Evidence that sugar fuels oncogenes and cancer’s growth

Increased glycolysis is  viewed by conventional oncology as a consequence of oncogenic events that drive malignant cell growth and survival. However, there is emerging evidence that increased glycolytic activation is followed by oncogenic development.

Regarding this aspect of carcinogenesis, in the Journal of clinical investigation it was shown that overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. (EXHIBIT A).

To make matters worse, increased fructose consumption  promotes even more cancer pathways, in particular insulin resistance, inflammation and reactive oxygen species production. For tumor growth, both glucose and fructose work in a complementary way. Fructose can also induce a change in the gut permeability and promote the release of inflammatory factors to the liver, which has potential implications in increasing hepatic inflammation. Fructose has been associated with colon, pancreas, and liver cancers, and we shall discuss the evidence for these observations. (EXHIBIT B).

MECHANISMS OF ACTION

High insulin and insulin-like growth factor (IGF-1) are needed for the control of blood sugar levels that result from chronic ingestion of high-carbohydrate meals. Increased insulin levels are pro-inflammatory and pro-cancer and can directly promote tumor cell proliferation via the insulin/ IGF-1 signaling pathway. (Source)

When the insulin levels are up, free-estrogen also goes up, thereby  speeding  up cell division.  Dr. Horner, who we interviewed,  talks about a study conducted by Harvard Medical School (2004) that found that women who, as teenagers, ate high-glycemic foods that increased their blood glucose levels had a higher incidence of breast cancer later in life.  Furthermore, the insulin receptor content in breast cancer tissues is also high (EXHIBIT C)

GLUCOSE DEPRIVATION ACTIVATES ANTI-CANCER METABOLIC AND SIGNALING LOOPS.

To substantiate these above-mentioned claims, Dr. Thomas Graeber, a professor of molecular and medical pharmacology, investigated how the metabolism of glucose affects the biochemical signals present in cancer cells. In a research piece published in June 26, 2012 in the journal Molecular Systems Biology, Graeber and his colleagues demonstrated that glucose starvation (ie, depriving cancer cells of glucose) activates a metabolic and signaling amplification loop that leads to cancer cell death as a result of the toxic accumulation of reactive oxygen species (ROS). (1)

STATE OF THE EVIDENCE

The evidence clearly shows that  elevated blood glucose, insulin resistance and high  IGF-1 levels facilitate tumor genesis and worsen the outcome in cancer patients.

ACRI’S RECOMMENDATION

Because sugar and carbohydrates  can have direct and indirect effects on tumor cell proliferation, (2)  it is highly recommended that cancer patients stop sugar intake, especially the processed sugars and anything that can spike insulin. (3).  Many medical scientists and  holistic practitioners know that the most logical, effective, safe, necessary and inexpensive way to slow down cancer’s growth is to cut off the supply of food to tumors and cancer cells. Strong science supports this knowledge.

It thus remains incomprehensible why allopathic conventional oncologists still don’t recommend this simple protocol, and all the more so that  conventional oncologists have known for many decades that cancer thrives on glucose, at least since the introduction of Pet Scans, as these scanners use dyed glucose to find tumors. And two times Nobel winner Otto Warburg already explained much of this carcinogenesis science since 1924. (4)

Worse, many cancer clinics have candies they offer cancer patients, if only to sooth their “terminal” verdict. Yet, as we have briefly seen,  the therapeutic strategy for selective starvation of tumors by dietary modification is one of the easist and most effective  holistic technique to put in place.  Depriving patients from this knowledge, offering them office candies and telling them they can eat whatever they wans should be malpractice.

PRECISION AND REFERENCE NOTES

(1). Nicholas A Graham, Martik Tahmasian, Bitika Kohli, Evangelia Komisopoulou, Maggie Zhu, Igor Vivanco, Michael A Teitell, Hong Wu, Antoni Ribas, Roger S Lo, Ingo K Mellinghoff, Paul S Mischel, Thomas G Graeber. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Molecular Systems Biology, 2012;

(2). As seen, many cancer cells express insulin receptors (IRs) and show hyperactivation of the IGF1R-IR (IGF-1 receptor/ insulin receptor) pathway.

(3). Multiple reasons justify this recommendation.  First, and contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown anti-tumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients has exhibited an altered glucose metabolism characterized by insulin resistance and rapid cancer growth.

(4). Dr. Otto Warburg’s 1924 paper, “On metabolism of tumors,” stated, “Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar.” It has been shown that the metabolism of cancer is approximately eight times greater than the metabolism of normal cells.Warburg’s hypothesis was of course that cancer growth was caused when cancer cells converted glucose into energy without using oxygen. Professor Weinberg disputed this because cancer cells do use oxygen, though much less than normal cells. Healthy cells make energy by converting pyruvate and oxygen. The pyruvate is oxidized within a healthy cell’s mitochondria, and Warburg theorized that since cancer cells don’t oxidize pyruvate, cancer must be considered a mitochondrial dysfunction.

EXHIBIT A

J Clin Invest. 2014 Jan 2; 124(1): 367–384.

Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways

Yasuhito Onodera,1,2 Jin-Min Nam,3 and Mina J. Bissell1

There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between “normal” and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.

EXHIBIT B.

Horm Mol Biol Clin Investig. 2015 May;22(2):79-89. doi: 10.1515/hmbci-2015-0009.

The role of fructose in metabolism and cancer.

Charrez B, Qiao L, Hebbard L.

Fructose consumption has dramatically increased in the last 30 years. The principal form has been in the form of high-fructose corn syrup found in soft drinks and processed food. The effect of excessive fructose consumption on human health is only beginning to be understood. Fructose has been confirmed to induce several obesity-related complications associated with the metabolic syndrome. Here we present an overview of fructose metabolism and how it contrasts with that of glucose. In addition, we examine how excessive fructose consumption can affect de novo lipogenesis, insulin resistance, inflammation, and reactive oxygen species production. Fructose can also induce a change in the gut permeability and promote the release of inflammatory factors to the liver, which has potential implications in increasing hepatic inflammation. Moreover, fructose has been associated with colon, pancreas, and liver cancers, and we shall discuss the evidence for these observations. Taken together, data suggest that sustained fructose consumption should be curtailed as it is detrimental to long-term human health.

EXHIBIT C

J Clin Invest. 1990 Nov; 86(5): 1503–1510.

Elevated insulin receptor content in human breast cancer.

V Papa, V Pezzino, A Costantino, A Belfiore, D Giuffrida, L Frittitta, G B Vannelli, R Brand, I D Goldfine, and R Vigneri

The growth of breast cancer cells is under the regulation of hormones, growth factors, and their receptors. In the present study, we have employed a new, sensitive, and specific radioimmunoassay for the direct measurement of insulin receptors in surgical specimens of breast cancers. In 159 specimens the insulin receptor content was 6.15 +/- 3.69 ng/0.1 mg protein. This value was more than sixfold higher than the mean value found in both 27 normal breast tissues obtained at total mastectomy (0.95 + 0.68, P less than 0.001) and in six normal specimens obtained from reduction mammoplasty (0.84 +/- 0.78, P less than 0.001). The insulin receptor content in breast cancer tissues was also higher than in any normal tissue investigated including liver (Pezzino, V., V. Papa, V. Trischitta, A. Brunetti, P.A. Goodman, M.K. Treutelaar, J.A. Williams, B.A. Maddux, R. Vigneri, and I.D. Goldfine, 1989. Am. J. Physiol. 257:E451-457). The insulin receptor in breast cancer retained its ability to both bind insulin and undergo insulin-induced tyrosine kinase activation. Immunostaining of the specimens revealed that the insulin receptor was present in malignant epithelial cells, but was not detected in stromal and inflammatory cells. Univariant analysis revealed that the insulin receptor content of the tumors correlated positively with tumor size (P = 0.014), histological grading (P = 0.030), and the estrogen receptor content (P = 0.035). There were no significant correlations between insulin receptor content and the age, body weight, menopausal status, and nodal involvement of the patients. These studies indicate, therefore, that the insulin receptor content is increased in breast cancers and raise the possibility that the insulin receptor may have a role in the biology of these tumors.

EXHIBIT D

NutrMetab (Lond). 2011; 8: 75.

Is there a role for carbohydrate restriction in the treatment and prevention of cancer?

Rainer J Klement1 and Ulrike Kämmerer2

Over the last years, evidence has accumulated suggesting that by systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress, or at least delay, the emergence of cancer, and that proliferation of already existing tumor cells could be slowed down. This hypothesis is supported by the association between modern chronic diseases like the metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to which more complex carbohydrates are ultimately digested, can have direct and indirect effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown anti-tumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose metabolism characterized by insulin resistance and may profit from an increased protein and fat intake.
In this review, we address the possible beneficial effects of low CHO diets on cancer prevention and treatment. Emphasis will be placed on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.

Post Scriptum: Organic fruit sugars have a different molecular spin than processed sugars and because of their contextual enzymes, bioflavanoids, fibers etc, they can be included in a cancer diet provided that certain strategic and  fruits are favored, to the detriment of the high glycemic index ones, which should be avoided (Cf  ACRI’s Center’s recommended anti-cancer diets).

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DISCLAIMER: Nothing in this educational post should be construed to be medical advise.