction and the membrane was all-important as it responded to the environment. Environmental medicine is still regarded as fringe and predictably devoid of financial support by the game-players. However, this article reinforces what we have suspected for some time namely, that cancer results from a toxic and nutrient deficient environment. Change the latter and the cell can revert to normal. Thomas Tallberg in Helsinki at the Bio-Immunology Institute did this with malignant melanoma of the retina last century.
Todd Millions Comment left 8th April 2012 08:08:58
Caveat on the Asprin as a preventative- The pills are buffered and stuck together with starch.Usually loop hole labeled with the-'may contain'.So you can just bet its corn starch contaminated with unstabe and highly toxicBt insert insecticide mods.Same with the vit C powders and tablets.As well as all baking powders.In the case of ASA-you may wish too try experiments with willow bark teas as an alternative.Caveat-try small weak doses too test and when your gut gets queasy-STOP at that level,which varies fron species and time of harvest.
Stephanie Seneff Comment left 9th April 2012 07:07:18
Very interesting article, and I agree wholeheartedly with much of it. However, I believe that cancer is basically a metabolic disease, where the trigger for the cells to become immortal is tied to a need to dispose of excess serum glucose, fructose and methylglyoxal. Where I disagree is the dietary recommendations for avoiding cancer. The key factor here is dietary sugars, as well as carbohydrates, which are readily converted to sugar. Cancers form a useful function in converting massive amounts of sugar to lactate via aerobic glycolysis. Red meats, on the other hand, are an important source of sulfur-containing amino acids, especially taurine, which is only present in animal-based foods. Low serum taurine is associated with many cancers. Sulfur plays a key role in detoxifying environmental toxins, and sulfur deficiency therefore plays a key role in inducing cancer.
Alison Bleaney Comment left 9th April 2012 09:09:07
Makes perfect is the 'soup' around the cell that signals stress or non-stress...whatever that 'stress' may be that initiates this/these processes.
Dr. Townley Comment left 9th August 2012 10:10:58
I agree with dr.ravindra. Very enlightening, you should read My work
KAFUI ANKU KAETOZENA (ND) Comment left 6th December 2013 09:09:25
This article is very inspiring and I shall site it in my future discourse. I however disagree with the notion that the cause of cancer has eluded the army of cancer researchers. There is no iota of doubt in my mind! They know exactly what the causes of cancer are. To suggest otherwise is akin to saying that the researchers don't have ears; don't have eyes; don't have families; don't eat or breath; they don't walk on the same streets as all of us; they are hermits! What anybody will term an illusion is actually the control mechanism of the pharmaceutical industry! They control most of the funding of the research works on cancer! Cancer has become a big business just like the vaccines! A multi-trillion industry! It is crass capitalism! There are dozens of people curing cancer naturally; but have been hounded out of oblivion.
kyrani eade Comment left 7th April 2014 15:03:04
I have found that cancer is really about stem cell mediated immunity that is erroneously ignited in the body due to mistaken perceptions. Once the person has an aha experience their body will begin spontaneous remission. The genetic changes are deliberate (adaptive / epigenetic)both in creating cancer cells -what I call barrier and resistance cells- and in returning those cells back to being fully functional, fully specialized cells of whatever tissues they belong to. And the excesses are removed by apoptosis. It all has to do with immunity. The process can be hurried up by what I call mental prescriptions. Here is where I explain in ordinary language because my audience are lay people. I have even reached the level of avoiding cancer by "stage-managing" my biology.

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