The Ketogenic Diet: Making It Difficult for Cancer to Latch On?

colinchamp October 16, 2018 3 Comments

Adrienne Scheck, Ph.D., Senior Research Scientist at Phoenix Children’s Hospital in Phoenix, Arizona is one of the most prolific researchers when it comes to brain cancer and the ketogenic diet (AND, she is an amazing person). As a radiation oncologist and advocate of advancing the research on the potential benefits of enhancing current treatment options with diet, I naturally came across her work in 2012,¹ around the same time I was working on one of my first papers reporting our findings on the effect of the ketogenic diet on blood glucose levels in several patients undergoing treatment for the lethal brain tumor known as glioblastoma multiforme, or GBM.²

This behemoth has eluded us for decades, during which time we have only managed to budge an increase in average survival with chemotherapy and radiation therapy by several months. Scheck’s research attempts to improve this treatment by sensitizing cancer cells to the potential lethal effects of radiation therapy. Her studies show that the ketogenic diet, in conjunction with radiation therapy, work to rid the brain of tumor cells – in mice. She and others have been trying desperately to translate this benefit to humans, but these studies are difficult to run, expensive, and challenge the prevailing dietary dogma (want to experience a crazy situation – sit in a room of physicians and researchers that recommended a low-fat diet for the last twenty years and tell them you want to suggest an 80% fat diet to patients in the hope that it will increase their chances of cure).

While Dr. Scheck’s work is revolutionary, she is by no means the first person to show that diet can affect cancer initiation, treatment, or growth. That honor goes back over a century, when Dr. C. Moreschi changed the course of nutritional scientific research forever when he published a small study titled Beziehungen Zwischen Ernahrung und Tumorwachstum.³ Translated from German, the title reads Relationships Between Diet and Tumor Growth. Moreschi, who had faded into scientific oblivion during the twentieth century, is only now, with the help of the internet, being recognized over a century later for his scientific efforts. His seminal work on the effects of diet and cancer growth performed from his small laboratory in Europe, set the wheels in motion for the next century. Moreschi was focusing his efforts on sarcomas, the soft tissue tumors that grow almost superficially, emanating out of the fibrous tissues of tendons and muscles that track along the bones of our extremities. The location of these lesions allow them to be more easily observed, measured, and studied than other sites, like lung or even breast cancer.

Moreschi’s experiment included 36 mice in total, and he separated them into four groups. He supplied the first group with the least amount of daily food, considerably underfeeding them in what may have seemed like cruel and unusual punishment at the time. The other groups were placed in modestly more favorable circumstances, as they were supplied with slightly more food by Moreschi in a step-wise pattern until the fourth group, which could eat as they pleased. Known within the nutritional science world as ad libitum feeding, it is Latin for “at one’s pleasure.” While this would be viewed by an outsider as the most humane for the mouse subjects, the same cannot be said when considering cancer’s response. Tumors did not grow similarly across the four groups, as would be expected if diet played little role in cancer growth (a common prevailing thought of many oncologists unaware of Moreschi’s and other similar studies). Instead, the tumors grew in proportion to the amount of food the mice were fed, with those gluttonous mice eating to their pleasure suffering the worst fate, as they experienced the largest cancerous growths. Those so called tortured mice were actually spared the rapid tumor growth that was seen in the other groups that had been unknowingly fattening themselves up before their demise. They appeared to be feeding not only their pleasures, but also their implanted cancer cells, which grew in proportion to their food consumption. In an unprecedented twist of fate, the mice who were starved of food experienced the slowest tumor growth.

As rats were fed more chow, their tumors grew larger. Group 1 ate 1 g/day, Group 2 ate 1.5 g/day, Group 3 ate 2 g/day, and Group 4 ate until they were full.

As is the case with any groundbreaking experiment that challenges the status quo, Moreschi was criticized for his crude methods. He decreased all macronutrients – carbohydrates, protein, and fat – in the same proportions, and many felt that the tumors, along with the mice, were simply unable to grow due to malnutrition. Moreschi briefly faded into scientific obscurity following this experiment, but decades later he may have gotten the last laugh.

Intrigued by Moreschi’s work, Francis Peyton Rous began performing his own dietary experiments with mice. Rous, a pathologist and virologist, was experimenting with viruses at the Rockefeller Institute for Medical Research in New York around the same time Moreschi was running his experiments across the Atlantic Ocean. In 1911, only two years after Moreschi’s initial pioneering experiment, Rous observed in his studies that a virus could transfer a sarcoma from one bird to another – the same sarcomas that Moreschi was inhibiting by underfeeding mice. Eventually named the Rous Sarcoma Virus, Rous’ findings earned him a Nobel Prize in Physiology or Medicine in 1966 (after being originally nominated 40 years earlier in 1926). A newcomer to the field, Rous’ results were vehemently contested, following the trend of reluctance with accepting new ideas within the field of cancer research, especially in nutritional science.

Rous was accustomed to dealing with controversy and, following in Moreschi’s footsteps, it was nothing more than a new challenge for the Nobel Laureate as he turned his attention to studying the impact of diet on cancer growth. He even furthered Moreschi’s studies by attempting to prevent cancer with dietary changes, as Moreschi merely slowed its growth. Rous began harvesting tumors on mice, and then transplanted them to other mice whose diets were manipulated. Like Moreschi, he would calorically restrict the mice to varying degrees, but taking his studies a step further, he also exposed these mice, and the normally fed mice, to varying carcinogenic chemicals. This method would allow Rous to test whether diet alone could prevent tumor development in mice.

Rous’ second research focus would prove to be another first for the medical field. Shortly after completing his Nobel Prize-worthy work, he followed with several groundbreaking studies revealing that different diets can slow the growth of tumors, but more importantly, the dietary changes provided the mice with the ability to prevent cancer before it struck. For instance, simply decreasing the amount of food each mouse was fed would reduce their risk of successful implantation and growth of the foreign-grown tumors. Rous’s findings were staggering – he was able to successfully transplant a tumor that would become embedded and grow in 83% of mice eating an unrestricted ad libitum diet, while only 41% of those mice on a restricted diet experienced tumor growth.^4,5 Mice that ate less were also resistant to cancer after Rous exposed them to carcinogenic chemicals, further revealing the preventative potential of dietary restriction. However, even during Rous’ series of successful studies, he would report on the stubborn nature of cancer as some tumors were impervious to even the most extreme dietary changes. Much like in humans, it appeared that some cancers were destined to occur.

Colleagues of Rous and Moreschi shared their enthusiasm of the link between diet and cancer. Dr. Albert Tannenbaum, who served as president of the American Association for Cancer Research, dedicated perhaps the most time and effort in furthering studies on the connection between diet and cancer prevention. His peers teased him and his incessant weighing of the mice to ensure precision with their weight, the amount of food they were consuming, and the proportion of macronutrients. Despite the teasing, Tannenbaum was effectively eliminating the common criticisms of Moreschi’s study. When I sat down to discuss these studies with one of his colleagues, Dr. Renato Baserga, he smiled when I mentioned Tannenbaum. “Oh yes, Albert and his mice. He was always running to weigh them. He was quite particular.” Perhaps merely echoing the sentiment regarding diet research at the time, Tannenbaum seemed to all but disappear into oblivion, except that his valuable research papers remain.

But Tannenbaum’s meticulous nature would prove vital for future researchers, as he would provide the largest, and perhaps most important studies on the effects of dietary manipulation and cancer prevention to this day. Paralleling Tannenbaum’s precision, his studies no longer assessed crude states like underfeeding, but rather referred to the more precise term, caloric restriction. This term, created for more accuracy, would unfortunately create confusion within the field of nutrition and cancer for decades to come.

Years before Tannenbaum began withholding food from mice, and decades before researchers unsuccessfully attempted to connect fat with breast cancer, dietary fat had been indicted during several rudimentary animal studies. Tar, a major carcinogen in tobacco products, produces skin cancer when applied to the surface of mice. When fat was first applied to the skin of mice, the tar-painted mice experienced higher rates of skin cancer. Scientists eventually attempted the same experiment, instead feeding the fat to the mice, and it seemed to cause a similar increase in skin cancer rates – along with producing a fatty coating on the skin of mice over-consuming butter – leading to the hypothesis that fat within the diet increased fat within the skin, and ultimately, enhanced carcinogen-induced skin cancers.⁶ These series of studies, along with those of Moreschi, Rous, and Tannenbaum, prompted the medical establishment to place their targets on both calories and fat, with the latter taking focus. Much like Doll’s influence on Willett and his colleagues, Tannenbaum’s work lead to dozens of follow-up studies with the goal of narrowing down the mechanisms by which fat consumption may have increased the risk of cancer, or even cause it.

Tannenbaum would perform hundreds of experiments in mice. Much like Rous, his work focused on methods to prevent cancer by testing mice that were exposed to carcinogenic chemicals. He also began experimenting with genetically altered mice that were naturally prone to develop cancer. Both created a model of predetermined cancer in the mice, enabling him to assess whether an activity could alter their fate by lowering or raising their cancer occurrence rate. Furthermore, this was the first crude prototypical experiment to model the mice after humans – we have plenty of genetic alterations and daily exposure to carcinogens that could predispose us to a cancer diagnosis. As fat has more than double the calories of protein and carbohydrates, and Moreschi and Rous had already shown that high calorie diets could aid in cancer induction and growth, it was naturally felt that dietary fat would lead to higher rates of cancer growth. The same concerns from Moreschi’s original study were intriguing to later scientists – even if calories consumed were proportional to both mouse and tumor growth, was this not a potential mechanism to stunt tumor growth, or conversely, to cause its growth to accelerate? Indeed, Tannenbaum and his colleagues found that supplying mice with extra fat led them to consume more calories and experience higher rates of cancer.

Yet, predating the unexpected findings by Willett and the group at Harvard by almost 40 years, Tannenbaum and his contemporaries started to find the exact opposite of their expected results in a handful of their studies. By 1945, some of his meticulous data began to strangely point to something inherently detrimental about dietary carbohydrates. As Tannenbaum described in one of his paramount studies:

“It appears that mice receiving the diet restricted in carbohydrate only developed fewer tumors, and at a later mean time of appearance.”⁷

Tannenbaum, like his predecessors, found that calorie restriction would increase the ability to prevent cancer, but those mice with diets restricted in carbohydrates often experienced even lower rates of cancer.

It appeared that some unexpected inherent biologic property of dietary carbohydrates may have fueled cancer initiation and growth and restricting them in the diets of his study mice would both reduce the risk of cancer and delay its presentation. Yet, Tannenbaum’s findings were not unique. Decades before his results, several similar studies were completely overlooked by the medical research world. Perhaps the most famous of these forgotten studies was performed in 1913, around the same time as Peyton Rous’ groundbreaking experiments that would earn him a Nobel Prize, when the largest mouse study to date assessed the effect of diet on cancer growth in 303 mice.⁸ Silas Palmer Beebe, an early pioneer in the cancer research world, teamed up with Eleanor Van Ness Van Alstyn for the Huntington Fund for Cancer Research at Cornell University to complete the study. Much like Tannenbaum’s work, their data strongly implicated an unknown factor that was inherently favorable for cancer growth when carbohydrates were consumed in the diet. Their conclusions were somewhat bolder than Tannenbaum’s, though the overall theme was similar:

“There seems to be no reasonable ground for doubt in view of these experiments that a lack of carbohydrate in the diet produces such an influence upon the rats as to make them more resistant to tumor growth.”

“When the diet includes carbohydrate, the tumors grow luxuriantly. When the diet does not include carbohydrate, the animals show a marked resistance.”

After their presentation at the American Association for Cancer Research, where Tannenbaum would serve as president over 40 years later, Van Alstyne and Beebe’s data was published and fervently challenged. In a strange turn of events, Beebe was expelled from Cornell University two years later for apparently attempting to profit from an ineffective cancer treatment called autolysin.⁹ His work in research continued, albeit in a different direction as he focused his studies on the thyroid gland.

Several decades later, in 1947, Tannenbaum would present his work to the prestigious New York Academy of Science. His groundbreaking findings would reveal a consistent and considerable decrease in cancer rates – lung cancer, skin cancer, breast cancer, leukemia, and Moreschi’s sarcomas – through a simple reduction in calories. Furthermore, his underfed mice also experienced greater longevity and a healthier appearance. Over the decades, Tannenbaum’s work has been referred to thousands of times, yet only in an editorial was there a brief comment about one small, but potentially massive component of this work: Tannenbaum’s findings, knowingly or not, were paying homage to Van Alstyne and Beebe’s seminal study. While Tannenbaum’s coinage of the term calorie restriction defined his work for decades to come, a close examination reveals that the largest anticancer benefit was seen when dietary carbohydrates were restricted. In a 1945 editorial on earlier work by Tannenbaum in an issue of the Journal of the American Medical Association, titled “Cancer and Calorie Restriction,” the carbohydrate conundrum was only briefly mentioned, as it repeatedly referred to the remarkable effect of calorie restriction as the major finding of his work.¹⁰ Tannenbaum would provide summary graphs from his multiple studies, with the work illustrating the effect of underfeeding by carbohydrate withdrawal and its tendency to produce the largest decrease in cancer incidence. Tannenbaum even placed a “C” above them for “carbohydrates” for easy visualization, yet these findings remained understated throughout his text.

While much of Tannenbaum’s data would implicate carbohydrates, his meticulous nature would begin to unravel a phenomenon that would plague the dietary world for decades to come. Even with the first dietary study, Rous and his colleagues were feeding their mice a mixture of oatmeal, cornmeal, rye, flour, milk, and sugar. Such diets were often almost entirely consisting of carbohydrate ingredients, with little protein and fat. If these mice were being fed an almost entirely carbohydrate-based diet, it is difficult to tell if calorie restriction was indeed restricting calories, or simply providing less carbohydrates and the mysterious factor that stimulated cancer growth in the earlier mouse studies. Furthermore, Tannenbaum’s experiments suggested that increasing dietary fat while consuming a similar diet rich in carbohydrates – resembling that of the Standard American Diet – may be the perfect storm for cancer development. Over time, scientists began to ask whether the general restriction of calories was responsible for aiding in cancer prevention, or if it was simply reducing the amount of an unhealthy, cancer-promoting diet. Almost a century later, the question remains unresolved, but we have some hints to the answer.

The Ketogenic Diet: Making It Difficult for Cancer to Latch On

A common criticism about these older studies is that perhaps the tumors were unable to latch on after grafting and invading the poor mice where they were implanted. In other words, the question can be rephrased to ask whether calorie restriction, a low-carbohydrate or ketogenic diet made it more difficult for these tumors to latch on, grow, and spread in the mice. This question is an important one, and the criticism raises an important point. Perhaps the diet was simply making the implantation of these tumors more difficult in the mice. This is an important “perhaps”, and if it was in fact an issue with these studies, isn’t this exactly what we want for cancer prevention?

For instance, when we analyzed all the available randomized mouse studies within the literature where the researchers adequately placed the experiment mice on a ketogenic diet and assessed the ability of it to enhance the treatment of cancer with chemotherapy or radiation therapy, we found that it was neither able to affect the growth of cancer by itself nor work as an individual treatment.¹¹ Not the good news we were looking for, but the data did reveal that it enhanced current cancer treatments like radiation therapy and chemotherapy. Moreover, the studies also suggested that, much like with Tannenbaum and his colleagues, when the diet was implemented before tumor cells were implanted in mice, they had a more difficult time latching on, growing, and spreading. In other words, the diet worked as a preventative measure for cancer. It demonstrated that cancer cells prefer an environment that fosters their growth, like a nice mix of high blood glucose, insulin, inflammation, and a surplus of nutrients – the same environment Tannenbaum and his colleagues were creating as they fed their mice. Those mice on a ketogenic diet were likely receiving an insufficient amount of all the above. A ketogenic diet and restricted diet does not treat cancer by itself, but wouldn’t it be nice if it helped prevent it?

This criticism is exactly what we want. Which mouse would you want to be, the one where cancer has a difficult time latching on or the other, eating to their own demise as they feed their cancer a massive dose of fertilizer? Sure, these are mouse studies, but I know my pick. Making ourselves more difficult for cancer cells to latch to sounds like a prudent heath decision. We do not know for a fact whether this is occurring in humans, and the long, expensive, and unsexy studies required to answer this question are unlikely to ever occur. In the meantime, I will continue to hit periodic ketosis with a ketogenic diet, fight the battle against my health, hopefully prune my body of cancer cells, and make it more difficult for any transformed cancer cells to latch on and grow.

References:

1. Abdelwahab MG, Fenton KE, Preul MC, et al. The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. PLoS One. 2012;7(5):e36197. doi:10.1371/journal.pone.0036197.
2. Champ CE, Palmer JD, Volek JS, et al. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol. 2014;117(1):125-131. doi:10.1007/s11060-014-1362-0.
3. Moreschi C. Beziehungen zwischen Ernahrung und Tumorwachstum. Z Immunitatsforsch. 1909;2(651).
4. Rous P. The Influence of Diet on Transplanted and Spontaneous Mouse Tumors. J Exp Med. 1914;20(5):433-451.
5. Studies from the Rockefeller Institute for Medical Research, Volume 23 : Rockefeller Institute for Medical Research, Volume 23. Page 7. The Rockefeller Institute for Medical Research; 1916.
6. Watson AF, Mellanby E. Tar Cancer in Mice. II. The Condition of the Skin, when Modified by External Treatment or Diet, as a Factor in Influencing the Cancerous Reaction. Br J Exp Pathol. 1930;11(5):311.
7. Tannenbaum A. The Dependence of Tumor Formation on the Composition of the Calorie-Restricted Diet as Well as on the Degree of Restriction. Cancer Res. 1945;5(11):616-625.
8. Van Alstyne EVN, Beebe SP. Diet studies in transplantable Tumors – I. The Effect of non-carbohydrate Diet upon the Growth of transplantable Sarcoma in Rats. J Med Res. 1913;29(2):217-232.
9. The Autolysin Treatment for Cancer. JAMA: The Journal of the American Medical Association. Volume 65.; 1915.
10. Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN. Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis. 2010;31(1):83-89. doi:10.1093/carcin/bgp280.
11. Klement RJ, Champ CE, Otto C, Kämmerer U. Anti-tumor effects of ketogenic diets in mice: A meta-analysis. PLoS One. 2016;11(5). doi:10.1371/journal.pone.0155050.

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