In a recent article published in Nature Communications (1) by a group of scientists led by Belgian professor Johan Thevelein from VIB-KU Leuven, it was revealed that sugar breakdown activates Ras proteins in cancer cells. Ras proteins stimulate cell proliferation while also increasing sugar breakdown. Both mechanisms reinforce each other. The discovery received worldwide interest and made an exceptional impact, but it also raised some controversy. In this article we create a context to understand the impact of this breakthrough.
Ras and fructose-1,6-bisphosphate: the downward spiral feeding cancer
The essence of the discovery was that an intermediary compound in sugar breakdown, fructose-1,6-bisphosphate, is a potent activator of Ras proteins. These are abnormally active in many tumors and cause unbridled multiplication of tumor cells. This discovery was first made in yeast cells and was subsequently confirmed in human cells (normal cells as well as cancer cells) and with pure human Ras proteins. Cancer cells display an excessively active sugar breakdown, which is known as the Warburg effect. They switch, just like yeast cells, from aerobic respiration of sugar to fermentation of sugar into lactic acid (or ethanol in yeast cells). It was already well established that Ras and other cancer-inducing genes trigger strong stimulation of sugar breakdown, causing an elevated level of fructose-1,6-bisphosphate. The new discovery revealed a vicious cycle in which sugar breakdown and the Ras proteins continue to stimulate each other reciprocally. Hence, for the first time it has become clear that the Warburg effect is not merely a symptom of cancer; it further stimulates cancer through Ras proteins.
This breakthrough doesn’t mean that sugar causes cancer, but when you have cancerous cells, it might further stimulate their growth." - Johan Thevelein
The evidence is plenty
This discovery provides a logical explanation for multiple previous findings concerning sugar breakdown and cancer, which, up to now, remained without explanation. For instance, it was previously reported that the enzyme fructose-1,6-bisphosphatase, which breaks down fructose-1,6-bisphosphate, acts as a tumor suppressor in kidney cancer (2). A logical explanation is now immediately available for this finding. Also, the enzyme that synthesizes fructose-1,6-bisphosphate, phosphofructokinase, is known to be activated by cancer-stimulating proteins and inhibited by tumor suppressors (3). Compounds that attenuate the abnormally active sugar breakdown in cancer cells may enhance the efficiency of chemotherapeutics (4). Activation of Ras by fructose-1,6-bisphosphate has therefore provided the keystone between the sugar breakdown pathway in metabolism and the molecular-genetic factors that stimulate cancer. There is little discussion concerning this point, and its importance is recognized widely. CNN calls the recent developments in Ras research an “incredible breakthrough” (5).
A sugar-free diet to cure cancer?
The real controversy is over the implications of this discovery for the nutrition of cancer patients. For many years, a movement has propagated the use of sugar-poor or sugar-free diets, called ketogenic diets, for cancer patients. Ketogenic diets contain mainly fat and protein, and they allow few carbohydrates. The effect of sugar-poor and sugar-free diets has been the subject of scientific research, including tests in experimental animals and clinical tests in patients. In experimental animals, administration of a ketogenic diet exerted a positive effect on cancer patients’ survival, and this was observed for pancreas, prostate, intestinal, brain and lung cancers (6). The number of studies is still considered too low, however, for definite conclusions. In clinical tests on patients, positive results have been obtained for, among others, tumors in the brain (7).
Future research should also focus on drugs that can intervene with the sugar breakdown in cancer cells. However, the big challenge here is that the responsible glycolysis pathway is a normal process in every cell of the body. So you cannot just develop a glycolysis inhibitor, as that would kill both the cancer and the patient.” - Johan Thevelein
The correlation between sugar and cancer is also supported by observations in patients that display an abnormally high blood sugar level. The most important examples are diabetes and cases of obesitas. Although there are many variable factors in studies with patients, a general consensus has risen that patients with diabetes (8) or obesity (9) run more risk of getting cancer and also respond more poorly to chemotherapeutic treatments (10). Moreover, multiple studies have shown unexpectedly that the antidiabetic drug, metformin, exerts a positive effect in the treatment of multiple causes of cancer (11). It is still unclear whether it concerns a direct effect of metformin on the tumor cells rather than an indirect effect through reduction of the blood sugar level. Glucose, on the other hand, stimulates the aggressiveness of breast cancer in experimental animals and reduces the positive effect of metformin (12).
Another concession patients have to make
Doctors are confronted with an important dilemma when prescribing a diet for cancer patients. Many cancer patients develop, over time, a very weak condition and lose considerable weight. They often get the advice to take in enough calories (13), which in practice often means a sugar-rich diet, especially since many cancer patients like protein or fat less and sugar tastes less sweet to them (14).
Especially high glucose peak levels in your blood can activate the aggressiveness of cancer cells. When you eat complex sugars, which are released slowly throughout digestion, you don’t get these high blood-sugar levels. The point is not to starve the cancer by not eating sugar anymore, but to avoid exposing cancer to high blood sugar levels." - Johan Thevelein
The message is therefore to search for sugar-poor ways of providing enough calories to cancer patients (15) as, for instance, with a ketogenic diet, a possibility that has also been suggested in the scientific literature (16). Now that we know the mechanism by which sugar can stimulate cancer, it is time to search for alternative ways to provide the best nutrition to cancer patients so that they can get the maximum benefit from their therapy.
There is a lot of literature on the effect of sugar on cancer, from which can be concluded that a high sugar intake is not beneficial for cancer recovery. A low-sugar diet could be beneficial for the healing process of cancer patients.” - Johan Thevelein
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(2) Li, Bo, et al. "Fructose-1, 6-bisphosphatase opposes renal carcinoma progression." Nature 513.7517 (2014): 251-255
(3) Vander Heiden, Matthew G., Lewis C. Cantley, and Craig B. Thompson. "Understanding the Warburg effect: the metabolic requirements of cell proliferation." science 324.5930 (2009): 1029-1033
(4) Zhao, Yuhua, Ethan B. Butler, and Ming Tan. "Targeting cellular metabolism to improve cancer therapeutics." Cell death & disease 4.3 (2013): e532
(5) "Sugar and cancer: Is there a link" CNN, October 27, 2017
(6) Khodadadi, Soheila, et al. "Tumor cells growth and survival time with the ketogenic diet in animal models: A systematic review." International journal of preventive medicine 8 (2017)
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(10) Klil-Drori, Adi J., Laurent Azoulay, and Michael N. Pollak. "Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing?" Nature reviews Clinical oncology (2016).
(11) Franciosi, Monica, et al. "Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review." PloS one 8.8 (2013): e71583
(12) Wahdan-Alaswad, Reema, et al. "Glucose promotes breast cancer aggression and reduces metformin efficacy." Cell cycle12.24 (2013): 3759-3769
(13) Baldwin, Christine, et al. "Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis." Journal of the National Cancer Institute 104.5 (2012): 371-385
(14) Danhauer, S. C., et al. "A survey of cancer patient preferences: which types of snacks do they prefer during treatment?" European journal of cancer care 18.1 (2009): 37-42
(15) Bozzetti, Federico, and Beth Zupec-Kania. "Toward a cancer-specific diet." Clinical Nutrition 35.5 (2016): 1188-1195
(16) Smyl, Christopher. "Ketogenic diet and cancer—a perspective." Metabolism in Cancer. Springer International Publishing, 2016. 233-240