PerSpeCTIVeS

of great importance to many patients with

OPINION
cancer and their families. Diet and nutrition
have long been appreciated to contribute
A framework for examining how diet to cancer risk (not to be confused with
cancer progression, as discussed later)12.
impacts tumour metabolism For example, epidemiological, clinical
and laboratory research have linked
obesity and excess calorie consumption
Evan C. Lien and Matthew G. Vander Heiden    with increased cancer risk, while a low-​
carbohydrate, low-​fat diet is associated
Abstract | The way cancer cells utilize nutrients to support their growth and with lower cancer incidence13–16. While
proliferation is determined by cancer cell-​intrinsic and cancer cell-​extrinsic these studies are provocative, how they
factors, including interactions with the environment. These interactions can inform the best diet for individuals is more
define therapeutic vulnerabilities and impact the effectiveness of cancer therapy. complex. Inconsistencies remain in public
Diet-​mediated changes in whole-​body metabolism and systemic nutrient perception because of conflicting findings
in the scientific literature regarding how
availability can affect the environment that cancer cells are exposed to within dietary factors affect cancer risk and the
tumours, and a better understanding of how diet modulates nutrient availability challenges of studying this complex topic in
and utilization by cancer cells is needed. How diet impacts cancer outcomes is human patients12. Nevertheless, efforts have
also of great interest to patients, yet clear evidence for how diet interacts with been made to propose official guidelines
therapy and impacts tumour growth is lacking. Here we propose an experimental on nutrition for cancer prevention by the
American Cancer Society and the World
framework to probe the connections between diet and cancer metabolism.
Cancer Research Fund/American Institute
We examine how dietary factors may affect tumour growth by altering the access for Cancer Research, which have remained
to and utilization of nutrients by cancer cells. Our growing understanding of fairly consistent for the past 20 years17,18.
how certain cancer types respond to various diets, how diet impacts cancer In contrast to cancer risk, relatively
cell metabolism to mediate these responses and whether dietary interventions little is known about how diet influences
may constitute new therapeutic opportunities will begin to provide guidance on tumour progression when a person already
has cancer and whether certain diets
how best to use diet and nutrition to manage cancer in patients. may maximize survival, either alone or in
combination with other therapies. How to
Defining the different metabolic tissue-​specific contexts3–9. Selecting optimize diet for outcome is a concern for
requirements of proliferating cancer cells patients for treatment with antimetabolite most patients, yet beyond extrapolation
has suggested how cancer cell metabolism chemotherapies based on cancer tissue from data related to cancer risk or specific
might be exploited for better cancer of origin has been successful for decades, mechanisms related to nutrient-​associated
treatment1. Genetic alterations in oncogenes so considering only genotype in selecting hormones such as insulin, evidence is scant
or tumour suppressor genes that promote patients for novel treatments targeting for what patients with specific cancer types
cancer reprogramme cellular metabolism metabolism will not be sufficient in situations should eat. Studying this complex question
in a cell-​autonomous manner, diverting key in which systemic metabolism and the is complicated by the difficulties in finding
metabolites such as glucose and glutamine tissue environment impact the tumours’ suitable experimental models, discrepancies
towards biosynthetic processes that support dependence on the target. Thus, a better between animal and human physiology with
tumorigenesis. This insight has led to an understanding of how interactions between respect to diet and the lack of a clear and
improved understanding of how various cancer cells and their microenvironment consistent approach for testing hypotheses
metabolic pathways are regulated at the and macroenvironment define a tumour’s connecting diet with tumour metabolism
molecular level to facilitate the proliferation metabolic vulnerabilities will be critical for and progression.
and growth of cancer cells. From a developing more effective cancer therapies. Here we explore the idea that dietary
therapeutic perspective, it has also motivated One important environmental effects on tumour progression may be
a search for genotype-​specific metabolic determinant of cancer cell metabolism is mediated in part through changes in
vulnerabilities that can be exploited and has diet, which can affect the availability of the access to and utilization of nutrients
been successful in select contexts2. nutrients within tumours10,11. The study by cancer cells. We aim to provide a
Cancer genetics is not the only of cancer metabolism is often perceived scientific and experimental framework for
determinant of nutrient utilization by by the general public as our understanding approaching and testing hypotheses for how
cancer cells. Cancer cell metabolism of the connections between cancer and diet affects tumour progression and response
is also influenced by metabolic constraints nutrition, and the question of whether to therapy. We draw on observations from
imposed by environmental and certain diets may improve prognosis is various diets that have been explored in the

Nature Reviews | Cancer

Perspectives
literature to illustrate the general concepts
underlying this proposed framework.
We hope that a systematic approach to
probing the relationships between diet
and cancer metabolism will lead to better
scientific guidance for incorporating diet
and nutrition into cancer therapy and fill
a critical void for patients in the current
approaches to treat this disease.
A conceptual framework
Dietary factors can affect tumour growth
through a variety of mechanisms that alter
cancer cell metabolism. Multiple studies
have examined how different diets influence
Diet
Nutrients Blood
1 vessel
1 cell metabolism and therapeutic responses
Tumour
cell
3 Tumour growth
TIF
Intracellular Diet-associated
metabolism therapies
Fig. 1 | a proposed framework for examining
how diet impacts tumour metabolism, growth
and progression. Diet may affect tumour growth
and progression through mechanisms that alter
cancer cell metabolism. These dietary effects
may be mediated in part through changes in
access to and utilization of nutrients by cancer
cells within a tumour. We propose a framework
for exploring the impact of diet on tumour
metabolism and progression that rests on four
core ideas: (1) the concentrations of metabolites
that are available to a tumour can be changed by
altering components within the diet; (2) diet-​
induced changes in nutrient availability within
the tumour environment can affect how cancer
cells utilize these nutrients to support growth,
proliferation and survival; (3) changes in dietary
composition can affect the growth and progres-
sion of tumours; (4) diet-​induced changes in
cancer cell metabolism influence metabolic
vulnerabilities that create potential synergies or
antagonism between dietary factors and new
or existing therapies. Understanding which
cancer types respond to various diets, how diet
impacts cancer cell metabolism to mediate these
responses and whether dietary interventions may
open new therapeutic opportunities can help
build a foundation for providing better scientific
guidance for incorporating diet and nutrition
into cancer therapy. TIF, tumour interstitial fluid.
whole-​body hormone signalling to affect
tumour progression, and ways in which
these signals impact both cancer risk and
tumour growth have been extensively
reviewed15,19–25. Another way that dietary
factors can affect tumour growth is through
effects on the metabolism of cells within
tumours. Hormonal signalling alterations
in response to diet likely impinge on
metabolic processes within cancer cells
to alter proliferation; however, dietary
effects on tumour progression may also
be mediated in part through changes in
the access to and utilization of nutrients
by cancer cells. Perturbations to dietary
compositions contribute to changes in
plasma metabolite levels, which will in turn
influence metabolite levels in the tumour
microenvironment and thereby alter cancer
(Fig. 1). This hypothesis rests on several
key premises:
1. Changes in dietary composition can
affect the growth and progression of
tumours.
2. The concentrations of metabolites that
are available to a tumour can be changed
by altering components within the diet.
3. Diet-​induced changes in nutrient
availability within the tumour
microenvironment can affect how cancer
cells utilize these nutrients to support
growth, proliferation and survival.
4. Diet-​induced changes in cancer cell
metabolism influence metabolic
vulnerabilities that create potential
synergies or antagonism between dietary
factors and new or existing therapies.
These premises form a framework for
understanding the connections between diet
and cancer cell metabolism in a way that is
relevant for patients. In this Opinion, we will
consider diets with different macronutrient
compositions (Fig. 2), and the various
components of dietary formulations used in
animal studies are outlined in Box 1. Factors
that are important when one is designing
experiments to study questions related
to diet and cancer can be found in Box 2.
Of note, conducting experiments in patients
to probe connections between diet and
cancer is also relevant, but can be challenging
because of issues with feasibility, adherence
and the design of appropriate controls12.
Many of these challenges can be mitigated
to a certain extent by using animal models
of cancer in which aspects such as dietary
formulation, caloric intake, tumour genetics,
cancer type and procurement of biological
samples can be controlled. Although
aspects of animal physiology are distinct
from those of human physiology, valuable
information can nevertheless be obtained
from these preclinical animal models and
refine questions that can then be studied in
human clinical studies, in which control of
all variables is more difficult.
Studying diet–tumour interactions
In this Opinion, we focus primarily on
approaches to explore how diet impacts
cancer metabolism and progression in
mouse models of cancer so as to review key
concepts and questions that surround each
of the four premises in the previous section.
These premises have been tested in various
forms in the literature, and here we draw on
observations from various diets to outline
the evidence for the principles underlying
this conceptual framework.
How does dietary composition affect
tumour growth and progression? There
are extensive data showing that dietary
changes can modulate the growth of various
tumour types in animal models. Different
diets can either inhibit or accelerate tumour
growth, and studying both types from
the perspective of understanding cancer
metabolism is valuable for gaining insight
into the various physiological metabolic
demands of cancer cells. Low-​carbohydrate
diets such as caloric restriction or the
ketogenic diet are generally thought to
inhibit the growth of many cancers26.
Caloric restriction, in which overall caloric
intake is decreased by 30–40% typically
through carbohydrate limitation, in
particular has been shown across multiple
studies to robustly inhibit the growth of
diverse tumour types, including breast,
lung, prostate, brain, pancreatic and
colorectal cancers19,21,26–33. On the other
hand, a high-​fat diet (HFD), which is
distinct from the ketogenic diet because
it still involves substantial carbohydrate
consumption, generally increases the
incidence and growth of tumours, including
colorectal, pancreatic, prostate, breast and
hepatocellular carcinomas23,34–44. Finally,
specific amino acid-​defined diets have been
studied for their ability to inhibit the growth
of various tumour models. For example,
on the basis of observations that serine
and glycine metabolism is particularly
important for the growth of some cancer
cells, the serine and glycine-​free diet has
been shown to inhibit tumour growth in
several mouse cancer models10,45,46. Similarly,
it has been long appreciated that compared
with normal cells, cancer cells are
more sensitive to methionine starvation,
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and a methionine-​restricted diet can inhibit
the growth of multiple tumour types47–51.
A major challenge in interpreting these
dietary studies, however, is the extent
of variability in the observed effects of a
given diet. For example, although caloric
restriction impairs the growth of most
tumour models, the degree to which
different cancer types respond to caloric
restriction can be variable, and even
different tumour subpopulations within
the same tissue in a mouse model of lung
cancer can have different sensitivities to the
effects of caloric restriction19,29. Similarly,
the ketogenic diet has received considerable
popular attention in recent years because it
has been shown to inhibit tumour growth in
some cancer models, particularly in mouse
models of brain cancer52–57, and yet it can
also accelerate tumour progression in other
mouse cancer models20,58,59. The observation
of opposing effects of the same diet on
different tumour types illustrates that
caution is needed in extrapolating these
studies in animals to provide dietary
recommendations for cancer patients,
particularly without a clear understanding
of what mechanistically drives these
differences in tumour response.
Some of the variability in response
to diet may be explained by technical
experimental differences in study design,
such as differences across studies in diet
formulation, the composition of the
comparator control diet, the timing or
method of diet administration and the
types of animal cancer models being
tested (see Box 2 for a discussion of these
experimental considerations). It is also
probable that dietary effects on tumour
growth are context dependent, since
certain properties of a tumour can affect
whether it is sensitive to a particular diet.
Variation in experimental approaches across
different studies can make it difficult to
uncover these factors, and well-​controlled,
systematic evaluations of a given diet across
multiple tumour types within the same
study may be best suited to define tumour
characteristics that may dictate responses
to diet. These factors could include tumour
genotype, tissue of origin or location of
the tumour.
Several studies have demonstrated that
cancer-​promoting genetic alterations in
oncogenes or tumour suppressor genes
can predict tumour responses to various
diets. Cancer cell lines with mutations in
the PI3K signalling pathway are resistant
to the growth inhibitory effects of caloric
restriction, and genetically engineering
an activating PI3K pathway mutation
Nature Reviews | Cancer
Perspectives
Control diet Caloric restriction Ketogenic diet
High-fat diet Amino acid-defined diets
Control protein component
Amino acid mixture that
approximates casein composition
Serine and glycine-free protein
component
Methionine-restricted protein
component
20% methionine relative
to control
Carbohydrates Fat Protein Restriction
Fig. 2 | Different diets can be defined by the relative contributions of different macronutrients
to caloric intake. Diets are composed of three macronutrient categories — carbohydrates, fat and
protein — that each contributes to caloric intake. Diets also contain components that do not contri­
bute to caloric intake (not shown), such as vitamins, minerals and fibres (Box 1). Altering the relative
ratios by which these different macronutrients contribute to caloric intake results in different diets,
such as caloric restriction, the ketogenic diet and the high-​fat diet, which each have distinct effects
on systemic metabolism and whole-​body physiology. Caloric restriction can involve the long-​term
restriction of any combination of macronutrients, but is typically achieved through the restriction of
carbohydrates while maintaining equal feeding of protein, fat, vitamins and minerals to induce lower
blood glucose and insulin levels. The degree of restriction differs across studies, but a commonly used
regimen involves a 30–40% restriction in total calories relative to the control. Both the ketogenic diet
and the high-​fat diet are high in fat, with the key distinction being that the high-​fat diet still involves
substantial carbohydrate consumption, resulting in different physiological effects. Amino acid-​defined
diets involve replacing the protein component with purified mixtures of amino acids, allowing the
removal of specific amino acids such as serine, glycine and methionine, which can be done in a way
that does or does not hold the total amount of nitrogen in the diet constant. The control diet shown
represents the macronutrient composition of a widely used standard laboratory mouse chow.
into cancer cell lines can be sufficient to to tumour responses to diet. It is difficult,
confer resistance to caloric restriction19,29. however, to draw strong conclusions about
Genotype can also contribute to tumour which cancer types respond best to a given
response to the ketogenic diet; for example, diet, since observations are typically spread
the ketogenic diet enhances the growth of across different studies rather than being
BRAFV600E melanoma. The ketogenic diet, contained within a single well-​controlled
which restricts both carbohydrates and experiment. To illustrate this, use of the
protein to limit access to glucogenic amino ketogenic diet for brain cancers appears
acids, leads to ketogenesis primarily in the to be the most promising, although the
liver that converts fatty acids into ketone evidence in support of this diet slowing
bodies such as β-​hydroxybutyrate and glioma growth is spread out across different
acetoacetate, and acetoacetate augments experimental brain cancer models. A few
BRAF signalling59,60. Finally, while the serine studies demonstrated that the ketogenic
and glycine-​free diet is effective in increasing diet alone can inhibit tumour growth and
survival in a mouse model of Eµ-​Myc-driven extend survival in various mouse models
lymphoma and a model of intestinal cancer of glioma and glioblastoma52–54,61,62, while
driven by Apc loss, it does not inhibit the others show no effect in these models63–65.
growth of Kras-​mutant pancreatic and The ketogenic diet can also inhibit tumour
colorectal tumours10. growth in some other cancer types, such as
The cancer cell tissue of origin and/or prostate cancer55,56, pancreatic cancer66 and
tumour location may also contribute gastric cancer57, although the effect size is
Perspectives

minimal in some studies. Studies in other to be dependent on the expression of the will be an important step in translating
models report little to no effect, such as fatty acid receptor CD36 in metastasis-​ such knowledge into more well-​informed,
in colorectal, lung and pancreatic cancer initiating cancer cells69. Consistently, a HFD scientifically grounded and potentially
models20,67,68, and in some instances the also enhances metastasis in mouse models ‘personalized’ dietary recommendations
ketogenic diet may even accelerate tumour of prostate cancer driven by Pten and Pml for cancer patients.
growth20,58,59. That brain tumours may be loss70. These data suggest that uptake of
most sensitive to the ketogenic diet suggests dietary fatty acids from a HFD may help Do dietary alterations change metabolite
that some aspect of the brain environment facilitate metastasis. In another study, availability for tumours? The idea that
or lineage could contribute to this response, the synthesis and availability of the amino dietary effects on tumour progression
but more work is needed to determine acid asparagine was found to influence the may be mediated in part through changes
whether this is the case. epithelial–mesenchymal transition in breast in the metabolic environment to which
Differences in nutrient availability across cancer cells, and a diet high in asparagine cancer cells are exposed rests on the premise
tissues may also underlie distinct tumour was sufficient to drive increased metastatic that nutrient availability to cancer cells
responses to diet. For example, breast cancer burden71. These data are consistent in relevant microenvironments can be
cells arising in a mouse model driven by with nutrient availability within tissues modulated by dietary changes. Metabolite
Brca1 and Trp53 loss grow more slowly in influencing the ability of cancers to grow quantification by mass spectrometry and
mammary fat pad tissue that may be even in specific sites, and these types of studies nuclear magnetic resonance spectroscopy
more serine deficient when the animals can help reveal the metabolic requirements has made it feasible to gain a more complete
are consuming a serine and glycine-​free associated with metastasis as well as point understanding of how various diets impact
diet. On the other hand, the growth of to potential dietary interventions that help the metabolome in different biological
these same cancer cells in the more serine-​ limit tumour progression. samples72. Measurements of metabolite
replete pancreatic tissue is less sensitive For the most part, the molecular concentrations in the blood, which are more
to perturbations that affect serine and determinants of whether the growth and straightforward and feasible from a technical
glycine availability46. progression of a tumour will respond to a perspective, have been used as a proxy for
In addition to effects of diet on tumour particular diet are not well understood, and understanding nutrient availability to cancer
growth, how dietary interventions impact systematic efforts will be needed to explore cells within tumours. Indeed, various efforts
other aspects of tumour progression such as this question. As we discuss later, identifying have been made to characterize how nutrient
metastasis is also an important question. the responders versus non-​responders to availability in the blood is altered by both
For example, mice into which oral squamous a dietary intervention can aid in dissecting caloric restriction and short-​term fasting73–79,
cell carcinomas had been implanted which aspects of cancer metabolism dictate the ketogenic diet80–82, the HFD83–86, the
developed more lymph node metastases tumour responses. Moreover, understanding serine and glycine-​free diet10,11,46 and the
when fed a HFD. Increased metastatic the specific characteristics of tumours methionine-​restricted diet51,87–91. Box 3
potential under these conditions was found that define their responses to various diets provides a summary of how these diets
affect the levels of several key metabolites
in the blood.
Box 1 | Compositions of experimental rodent diets
However, blood does not always
experimental animal diets generally fall in two categories: standard chow and purified ingredient represent the local environment to
diets150. Chow diets are made from grains and cereals, containing ingredients such as ground corn, which cancer cells are exposed within
ground oats, alfalfa meal, soybean meal and ground wheat. these plant materials are not well a tumour. Thus, diet-​induced changes
defined, so the actual composition of the same diet can vary from batch to batch. therefore, it can in blood metabolite availability may
be difficult to accurately report the exact composition of these diets in studies, to reproduce the not necessarily be perfectly mirrored
identical effects of these diets across different batches and to modify specific components of
in the local metabolic environment of
these diets to test hypotheses. Rather, purified diets in which each nutrient is clearly defined by
a separate ingredient are more suitable for dietary studies in animal cancer models (for examples
tumours. Regions of tumours differ in
see Fig. 2). Purified animal diets are typically composed of four main macronutrient categories: their degree of vascularization, resulting
carbohydrates, fat, protein, and vitamins and minerals. in gradients of more hypoxic and nutrient-​
Carbohydrates are complex sugars (for example, corn starch and maltodextrin) or simple sugars deprived environments92,93. More recent
(for example, glucose, fructose and sucrose). Fat can be high in saturated fatty acids (for example, efforts to characterize tumour interstitial
lard and milk fat) or high in monounsaturated and/or polyunsaturated fatty acids (for example, fish fluid (TIF), which can be isolated by
oil, vegetable oil, canola oil and soybean oil). Consumption of fats with different fatty acid profiles various methods11,94–96, have found that
can impact the fatty acid composition of tissue lipids and membranes151,152. Given the impact of the metabolite composition of TIF can be
distinct fatty acid species on cancer cell proliferation153–159, dietary fat sources should be controlled distinct from that of plasma11,97–99. While
when different diets are being compared. Protein can be sourced from casein supplemented with
these measurements represent an average
sulfur-​containing amino acids or, if a specific subset of amino acids of interest is to be studied,
from a mixture of individual amino acids at levels that approximate casein or at levels that maintain
level of nutrients found in the tumour
isonitrogenicity. vitamins and minerals can be sourced from rodent-​optimized defined mixes. extracellular fluid and thus fail to capture
Most diets are also supplemented with cellulose as a fibre source and antioxidants such as different subdomains known to exist
tert-​butylhydroquinone. within tumours100, not all nutrients in
since each nutrient group in these purified diets is clearly defined by a separate ingredient, TIF are depleted relative to plasma; some
this allows relatively easy manipulation of dietary components and allows diets under study to metabolites are enriched in TIF, implying
be easily reported and reproduced across different studies. Commercial vendors offer support that the tumour microenvironment may
to assist with diet formulation, and this can be useful to ensure that any dietary modifications are not be as deprived of all nutrients as is
made in a controlled manner. important considerations for designing different diets are further sometimes assumed11. Importantly, TIF
discussed in Box 2.
metabolite concentrations can be modulated

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 Perspectives

Box 2 | experimental design considerations for dietary studies in animal cancer models mechanisms for how dietary changes might
impact cancer progression.
Dietary modifications Another key consideration is that dietary
Formulation of experimental diets should be controlled, such that experimental diets are derived perturbations may induce broad changes
from manipulations of a baseline control diet. a common starting point is the aiN-93G diet or in metabolite availability that extend
the aiN-93M diet, which are nutritionally adequate purified diets for rodents developed by the
beyond the specific metabolite of which
american society for Nutrition160. Outside the intended modifications, the experimental diet
should be identical to the control diet, and three important points must be considered. First, the availability was changed in the diet.
the macronutrients that contain calories have different caloric densities: carbohydrates, proteins For instance, the serine and glycine-​free diet
and fat have 4, 4 and 9 kilocalories per gram, respectively. As a result, a higher-​fat diet will be more changes the levels of other amino acids and
calorically dense than a lower-​fat diet. second, on a dietary change, animals will adjust their food potentially other metabolites that have not
intake to maintain the same caloric consumption, not food weight. Finally, because animals eat yet been measured10,11. Whether changes
for calories, all dietary modifications (other than caloric restriction) require reciprocal changes in the availability of other metabolites also
to at least two components: raising the level of one component necessarily means that the level contribute to the effects of this diet is not
of a second component is lowered (Fig. 2). For example, a high-​fat diet often involves replacing known. Similarly, the methionine-​restricted
carbohydrates with fat, which means that it is also a lower-​carbohydrate diet. Due to the different diet not only lowers blood methionine
caloric densities of these two components, this adjustment cannot be made gram for gram, but
levels but both increases and decreases
rather must be made calorie for calorie. Making calorie-​for-calorie adjustments ensures that
animals consuming diets with different caloric densities will eat the same absolute amounts of the levels of numerous other metabolites51.
all nutrients within the diet other than those that are intentionally changed. For a more in-​depth This concept is particularly relevant to diets
discussion of these concepts, see ref.150 with macronutrient compositions that are
known to impact whole-​body systemic
Caloric intake
although animals tend to maintain their caloric intake across different diets, this may not always
metabolism. A low-​fat, high-​carbohydrate
hold true for all species or strains. it is therefore important to measure caloric consumption diet, for example, does not lower blood
between animals consuming different diets to ensure that different diet groups in fact have similar triglyceride levels but rather increases them
daily caloric consumption, as differences in caloric intake may lead to differences in phenotype that by stimulating hepatic de novo lipogenesis103.
are independent of the source of calories. the effect of diet on body weight may also be important Similarly, a HFD not only raises blood lipid
to consider. For example, the ketogenic diet and caloric restriction typically lead to weight loss, levels but also leads to hyperglycaemia104.
and it may be informative to normalize their effects on tumour growth to the concomitant loss in Dietary fructose does not necessarily lead
body weight33. to high levels of circulating fructose unless
Method of diet administration it is administered at high doses, since at
animal diets are frequently fed ad libitum, in which animals have free access to the food. in most lower doses fructose is mainly cleared in the
cases, this method of administration is sufficient provided that caloric consumption between small intestine by conversion into glucose105.
different cohorts is similar. In situations in which caloric consumption across experimental groups Nevertheless, a high-​fructose diet can also
is not consistent, pair feeding strategies can be considered161. Moreover, diets involving food induce hyperglycaemia, hyperinsulinaemia,
restriction should involve controlled daily feedings of both the control group and the experimental
hyperlipidaemia and insulin resistance106,107.
diet group162.
Low-​carbohydrate diets such as caloric
Timing of diet administration restriction and the ketogenic diet not
if the effects of a diet on tumour initiation are being studied, then diet administration should be only lower blood glucose levels but also
initiated before the establishment of a tumour. if tumour maintenance and progression are being
change the concentrations of many other
examined, then the experimental diets should be initiated after the formation of a palpable and/or
metabolites, such as amino acids, ketones
measurable tumour mass.
and lipids73,75,81. Such broad changes elicited
by dietary perturbations illustrate a major
by diet, although the extent to which plasma concentrations in the blood and TIF are challenge in studying the effects of diet
changes in metabolite concentrations in the millimolar range11, and whether on tumour metabolism. Comprehensively
scale with changes in TIF metabolite these diets decrease glucose levels in the defining how various diets of interest
concentrations differs11. Furthermore, the tumour enough to alter metabolism and alter systemic nutrient availability will be
extent to which various diets alter the TIF slow growth is not known, particularly an important first step in understanding
metabolome across different tumour types given that glucose is often not limiting for how diet might impact tumour growth by
is not known. many cancer cells in vitro when present modulating the access to and utilization of
When biological fluids are being above the micromolar range102. Similarly, metabolites by both cancer cells and stromal
analysed in most metabolomic studies, serine and glycine concentrations in the cells within a tumour.
relative differences in metabolite levels blood are ~150–200 µM under a control
are typically measured in response to an diet, and the serine and glycine-​free diet Do diet-​induced changes in nutrient
experimental perturbation. However, lowers the concentration to ~50–100 µM availability affect tumour metabolism?
it may also be informative in many cases (refs10,46). Culturing cancer cells in these Although some efforts have been made
to measure the absolute concentration lower physiological concentrations of serine to evaluate how dietary alterations
changes of metabolites upon a dietary and glycine in vitro can limit proliferation, change systemic nutrient availability in
alteration. For example, the tumour growth-​ thus providing evidence that the serine and the blood, the challenge is determining
inhibiting effects of low-​carbohydrate glycine-​free diet may in fact be impairing how to mechanistically connect these
diets such as caloric restriction and the tumour growth by starving tumours of these changes to dietary effects on tumour
ketogenic diet are frequently attributed in amino acids46. These examples illustrate how metabolism. One approach is to consider
part to their ability to lower blood glucose absolute quantification of metabolites in how the metabolism of cancer cells can
concentrations54,63,64,101. However, glucose biological samples can provide insight into shift depending on the concentrations of

Nature Reviews | Cancer

Perspectives

Box 3 | Diets can change the levels of metabolites available to a tumour
the table provides a summary of how the diets described in this Opinion affect the levels of several
key metabolites in the blood. although some metabolites are robustly affected by specific diets
(for example, the ketogenic diet always increases ketone body levels), other metabolites may be
affected variably across different studies. Moreover, it is possible that the levels of some metabolites
may have time-​dependent, complex responses that fluctuate depending on how long a diet has
been administered81,86. as more studies begin to apply improved metabolomics platforms to the
study of different diets, we will increase our understanding of how diet may alter the availability
of a broader range of metabolites to tumours.
Glucose Insulin Ketone Trigly­ neFa Choles­ amino
bodies cerides terol acids
Caloric ↓↓ ↓↓ ↑ Variable Variable ↔ Variable 73,75–78,80
restriction
Ketogenic ↓↓ ↓↓ ↑↑ ↔ ↑ ↑ Variable
diet
High-​fat ↑↑ ↑↑ ↔ ↑ ↑ ↑ Variable
diet
Serine and ↔ ND ND ND ND ND Serine ↓
glycine-​free
Glycine ↓
diet
Methionine-​ ↔ ↓ ND ↓ ↓ ↔ Methionine ↓
restricted
diet
↑, increased; ↓, decreased; ↔, unchanged; ND, not determined; NeFa, non-​esterified fatty acid.
metabolites in their local environment. dietary effects on metabolite levels in the
This has been highlighted by work exploring tumour microenvironment can change
the metabolic differences observed in the metabolism of a nutrient the local
cancer cells growing in vitro versus in vivo. concentration of which is not affected by
For example, glutamine is highly consumed the dietary intervention.
by lung cancer cells grown in culture, One approach for studying how diet
where it serves as a major anaplerotic might affect cell metabolism is to mimic the
carbon source for the tricarboxylic acid diet-​associated metabolic microenvironment
cycle108. However, when the same cancer in cell culture. A challenge with preclinical
cells are grown as a tumour in a mouse, dietary studies in cancer is that such
glutamine contributes minimally to the experiments typically need to be conducted
tricarboxylic acid cycle within tumours, in animal models. However, recent data
and tumour growth is not dependent on have suggested that culturing cancer cells
glutaminase activity3,109. Subsequent work in more physiological tissue culture media
demonstrated that the high reliance of can recapitulate some metabolic features of
cancer cells on glutamine in culture is in cancer cells that are observed in vivo6–8,110.
part due to supraphysiological levels of the Therefore, measurement of metabolite
amino acid cystine (the oxidized dimer concentrations in either plasma or TIF
form of cysteine) found in standard culture under a diet (as discussed in the previous
media, and administering a bolus of cystine section) may provide an opportunity to
to mice can indeed increase glutamine mimic the metabolic effects of that diet by
incorporation into the tricarboxylic acid constructing a tissue culture medium that
cycle within tumours6. Hence, the levels of resembles the diet-​induced TIF or plasma
cystine in the local environment can alter metabolome. Such an approach could then
the extent to which cancer cells metabolize provide an experimentally tractable system
glutamine. It is notable that in this case it to assess molecular and mechanistic aspects
is not environmental glutamine levels that of how diet impacts cancer cell metabolism
modulate glutamine utilization but rather and proliferation.
the local concentrations of a seemingly A few efforts have been made to alter
unrelated amino acid, illustrating that broad culture media to mimic a specific diet,
alterations in the metabolic environment although most have only manipulated
can result in unexpected changes in nutrient a subset of components within existing
utilization by cancer cells. Observations medium formulations. For example,
such as these are consistent with the fact some studies have tried to mimic caloric
that many nutrient transporters function restriction or fasting by culturing cells in
by metabolite exchange and illustrate how media with low concentrations of glucose
and serum111–114, and others have tried
to mimic the ketogenic diet by culturing
cells in the presence of ketones such as
β-hydroxybutyrate and acetoacetate66,101,115,116.
Tissue culture media supplemented with
lipids and/or fatty acids such as palmitate
have also been used to model the effects
of the HFD23, and media either lacking
or containing low levels of serine and
glycine can mimic effects of the serine
refs and glycine-​free diet10,45,46. Mimicking
dietary perturbations in vitro might be
further improved by adjusting additional
aspects of medium compositions on
20,80,81 the basis of the measured physiological
concentrations of metabolites found in the
80,83–86 plasma or TIF from animals consuming a
given diet. If plasma or TIF-​like medium
10,46 mimics the effects of a diet on tumour
growth, metabolite dropout or add-​back
experiments could then be used to identify
51,87–91 the key metabolites modulated by the diet
that are limiting for proliferation or survival.
It would also provide an experimental
system to conduct nutrient tracing
experiments to understand how various
nutrients are utilized by cancer cells.
Any conclusions derived from in vitro
tissue culture models still need to be
corroborated in vivo, and a variety of
analyses can help characterize how
different diets alter tumour metabolism
in animal models. One approach is to use
mass spectrometry to obtain metabolomic
profiles of tumours harvested from animals
fed with different diets. Although the
measurement of steady-​state metabolite
levels provides limited information on the
activities of metabolic pathways117 and bulk
tumour measurements are complicated
by cell-​type heterogeneity, such data may
point to specific metabolites or classes of
metabolites that are perturbed by a given
diet that may warrant further investigation.
Furthermore, there are network analysis
resources that can correlate metabolite
pool sizes with the expression of metabolic
genes118,119, which may aid in inferring the
activities of different metabolic pathways.
Together, such analyses may reveal
potential metabolic pathways that are
altered within tumours in response to a
given diet.
Another tool to characterize how diets
affect tumour metabolism is to trace the
fate of isotope-​labelled nutrients within
tumours and other tissues in vivo. This
method can provide information about how
a dietary perturbation influences the relative
utilization of the labelled nutrient and its
incorporation into downstream metabolites.
However, while in vivo metabolite tracing

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is a powerful tool, the interpretation of such
labelling data is complicated particularly
within the context of animal physiology.
For example, normal tissues can rapidly
consume the labelled nutrient and convert
it into labelled intermediates that can in
turn supply the label indirectly to cancer
cells within the tumour120. Tumours are
also composed of a heterogenous mixture
of non-​cancer and cancer cells121,122,
which both contribute to the labelling
patterns observed within tumours. Label
incorporation is also often assumed to
represent net nutrient consumption by
a tumour, but this interpretation can be
confounded by exchange flux, wherein
rapid substrate–product interconversion
by reversible metabolic reactions can lead
to the labelling of a metabolite regardless
of the net direction of that reaction9,117,123.
Finally, another consideration is that many
assumptions for interpretation require
steady-​state labelling, particularly when
different diets may alter the kinetics of
labelled-​nutrient uptake in different
tissues. Depending on the diet, achieving
steady-​state labelling may be challenging
for some labelled nutrients. For example,
tracing labelled glucose in mice consuming
a ketogenic diet can be difficult because
the diet itself lowers blood glucose levels.
Compared with glucose tracing in mice
consuming a normal diet, the administration
of labelled glucose must be adjusted for
mice consuming a ketogenic diet to avoid
substantially raising blood glucose levels
during the course of the tracing experiment.
Moreover, achieving steady-​state labelling
for some metabolites may not be possible
via infusion, because while the body
has a feedback mechanism to maintain
euglycaemia and allow steady-​state glucose
labelling, such feedback systems do not
exist for all other metabolites. Despite these
caveats, in vivo metabolite tracing methods
can provide insight into how diets alter
tumour metabolism.
Once candidate metabolic pathways
have been identified, determining whether
these metabolic changes mediate the tumour
response to a diet can also be challenging.
One useful approach is to compare tumours
that respond to a diet with tumours that
do not respond. For instance, if a metabolic
pathway that promotes proliferation is
consistently inhibited in all tumours that
have impaired growth in response to a
diet, then genetically or pharmacologically
targeting enzymes in this pathway may
mimic the effects of that diet (Fig. 3).
For example, due to observations that
caloric restriction can extend longevity
Nature Reviews | Cancer
and impair tumour development, there has
been much interest in identifying caloric
restriction mimetics that can mediate the
effects of caloric restriction without
the need for significant food restriction.
Compounds such as resveratrol, metformin
and rapamycin have been explored as
potential mimetics because of their ability
to induce similar metabolic changes as
caloric restriction, such as decreases in
blood glucose, insulin and triglyceride
levels15,124–126. Indeed, rapamycin and
metformin have been extensively studied
for their antitumour effects, although it is
unclear if the mechanism by which caloric
restriction inhibits tumour growth is the
same as that of these compounds15.
Alternatively, metabolic pathways that
correlate with resistance to the effects of a
diet may point to metabolic enzymes that
can be genetically or pharmacologically
manipulated to alter the sensitivity of
tumours to that diet (Fig. 3). For instance,
Kras-​mutant colorectal tumours are
resistant to the growth inhibiting effects
of a serine and glycine-​free diet because
KRAS activation leads to the expression of
higher levels of the de novo serine synthesis
genes, rendering these cancer cells less
dependent on exogenous sources of serine
and glycine10. To show that the serine and
glycine-​free diet inhibits tumour growth
by starving tumours of serine and glycine,
genetically ablating the serine synthesis
pathway in resistant tumours, such as in
Brca1-null, Trp53-null breast cancer cells,
sensitizes them to the diet46. Conversely,
overexpressing the serine synthesis pathway
genes in sensitive tumours, such as in breast
cancer cells lacking the expression of these
genes, makes them resistant to the effects
of the serine and glycine-​free diet46.
Another study demonstrated that
dietary supplementation with high-​fructose
corn syrup at amounts that mimic human
consumption of ~12 ounces of sugar-​
sweetened beverages per day enhances
the growth of intestinal tumours in an
Apc-​deficient mouse model107. Tumours
from mice treated with this diet had
increased levels of long-​chain fatty acids,
suggesting that high-​fructose corn syrup
activates fatty acid synthesis. Of note,
knockout of the fatty acid synthase gene
(Fasn) in Apc-​deficient intestinal tumours
rendered them insensitive to the growth-​
promoting effects of high-​fructose corn
syrup, indicating that de novo lipogenesis
is necessary for the tumour response to
this diet.
Finally, in the case of the ketogenic diet,
it has been proposed that some cancer
Perspectives
Diet
Tumour metabolism
Metabolic Diet-induced Metabolic
perturbations metabolic or alterations
that mediate the synthetic that confer
dietary growth lethal resistance to
response vulnerabilities dietary effects
Diet Synergistic Diet-
mimetics diet–drug sensitizing
combinations drug targets
Fig. 3 | Understanding how dietary factors
impact tumour metabolism may help incorpo­
rate dietary interventions into cancer therapy.
Some diets may inhibit tumour growth by per-
turbing specific metabolic pathways that influ-
ence cancer progression. Targeting these
metabolic pathways pharmacologically could
mimic the effects of those diets. For example,
interventions that mediate the effects of caloric
restriction without the need for significant food
restriction could improve cancer outcomes.
Alternatively , adaptive metabolic alterations may
occur that mediate resistance to dietary effects
by tumours. Targeting these pathways may pro-
vide a means to sensitize tumours to the effects
of certain diets. Finally , although dietary changes
may influence overall patient survival, it is
unlikely that any one diet can be used on its own
to reliably induce tumour regression. The maxi-
mum utility of dietary interventions may lie in
potential synergies when combined with either
existing or novel cancer therapies.
cells do not express the enzymes necessary
to metabolize ketones65,115,127–129, and the
presence of β-​hydroxybutyrate may be able
to suppress proliferation and even cause
cell death in some of these cases66,101,130.
By contrast, other cancer cells can metabolize
ketones in culture116,131, raising the question
of whether a tumour’s ability to consume
ketones might contribute to whether it
responds to a ketogenic diet. In a comparison
between two cancer cell lines, response to a
ketogenic diet appears to be correlated with
the expression of the ketone metabolism
genes BDH1 and OXCT1 (ref.115). Xenograft
growth of Panc-1 cells, a pancreatic cancer
cell line that lacks BDH1 and OXCT1
expression, is impaired by a ketogenic diet,
whereas HeLa cells, which express BDH1 and
OXCT1, are resistant to the diet. Knockdown
of BDH1 and OXCT1 in HeLa cells sensitizes
them to the ketogenic diet. Therefore,
expression of ketone metabolism genes may
be one factor that predicts tumour responses
to the ketogenic diet, a conclusion that
Perspectives
will need to be more systemically explored
among more tumour models.
In summary, identifying metabolic
pathways that can be perturbed to either
mimic a diet or modulate tumour sensitivity
to dietary effects can enhance understanding
of how dietary perturbations alter cancer
cell metabolism to affect tumour growth.
Can dietary changes reveal metabolic
vulnerabilities or drug synergies? Although
dietary perturbations can affect tumour
progression and may extend survival10,19,33,46,
few diets, if any, have been shown to
robustly cause tumour regression on
their own, possibly because restricting
nutrients through dietary means typically
impairs proliferation without affecting
cell survival. An important opportunity
afforded by dietary interventions may
therefore lie in potential synergies with
other cancer therapies (Fig. 3). The idea
that diet-​induced changes in cancer cell
metabolism may contribute to potential
diet–drug synergies is supported by
observations that environmental nutrient
availability can not only change cancer
cell metabolism but can also significantly
impact the efficacy of existing therapies.
For example, as described earlier, in
the presence of physiological levels of
exogenous cystine, lung tumours depend
less on glutaminolysis for proliferation,
which may explain in part why CB-839,
a glutaminase inhibitor currently in clinical
trials, may show limited efficacy in some
cancer patients6,132. Whether increasing
cystine availability within tumours in turn
sensitizes them to glutaminase inhibitors
remains to be determined. Similarly, the
antidiabetic drug metformin can slow
the growth of lung tumour xenografts in
a mouse model but not in tissue culture
models, in which supraphysiological
levels of pyruvate abolish the sensitivity
of cancer cells to metformin4. Another
study demonstrated that when leukaemia
and colorectal cancer cells are cultured in
media with polar metabolite concentrations
similar to that of human plasma, they are
less sensitive to 5-fluorouracil, a commonly
used chemotherapeutic compound7.
Observations such as these demonstrate that
at least in vitro the metabolic environment
of cancer cells can alter their responses to
various drugs. Extension of this concept
to an in vivo setting implies that diet-​
mediated changes to systemic nutrient
availability can also affect how tumours
respond to certain cancer therapies. Thus,
it may be possible to rationally determine
whether diet will synergize or antagonize
the effects of existing cancer therapies or
novel metabolism-​targeting drugs.
A few combinations between different
diets and cancer drugs have already been
explored. For example, the ketogenic diet
augments the efficacy of PI3K inhibitors in
acute myeloid leukaemia and pancreatic,
breast, endometrial and bladder cancer
mouse models20. PI3K inhibitors block
insulin signalling, which subsequently
prevents glucose uptake in tissues and leads to
an increase in blood glucose concentrations.
This transient hyperglycaemia induces the
release of insulin from the pancreas, which
is then proposed to override the effects
of PI3K inhibition in tumours by reactivating
PI3K signalling. Since the ketogenic diet
lowers blood glucose and insulin levels,
it can blunt the rise in blood glucose and
insulin levels caused by PI3K inhibitors,
thereby improving the antitumour activity
of the drugs. This observation illustrates
how the effects of a diet on whole-​body
metabolism can be exploited to augment
the efficacy of a targeted therapy currently
under development. Moreover, given that
the ketogenic diet leads to broad changes
in systemic nutrient availability80,81 and the
PI3K signalling pathway is a major regulator
of cancer cell metabolism133, there may
be additional mechanisms by which the
ketogenic diet sensitizes tumours to PI3K
inhibitors by affecting cancer metabolism
or by altering the metabolic environment
within the tumour.
In another recent study, a CRISPR–Cas9
screen identified histidine metabolism as a
modulator of cancer cell sensitivity to the
chemotherapeutic drug methotrexate134. Loss
of formimidoyltransferase cyclodeaminase
(FTCD), which is required for histidine
degradation, caused various haematopoietic
cancer cell lines to become more resistant
to methotrexate. One mechanism for
the anticancer effects of methotrexate is the
inhibition of dihydrofolate reductase, which
generates the cofactor tetrahydrofolate
(THF)135. Depletion of THF by methotrexate
can lead to cell death because it is required
for various metabolic processes, perhaps
most notably nucleotide synthesis. In
the histidine degradation pathway, the
FTCD reaction utilizes THF, and histidine
catabolism was therefore proposed to
synergize with methotrexate by further
depleting the THF pool. Remarkably,
dietary supplementation with histidine in
tumour-​bearing mice raised histidine levels
within the tumours and led to increased
histidine breakdown, and this synergized
with methotrexate treatment to inhibit
tumour growth. This observation illustrates
how dietary interventions can alter cancer
cell metabolism in a way that sensitizes
tumours to an existing chemotherapy.
Similarly, multiple studies have
demonstrated that fasting regimens and
low-carbohydrate diets such as caloric
restriction and the ketogenic diet can
sensitize tumours to the effects of various
chemotherapies while protecting normal
tissues (recently reviewed extensively in
ref.136). The methionine-​restricted diet
has also been shown in multiple studies to
synergize with various chemotherapies51,137,138.
Some studies advocate a short-term but
more extreme dietary change, such as
extreme caloric restriction (greater than 90%)
or fasting for a few days before chemotherapy,
immunotherapy or treatment with other
targeted agents. These short-term dietary
interventions may still enhance the anticancer
effects of therapies and enable patients to
benefit from a diet without the negative
effects associated with long-​term exposure
to a diet111,139. These findings have motivated
clinical trials evaluating these diets in
combination with chemotherapy140–146.
The mechanisms underlying these
combinations have largely been attributed
to how these diets lower blood glucose
levels and reduce IGF1 and insulin
signalling25,111,136,139,147. However, these diets
may also alter cancer and normal tissue cell
metabolism in other ways that contribute
to increased drug sensitivity. For example,
lung and ovarian cancer cell lines that are
resistant to cisplatin are more sensitive
to nutrient deprivation and glutamine
starvation, which leads to the impairment
of nucleotide synthesis and can resensitize
these cells to cisplatin-​induced cell death148.
Thus, it is possible that limiting tumour
access to glutamine by fasting regimens in
this context could synergize with cisplatin
treatment. Further studies will improve our
understanding of whether changes in tumour
metabolism mediated by fasting regimens or
low-​carbohydrate diets can contribute in part
to increased chemotherapy sensitivity.
Finally, in some instances certain diets
will not modulate or even antagonize the
effects of a specific drug. For instance, even
though serine and glycine starvation can
synergize with mitochondrial inhibitors
such as oligomycin and metformin in
some contexts45,149, in other contexts this
combination has no effect or may even
increase tumour burden10. Taken together,
these examples highlight the value of
studying diet and drug combinations
in defined contexts. As we increase our
understanding of how diet-​mediated
changes to cancer cell metabolism may
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reveal new therapeutic strategies, new
insight will be gained to aid efforts to tailor
dietary recommendations to specific cancer
drugs and tumour types.
Conclusion
How diet and nutrition affect cancer
progression is a question of critical
importance to many cancer patients, and one
that will benefit from more study and
evidence-​based conclusions. It has become
increasingly clear that the way cancer cells
utilize nutrients to support their growth
and proliferation is determined not only by
cancer-​promoting genetic alterations but
also by the tumour’s interactions with its
local metabolic environment. Applying this
understanding to study the connections
between diet and cancer provides a
framework for how to probe dietary effects
on nutrient access and utilization by cancer
cells that influence tumour progression.
This could lead to a better understanding of
which cancer types respond to various diets,
how diet impacts cancer cell metabolism
to mediate these responses and whether
dietary interventions may open new
therapeutic opportunities in combination
with current cancer treatments. It will also
build a foundation for providing better
scientific guidance for incorporating diet
and nutrition into cancer therapy.
Evan C. Lien1,2 and Matthew G. Vander Heiden   1,2,3*
Koch Institute for Integrative Cancer Research,
1
Massachusetts Institute of Technology, Cambridge,
MA, USA.
2
Department of Biology, Massachusetts Institute
of Technology, Cambridge, MA, USA.
3
Department of Medical Oncology, Dana-​Farber
Cancer Institute, Boston, MA, USA.
*e-​mail: mvh@mit.edu
https://doi.org/10.1038/s41568-019-0198-5
Published online xx xx xxxx
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Acknowledgements
The authors thank members of the Vander Heiden laboratory
for thoughtful discussions and comments on the manuscript.
E.C.L. is a Damon Runyon Fellow supported by the Damon
Runyon Cancer Research Foundation (DRG-2299-17). M.G.V.H.
is supported by the Emerald Foundation, the Lustgarten
Foundation, SU2C, the Ludwig Center at MIT, the US National
Cancer Institute, the MIT Center for Precision Cancer Medicine
and a Faculty Scholars award from the Howard Hughes Medical
Institute.
Author contributions
Both authors contributed to the discussion of manuscript
content, writing of the manuscript and reviewing or editing of
the manuscript before submission.
Competing interests
M.G.V.H. is a consultant for and scientific advisory board mem-
ber of Agios Pharmaceuticals, Aeglea Biotherapeutics and
Auron Therapeutics. E.C.L. reports no competing interests.
Peer review information
Nature Reviews Cancer thanks L. Hodson, V. Longo and the
other, anonymous, reviewer(s) for their contribution to the peer
review of this work.
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