The Warburg Cancer Theory
The mysterious relationship between the Warburg effect and oncogenesis has been debated for nearly a century. Recently, however, a team of Belgian molecular biologists found a possible explanation —and a direct link between sugar intake and cancer.
The result of their 9-year study not only provides a clear warning for patients to reduce sugar consumption, but also a new and novel avenue for therapy, the lead author, Johan Thevelein, PhD, a professor at KU Leuven and Vlaams Instituut for Biotechnology in Belgium, said in a telephone interview with Cancer Therapy Advisor.
"The direct significance of our work is that patients have to be careful with sugar," he said, "because we have identified a mechanism by which high sugar activates the aggressiveness of cancer."
Simply put, Dr Thevelein said, he and his colleagues found a clear link between fructose 1,6-bisphosphate and activation of oncogenic Ras proteins.
The study appeared almost simultaneously to an opinion article positing that similarities between the glycogen shunt in yeast and cancer explains lactate produced in the Warburg effect.
The "glycogen shunt," the paper explains, "describes conditions when glucose is shunted to glycogen and subsequently consumed through glycolysis even though adequate glucose and other energy supplies are present, thereby coupling glycogen synthesis and breakdown pathways to glycolysis."
That, the authors suggested, would explain the central paradox of the Warburg effect — aerobic glycolysis, or why cancer cells ferment glucose to produce lactate even when oxygen is present.
"The coordinated action of the glycogen shunt and glycolysis allows the cells to store glucose as glycogen while maintaining homeostasis of glycolytic intermediates and ATP and supplying glycolytic substrates for the PPP [pentose phosphate pathway] when needed," they wrote. "The storage of excess glucose intake as glycogen allows energy to be preserved for future use, even though efficiency is slightly reduced by the net production of lactate."
The Warburg effect takes its name from Otto Warburg’s discovery in the 1920s that tumors take up huge amounts of glucose, which they ferment into lactate rather than respire. He postulated that dysfunctional mitochondria might be to blame, and that aerobic glycolysis is the primary cause of cancer.
Since then, thousands of papers have been published with multiple explanations of the effect proposed. Among them, a 2016 review noted, is "an adaptation mechanism to support the biosynthetic requirements of uncontrolled proliferation," as "a tradeoff to support biosynthesis," in acidification of the tumor microenvironment, and "in direct signaling functions to tumor cells."
That led the review’s authors to conclude that "it is likely we will require a better understanding of the biology of Warburg Effect if therapeutic advances are to be made in treating and preventing cancer using dietary and pharmacological intervention in metabolism, and in using glucose metabolism to manipulate the immune system, which are currently subjects of intense interest."
The connection between Ras proteins and cancer is, however, much better understood.
As a 2011 overview stated: "Studies during the last quarter century have characterized the Ras proteins as essential components of signaling networks controlling cellular proliferation, differentiation, or survival. The oncogenic mutations of the H-ras, N-ras, or K-ras genes frequently found in human tumors are known to throw off balance the normal outcome of those signaling pathways, thus leading to tumor development.
"Interestingly, the oncogenic Ras mutations and the mutations in other components of Ras/MAPK signaling pathways appear to be mutually exclusive events in most tumors, indicating that deregulation of Ras-dependent signaling is the essential requirement for tumorigenesis."
Sugar has long been linked to cancer indirectly through, for example, well-established associations between obesity and cancer. A 2014 policy paper by the American Society of Clinical Oncology (ASCO) noted that "obesity is a major under-recognized contributor to the nation’s cancer toll and is quickly overtaking tobacco as the leading preventable cause of cancer."
The ASCO paper did not mention sugar, but as Clare McKindley, a clinical dietitian, explained, "too much daily sugar can cause weight gain. And, unhealthy weight gain and a lack of exercise can increase your cancer risks."
In fact, a study recently published in The Lancet Diabetes & Endocrinology determined that diabetes and obesity were the cause of nearly 6% of all cancers in 2012, accounting for some 792,600 cases around the world. And, the authors estimated, at current rates of increase in the prevalence of diabetes and obesity, "a substantially larger share of cancers would be attributable to these risk factors."
Still, a direct connection between sugar and tumor growth remains elusive. Dr Thevelein noted, however, that there is a clear correlation between diabetes and cancer, which may be a result of higher sugar levels in their blood. And, he continued, some recent clinical trials indicate that "sugar-poor diets are beneficial for recovery of patients with cancer. For instance, patients who undergo chemotherapy recover better with a sugar-poor diet."
An immediate takeaway of his study’s findings, he added, is that hospitals should revisit the practice of giving patients glucose infusions to help strengthen them for continued chemotherapy.
"The message now is that strengthening of the normal cells with high sugar may actually lead to activation of the cancer," he said.
The challenge, Dr Thevelein said, is that all cells need sugar, so eliminating sugar intake completely would not only kill cancer cells, but normal cells as well. If, however, oncologists can block the hyperactivity of the sugar to lactic acid conversion pathway only, normal cells might be spared.
The study’s results might therefore still offer a new target for cancer treatment.
"I think that we have a lead to find the primary cause of the high influx of sugar into the cancer cells," Dr Thevelein said. "This hyper-rapid influx of sugar into the cancer cells is not present in regular mammalian cells.
"We can go for drugs that inhibit this hyper-rapid sugar influx and these drugs should then make life for the cancer cells very difficult because the cancer cells need this rapid influx for survival. This is what we are following up now."