How Does Diet Affect Tumor Metabolism?

How certain cancers respond to different diets and how diet affects cancer cell metabolism have become subjects of growing interest. We will examine how best to use diet and nutrition to manage cancer in patients. The ways cancer cells use nutrients are determined by intrinsic and extrinsic factors, including interactions with their environment. These interactions can influence cancer treatment effectiveness. Dietary changes may alter the environment to which a tumor is exposed. There is clear evidence showing how diet interacts with treatment and blocks tumor growth. In this article, we examine how dietary factors may influence tumor growth . Nutrient use is not the sole determinant of cancer genetics. Cancer cell metabolism is also affected by environmental and tissue-specific metabolic constraints. The goal is to understand better how interactions between cancer cells and their micro- and macroenvironments define tumors’ metabolic vulnerabilities, and to develop more effective cancer treatments. Diet and nutrition have long been known to contribute to cancer risk. For example, clinical and laboratory research has associated obesity and excess calorie intake with increased cancer risk, while linking low-carbohydrate, low-fat diets with lower cancer incidence. In contrast to cancer risk, once a person already has cancer, little is known about how diet affects tumor progression or whether using particular diets alone or with treatments increases survival. Various studies are being conducted to understand this issue.

Remember that investigating links between diet and cancer in patients is difficult because feasibility, adherence and designing appropriate controls can pose challenges. Many of these difficulties involve conditions such as dietary formulation, calorie intake, tumor genetics, cancer type and collection of biological samples. Using animal cancer models in which these can be controlled can alleviate these challenges to some extent. Although animal physiology differs from human physiology, valuable information can still be obtained from these preclinical animal models, helping refine questions for subsequent human clinical studies where controlling all variables is more difficult.

Examining specific diets and tumor interactions

Diets consist of three macronutrient categories—carbohydrates, fats and proteins—each contributing to calorie intake. Diets also include vitamins, minerals and fiber/roughage and other components that do not contribute to calorie intake. Altering the proportions of these macronutrients produces diets with different effects on metabolism and whole-body physiology. Calorie-restricted, ketogenic and high-fat diets are different dietary patterns that emerge. A calorie-restricted (low-carbohydrate) dietis typically achieved by restricting carbohydrates while maintaining equal amounts of nutrients such as protein, fat, vitamins and minerals to induce lower blood glucose and insulin levels. It involves a 30-40% restriction in total calories relative to the control group. Both ketogenic and high-fat diets contain high levels of fat. The main distinction is that a high-fat diet still involves substantial carbohydrate consumption, leading to different physiological effects. A ketogenic diet, however, aims to restrict carbohydrates. The control diet represents the macronutrient composition commonly used for a standard laboratory mouse: carbohydrates, fat, protein, vitamins and minerals.

Laboratory / cell line studies of dietary types and cancer risk

Low-carbohydrate diets such as calorie-restricted or ketogenic diets have been observed to reduce the development of many cancers in laboratory studies using cell lines. Numerous laboratory studies have shown that a diet reducing calorie intake by 30-40%, typically through carbohydrate restriction, strongly inhibits the growth of various tumor types, including breast, lung, prostate, brain, pancreatic and colorectal tumors. In contrast, a high-fat diet, which still includes substantial carbohydrate consumption, generally increases the incidence and growth of tumors including colorectal, pancreatic, prostate, breast and hepatocellular carcinomas (liver cancer). With studies providing mechanistic explanations of how high-fat diets increase colon cancer risk, the young Turkish scientist Semir Beyazhas attracted the scientific world’s attention in recent years.

Who is Semir Beyaz, and what is his research?

In 2009, Semir Beyaz received his undergraduate degree from the Department of Molecular Biology and Genetics at İzmir Institute of Technology, graduating in 1st place. After working from 2009-2010 at the Bone Marrow Transplantation Center at Massachusetts General Hospital, he joined Harvard University’s Immunology PhD program. There, at Boston Children’s Hospital, he studied blood cell development and its epigenetic regulation, and also worked on intestinal stem cell function and the dietary regulation of cancer development at the Massachusetts Institute of Technology. After receiving his doctorate in 2017, he established his research laboratory at Cold Spring Harbor Laboratory (CSHL) in New York, where he is a CSHL Fellow and Donaldson Trust Translational Fellow. His laboratory focuses on how diet and metabolic disturbances affect cellular networks in tissues and contribute to cancer risk. He has received various awards for scientific achievement, including the American Association of Immunologists Thermo-Fisher Trainee Achievement Award and the TASSA Aziz Sancar Young Scholar Award. In November 2019, in Antalya, at the Summit of Those Who Left Their Mark on Oncology, his talk entitled "Diet, Microbiome and Cancer" attracted great interest.

Finally, specific amino acid-defined dietshave been studied for their ability to inhibit growth in various tumor models. For example, the metabolism of serine and glycine (amino acid components) is particularly important for the growth of some cancer cells. A diet free of serine and glycine has been shown to suppress tumor growth in several mouse cancer models. Similarly, it has long been appreciated that cancer cells are more sensitive to methionine deprivation than normal cells, and that a methionine-restricted diet can inhibit the growth of many tumor types. The greatest challenge in interpreting dietary studiesis the variability of observed dietary effects and the fact that results from laboratory studies often do not apply to humans. For example, although calorie restriction impairs growth in most tumor models, the extent to which different cancer types respond may vary. Similarly, ketogenic diets have attracted much interest in recent years. Studies have shown suppression of tumor growth, particularly in mouse models of brain cancer. Yet in other mouse cancer models, they accelerated tumor progression. These different results arise because the same diet affects different tumor types differently. - Related topic: New Evidence on the Medical Use of Ketogenic Diets – Which Patients Benefit? Various studies have shown that cancer-promoting genetic changes in oncogenes or tumor suppressor genes can predict tumor responses to various diets. Cancer cells with mutations in P13K signaling pathways are, to the growth-inhibitory effects of calorie restriction, resistant. This genetic state also affects the tumor’s response to a ketogenic diet. For example, a ketogenic diet in BRAF-positive melanoma increases cancer progression. Brain tumors may be considered the tumors most sensitive to ketogenic diets. However, more research is needed. Some variability in dietary response may be explained by technical experimental differences in study design, such as differences in diet formulation, composition of the comparison control diet, timing or method of dietary implementation and types of animal cancer models. Besides effects on tumor growth, an important question is how dietary interventions affect tumor progression such as metastasis . For example, mice implanted with oral squamous cell carcinomas developed more lymph node metastases when fed a high-fat diet. The increased metastatic potential under these conditions was found to depend on expression of the fatty acid receptor CD36 in metastasis-initiating cancer cells. Consistently, high-fat diets also increased metastasis in mouse prostate cancer models driven by loss of Pten and Pml. These data suggest that fatty acids may help facilitate metastasis. Another study found that synthesis and availability of the amino acid asparagine affected epithelial-mesenchymal transition in breast cancer cells, and a diet high in asparagine was associated with increased metastatic burden. These data are consistent with nutrient availability in tissues affecting the ability of cancers to grow in specific sites. Such studies may reveal metabolic requirements associated with metastasis and point to potential dietary interventions that help limit tumor progression.

Do dietary changes alter metabolite availability to tumors?

Measuring blood metabolite concentrations, which is technically simpler and more feasible, has been used to understand nutrient availability to cancer cells in tumors. However, blood does not always represent the environment to which cancer cells are exposed within a tumor. Dietary changes in blood metabolite availability may therefore not perfectly reflect the local metabolic environment of tumors. New efforts to characterize tumor interstitial fluid (the fluid between cancer cells), which can be isolated by various methods, have found that its composition may differ from blood plasma. This means the tumor microenvironment may not be depleted of all nutrients, as is sometimes assumed. It is also unknown to what extent different diets change the fluid content between cancer cells in different tumor types. For example, the tumor-growth-inhibiting effects of low-carbohydrate diets such as calorie-restricted and ketogenic diets are often attributed to their effects in lowering blood glucose. Yet glucose concentrations in blood and tumor interstitial fluid are in the millimolar range. Whether these diets reduce tumor glucose levels enough to slow growth is unknown. You can think of this like a fetus in the womb taking many nutrients from its mother almost selfishly: even if the mother is thin, fetal growth will often be normal. These examples show how determining absolute quantities of metabolites in biological samples can help understand mechanisms through which dietary changes may affect cancer progression. Understanding how dietary factors influence tumor metabolism may help incorporate dietary interventions into cancer treatment. Some diets may inhibit tumor growth by disrupting specific metabolic pathways affecting cancer progression. Pharmacologically targeting these pathways could mimic the diets’ effects. Interventions mediating the effects of calorie restriction without requiring substantial food restriction, for example, could improve outcomes. Alternatively, metabolic pathways resistant to dietary effects may emerge. Targeting them could be a tool for sensitizing tumors to particular diets. Finally, although dietary changes may influence patient survival, any diet alone is unlikely to reliably induce tumor shrinkage. KRAS-mutant colon tumors are not inhibited by a serine- and glycine-free diet. KRAS activation increases genes enabling serine synthesis, making these cancer cells less dependent on exogenous (external) sources. This means the cells become less dependent on exogenous serine sources. Another study showed that dietary supplementation with high-fructose corn syrup in quantities mimicking daily consumption of 340 grams of sugary drinks increased intestinal tumor growth in an Apc-deficient mouse model. In tumors in mice on this diet, high-fructose corn syrup increased fatty acid synthesis, raising long-chain fatty acid levels. Deleting the fatty acid synthesis gene (Fasn) in Apc-deficient intestinal tumors made them insensitive to the growth-promoting effects of high-fructose corn syrup. This shows that lipogenesis (fatty acid synthesis) is necessary for tumor response to diet. Several combinations of different diets and cancer drugs have already been discovered. For example, a ketogenic diet combined with PI3K inhibitors in acute myeloid leukemia, pancreatic, breast, endometrial and bladder cancer mouse models increases their effectiveness. Because ketogenic diets lower blood glucose and insulin levels, they may cause the elevation of blood glucose and insulin levels induced by PI3K inhibitors, thus increasing the drugs’ antitumor activity. This observation shows how a diet’s effects on whole-body metabolism can be used to enhance the effectiveness of a targeted treatment currently under development. Similarly, many studies have shown that intermittent fasting, calorie restriction and ketogenic diets and other low-carbohydrate diets sensitize tumors to the effects of all chemotherapies while protecting normal tissues. Some studies propose short-term dietary changes such as fasting or extreme calorie restriction for a few days before treatment with chemotherapy, immunotherapy or other targeted agents. These findings have been seen in encouraging clinical studies evaluating these diets in combination with chemotherapy. The underlying mechanisms are largely attributed to these diets lowering blood glucose levels and reducing IGF1 and insulin signaling. However, they may also alter cancer and normal tissue cell metabolism through other mechanisms increasing drug sensitivity. For example, cisplatin -resistant lung and ovarian cancer cells are more sensitive to nutrient deprivation and glutamine starvation. This disrupts nucleotide synthesis and may resensitize these cells to cisplatin-induced cell death. Restricting tumors’ access to glutamine through fasting may therefore synergize with cisplatin treatment. Further studies will help us understand whether fasting regimens or low-carbohydrate diets contribute to chemotherapy. Finally, in some cases, certain diets may not modulate a particular drug’s effects and may even cause harm. For example, serine and glycine starvation has no effect in some contexts or may increase tumor burden. Taken together, these examples emphasize the value of diet and drug combinations in defined contexts.

In conclusion

How nutrition affects cancer progression is a critically important question for many patients. The way cancer cells use nutrients to grow and proliferate depends not only on cancer-promoting genetic changes but also on interactions with the tumor’s own local metabolic environment. This understanding provides a framework for examining links between diet and cancer and investigating dietary effects on cancer cells’ nutrient access and use. It may lead to a better understanding of which cancers respond to different diets. Further studies will show whether combining dietary interventions with existing cancer treatments can contribute new treatment options. These studies may provide a foundation for further research.