Essentials: Cancer

This 2017 review summarizes the potential of a ketogenic diet to enhance the effects of radiotherapy. Radiotherapy is constrained by the damage it causes to healthy cells. As a result, any simultaneous treatment that can either increase the damage radiotherapy does to cancer cells or protect healthy cells from damage may increase its effectiveness. Potential benefits of a ketogenic diet alongside radiotherapy include the reduction of cancer cells’ ability to repair DNA, the slowing of tumor growth and repopulation, and the protection of healthy cells against the harms of radiotherapy by shifting them from an anabolic/growth-centric state to a non-dividing state.

This 2016 paper describes four common variations of the ketogenic diet and reviews the effects of the ketogenic diet on cancer, neurodegenerative disease, and specific inherited conditions. Though research on the diet’s effects on these specific conditions remains preliminary (i.e., in vitro or animal), existing data suggest ketogenic diets may have clinically significant benefits.

This 2017 comment, written by leaders in the fields of cancer and ketogenic diet research, responds to a review by Nicole Erickson et al. that claims evidence supporting the use of the diet for cancer treatment is lacking. The comment authors argue the ketogenic diet is an effective cancer therapy that functions through multiple mechanisms. They also note the diet has limited risk and is an effective adjuvant therapy to other treatments. They conclude the apparent lack of evidence in support of the diet merely results from the preliminary but rapidly advancing state of keto research.

The reported links between red and/or processed meat consumption and negative health outcomes (e.g., increased cancer risk, increased mortality, etc.) are largely based on observational evidence. This 2015 review addresses a few of the consistent issues with this evidence.

This post from the University of California, San Francisco’s Osher Center for Integrative Evidence reviews the evidence surrounding the claim that “fasting and calorie restriction can slow and even stop the progression of cancer, kill cancer cells, boost the immune system, and significantly improve the effectiveness of chemotherapy and radiation therapy.”

This 2016 paper reviews the mechanisms by which fasting may improve cancer prognosis or reduce cancer risk. The authors observe specific metabolic improvements are associated with fasting. Additionally, they find patients experience fewer and less severe side effects with fasting than caloric restriction, particularly given the needs of cancer patients.

This 2018 editorial summarizes key challenges facing the implementation and study of the ketogenic diet in glioblastoma multiforme (GBM).

Thomas Seyfried, Ph.D., is a biochemical geneticist, professor of biology at Boston College, and author of the groundbreaking book Cancer as a Metabolic Disease. As part of a lecture delivered on July 31, 2018, at the annual CrossFit Health Conference, Seyfried presented a report card on our current approaches to treating cancer in the United States. Death rates from cancer are on the rise, he explained, because of “a fundamental misunderstanding of what the nature of this disease is.” Here, he explains the evidence that supports understanding cancer as a metabolic rather than a genetic disease. He also explains why he believes calorie restriction and therapeutic ketosis are more effective for treating cancer than traditional standard of care.

A 2010 basic research study finds fructose supports greater RNA production in pancreatic cancer cells than glucose, and by extension may preferentially support cancer cell growth and replication.

Professor Richard Feinman delves further into the underlying biochemical processes that regulate energy metabolism. He explains how cellular structure alters in a cancerous state, focusing in particular on how cancer disrupts the entry of pyruvate into the mitochondrion. Several cancers, such as squamous cell carcinomas of the head and neck, have been shown to inhibit pyruvate dehydrogenase regulation. Feinman observes that looking at pyruvate reveals several of the ways in which the normal link between glycolysis and respiration becomes disturbed in a cancerous state. It remains to be discovered whether any of these disturbances can be targeted for therapy.

The year 2021 will see the 50th anniversary of Nixon’s declaration of the war on cancer, but a victory celebration does not appear to be in view. Dr. Richard Feinman suggests this may be due to an overemphasis on the somatic mutation theory of cancer and insufficient attention to the metabolic approach to understanding the disease. Here, he explains Otto Warburg’s research on cancer cell metabolism, breaks down the processes that shape healthy energy metabolism, and describes why scientists believe the ketogenic diet may have anti-cancer effects.

Diabetics have been shown to have higher rates of cancer metastasis than non-diabetics. This 2019 study investigates the promotion of tumor cell mobility by collagen matrix glycation as a possible mechanism for the increase.

“Here, we have taken advantage of cancer cells’ relative independence from growth signals and unresponsiveness to anti-growth signals to show that this inability of cancer cells to properly respond to extreme environments renders them unable to cope effectively with the markedly altered concentrations of glucose, growth factors, and other molecules caused by fasting.”

This 2018 review summarizes current research investigating the use of a fasting-mimicking diet (i.e., a precise dietary intervention designed to achieve the metabolic response of fasting without the side effects) as an element of cancer treatment.

In this 2019 review, Thomas Seyfried et al. argue that, due to the significant drawbacks of the existing standard of care for glioblastoma multiforme (GBM) and the potential benefits of ketogenic metabolic therapy, ketogenic therapies should be tested in patients with GBM.

In this February 2019 study, researchers investigated exercise’s known effect on mortality rates for cancer survivors by observing male colon cancer survivors’ blood cytokine levels during a month of high-intensity interval exercise (HIIE). Their data suggest exercise temporarily increases levels of blood inflammatory markers, and these increases may suppress tumor growth.

“Described decades ago, the Warburg effect of aerobic glycolysis is a key metabolic hallmark of cancer, yet its significance remains unclear. In this Essay, [authors David Sabatini and Peggy Hsu] re-examine the Warburg effect and establish a framework for understanding its contribution to the altered metabolism of cancer cells.”

“Although the complete ramifications of obesity as it relates to cancer are still unclear, there is convincing evidence that reducing the magnitude of the systemic hormonal and inflammatory changes has significant clinical benefits. This review will examine the changes that occur in the obese state and review the biologic mechanisms that connect these changes to increased cancer risk. Understanding the metabolic changes that occur in obese individuals may also help to elucidate more effective treatment options for these patients when they develop cancer.”

In this interview, Lewis Cantley, Director of the Cancer Center at Weill Cornell Medical College and discoverer of the phosphoinositide-3-kinase enzyme, discusses the links between diabetes and cancer's metabolic disturbances, the differences between fructose and glucose metabolization, and the brain’s response to sweeteners. Cantley concludes: “The consequence of people eating lots of sweeteners, no matter what they are—whether they’re natural or unnatural—is that it increases the addiction for the sweetness. As a consequence, at the end of the day, your brain says, 'OK, at some point I need some glucose here'. And then you eat an entire cake, because nobody can hold out in the end. The only way really to prevent this problem—to break the addiction—is to go completely cold turkey and go off all sweeteners—artificial as well as fructose. Eventually the brain resets itself and you don’t crave it as much.”

"Cancer cells have different metabolic requirements from their normal counterparts. Understanding the consequences of this differential metabolism requires a detailed understanding of glucose metabolism and its relation to energy production in cancer cells. A recent study in BMC Systems Biology by [Alexei Vazquez] et al. developed a mathematical model to assess some features of this altered metabolism. Here, we take a broader look at the regulation of energy metabolism in cancer cells, considering their anabolic as well as catabolic needs."