Trends in Cancer

Review
The Metabolic Interplay between Cancer and
Other Diseases
Anne Le,1,2,* Sunag Udupa,1,3 and Cissy Zhang1

Over the past decade, knowledge of cancer metabolism has expanded exponentially and has Highlights
provided several clinically relevant targets for cancer therapy. Although these current ap- The metabolic features of many
proaches have shown promise, there are very few studies showing how seemingly unrelated diseases have a striking overlap
metabolic processes in other diseases can readily occur in cancer. Moreover, the striking meta- with cancer.
bolic overlap between cancer and other diseases such as diabetes, cardiovascular, neurological,
The metabolism of diseases is an
obesity, and aging has provided key therapeutic strategies that have even begun to be trans-
interconnected network.
lated into clinical trials. These promising results necessitate consideration of the interconnected
metabolic network while studying the metabolism of cancer. This review article discusses how Connecting of cancer metabolism
cancer metabolism is intertwined with systemic metabolism and how knowledge from other dis- to the broader context of aberrant
eases can help to broaden therapeutic opportunities for cancer. metabolism is necessary and may
reveal new therapeutic strategies.
Connecting Cancer Metabolism to the Broader Context of Aberrant
It is important to know whether a
Metabolism potential cancer therapeutic target
The notion of cancer as a metabolic disease predates the discovery of oncogenes, tumor suppres- has been already established in
sors, and epigenetics. As early as 1924, Otto Warburg revealed a characteristic feature of the meta- other diseases.
bolism of cancer: aerobic glycolysis [1,2]. However, cancer metabolism is extremely heterogeneous
[3–5,116] and how cancer connects with the whole biological system remains among the key unre-
solved questions today (Figure 1 and Table 1).

Despite the many advances in cancer research, cancer is still largely studied as an isolated disease.
Nonetheless, some recent repurposing of therapeutic strategies across diseases is allowing for better
therapeutic outcomes [6]. For example, metformin, the commonly prescribed drug for type 2 dia-
betes (T2D) [7], is currently being tested in Phase III clinical trials for cancer treatment [8], where it
was effective in decreasing the proliferation of colorectal cancer [9]. Taking advantage of metabolic
overlap between diseases should not be solely applied to the repurposing of drugs, however. Re-
searchers should also take advantage of existing knowledge and pharmacological approaches
from other diseases for cancer therapy.

Cancers rely heavily on adaptive metabolic shifts to afford sufficient sources of precursors for cellular
bioenergy, redox homeostasis, and other metabolic building blocks to maintain high rates of prolif-
eration and growth. The metabolism of glucose and the catabolism of glutamine are the two main
pathways targeted with metabolic inhibitors in current clinical trials [8–10]. However, there is an
ongoing debate about which metabolic pathways should be targeted for cancer therapy. Specifically,
which of these pathways are best suited for pharmacological targeting? Moreover, are some of these
targets already established in other diseases? This poses the fundamental question for cancer meta-
bolism: are the ‘hallmark’ reprogrammed metabolic features of cancers unique to cancers? Here we
review metabolic pathways that are shared between cancers and other diseases and discuss potential
therapeutic opportunities. 1Department of Pathology, Johns Hopkins

University School of Medicine, Baltimore,

MD 21205, USA
From High Blood Glucose in Diabetes to Cancer: From the Epidemiological 2Department of Oncology, Johns Hopkins
Association to the Mechanistic Explanation University School of Medicine, Baltimore,
Following Warburg’s discovery, research on glucose metabolism in cancers has focused extensively MD 21205, USA
3Department of Chemical and
on the fundamental biochemical pathways of glucose-derived metabolites that sustain cancer growth
Biomolecular Engineering, Johns Hopkins
[11,12]. Could high blood glucose itself lead to cancer? Over the past decade, several epidemiolog- University Whiting School of Engineering,
ical findings have linked an elevated risk of developing cancers in patients with T2D [13,14]. According Baltimore, MD 21218, USA
to Sacerdote et al., the risk of developing colorectal cancer is significantly elevated in patients who *Correspondence: annele@jhmi.edu

Trends in Cancer, December 2019, Vol. 5, No. 12 https://doi.org/10.1016/j.trecan.2019.10.012 809

ª 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Trends in Cancer

Figure 1. Connecting Cancer Metabolism to the Broader Context of Aberrant Metabolism.

The metabolism of diseases is an interconnected network. Diseases are shown as segments of the systemic
metabolic network (each disease is depicted as a piece of the same jigsaw puzzle) and cancer is shown as a part
of this metabolic network (depicted as a piece of the puzzle).

have T2D, with the risk being around 30% higher than in people who do not have T2D [15]. The risks
for several other types of cancer are also significantly higher in T2D patients [15]. Specifically, more
than half of pancreatic ductal adenocarcinoma patients have T2D [16]. The epidemiological associa-
tion between T2D and pancreatic cancer was recently explained by a possible mechanism by which
high blood glucose levels can transform normal pancreatic cells into cells carrying cancerous pheno-
types [17]. This study demonstrated that high glucose in T2D can induce de novo oncogenic muta-
tions through increased O-GlcNAcylation of ribonucleotide reductase, leading to nucleotide pool
imbalance and KRAS mutations (Figure 2). O-GlcNAcylation is a post-translational modification
that results from the addition of glucose-derived O-linked N-acetylglucosamine (O-GlcNAc) moieties
to cellular proteins [18]. While other studies provide evidence that oncogenes and tumor suppressors
regulate metabolic processes in cancer – for example, KRAS and MYC are known regulators of
metabolism that render cancer cells addicted to glutamine [19–23] and glucose metabolism
[11,24–26] – this study showed that aberrant metabolism can in turn dictate gene regulation, even
in noncancerous pancreatic cells [17].

Elevated levels of O-GlcNAcylation and the glycosylating enzyme O-GlcNAc-transferase (OGT) have
been observed in many cancers, such as breast, lung, colon, liver, bladder, endometrial, prostate, and
chronic lymphocytic leukemia cells [27]. These findings are consistent with the high uptake of extra-
cellular glucose in cancer [28]. Targeting O-GlcNAcylation is a relatively recent addition to cancer
therapy [17,29–31]. Specifically, pharmacological inhibition of OGT results in apoptosis in breast can-
cer cells [29]. Genetic silencing of OGT also leads to increased sensitivity of cancer cells to other
pharmacological inhibitors such as GDC-0941, a PI3K inhibitor [30]. Similar to cancer, T2D has
been associated with increased O-GlcNAcylation [32]. Hence, the metabolic process overlapping
T2D and cancer may provide a basis for new targeted therapeutics in cancer (Figure 2).

We now know of one possible explanation for how high blood glucose in T2D could lead to cancer.
Thus, how can we take advantage of this new knowledge for cancer therapy? Previously, many ther-
apeutic approaches have been aimed at inhibiting key glycolytic enzymes in cancer, such as lactate
dehydrogenases (LDHs) [12], glucose transporters (GLUTs/SGLTs) [28,33], and hexokinases (HKs) [34],

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Table 1. Common Metabolic Pathways between Nonmalignant Diseases and Cancer

Common metabolic Disease

pathway
Nonmalignant Cancer

Glucose metabolism through
O-GlcNAcylation
T2D [32] Breast cancer, lung cancer, colon
cancer, liver cancer, bladder cancer,
endometrial cancer, prostate
cancer, and chronic lymphocytic
leukemia cells [27]

Pyruvate metabolism through Hyperpyruvicemia, lactic acidosis Breast cancer and NSCLC [54]
OXPHOS [42], and cardiovascular diseases
[45]

Glutamine metabolism Neurological diseases (AD [57,58], Pancreatic cancer, lymphoma,

ischemic stroke, and epilepsy [56]) prostate cancer, breast cancer,
and hyperammonemic diseases glioma, ovarian cancer, renal cell
(hepatic encephalopathy and inborn carcinomas [20]
errors of the urea cycle [63])

NAAG metabolism Neurological diseases (stroke, Ovarian cancer, brain cancer,

amyotrophic lateral sclerosis, and lymphoma, and pancreatic cancer
schizophrenia [71,72]) [65]

GABA metabolism Neurological diseases (epilepsy and Colon cancer, breast cancer,
schizophrenia [77]) prostate cancer, gastric cancer,
glioma [83], and pancreatic cancer
[82]

Increased ROS and Obesity Renal cell carcinomas, colon cancer,

mitochondria Age-related diseases breast cancer, and prostate cancer
dysfunction [104]

which have shown promising results in preclinical cancer models. However, none of the studies thus
far has taken into account the fact that controlling aberrant glucose levels could have a greater effect
on preventing cancer initiation than just inhibiting cancer progression. Recent approaches have re-
purposed metformin, which has been used to control blood glucose in T2D for the past 25 years
[35,36], for cancer therapy. Currently, metformin is in Phase III clinical trials for the treatment of a num-
ber of cancers [37]. Metformin is a mitochondrial complex 1, glycolysis, and glycogenesis inhibitor
[38–40] (Figure 2). However, the mechanism of action of metformin is still being investigated [41].

Pyruvate Metabolism: Connecting Cardiovascular Diseases to Cancer

If a therapeutic approach has already been established in another disease and its metabolic overlap
with cancer is clear, why should we not jump straight into clinical trials for cancer therapy? Since tar-
geting glucose metabolism (discussed in the previous section) seems to be a promising therapeutic
avenue, investigation of the metabolism of other metabolites derived from glucose closely related to
cellular bioenergy appears to be the next logical step. The six-carbon backbone of glucose can be
readily converted into a wide variety of different metabolites, including pyruvate, a cellular bioenergy
precursor [42]. Dysregulation of pyruvate metabolism is a common metabolic feature across diseases
such as hyperpyruvicemia, lactic acidosis, and cancer [42]. A major reaction of pyruvate catabolism is
regulated by pyruvate dehydrogenase complex (PDC), the enzyme complex responsible for the con-
version of pyruvate to acetyl-CoA, the metabolite oxidized via oxidative phosphorylation (OXPHOS)
[42]. Cancers are characterized by their upregulated utilization of aerobic glycolysis in addition to
OXPHOS [43]. Although aerobic glycolysis is a less efficient source of ATP than oxidation of pyruvate
through the TCA cycle, it is much quicker and thereby upregulated to support the rapid rate of cancer

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Figure 2. Metabolic Crossroads between Cancer and Type 2 Diabetes (T2D).

Glucose from systemic circulation (green spheres) can be converted to glucose 6-phosphate and fructose 6-phosphate through the enzymes hexokinase and
glucose 6-phosphate isomerase, respectively. Fructose 6-phosphate can then enter the hexosamine biosynthetic pathway or continue in glycolysis. The
hexosamine biosynthetic pathway provides precursors for O-GlcNAcylation, which forms the metabolic intersection between T2D (blue circle) and
cancer (yellow circle). Increased O-GlcNAcylation in T2D can lead to insulin resistance; increased O-GlcNAcylation in cancer can lead to the de novo
induction of oncogenic mutations; namely, KRAS. Metabolites are shown in black. Enzymes are shown in light blue. Metformin, shown in pink, is a
pharmacological inhibitor used in T2D and is currently in clinical trials for cancer therapy due to its inhibition of mitochondrial complex 1, glycolysis, and
glycogenesis.

proliferation [44]. Thus, ways to attenuate cancer’s aerobic glycolysis may provide a potential thera-
peutic option for cancer therapy [12].

Regulation of the glycolysis–OXPHOS axis has long been investigated in cardiovascular diseases,
where the challenge is to increase metabolic efficiency by increasing OXPHOS to improve cardiac
function [45]. Recent developments have been focused on increasing the activation of PDC, the gate-
keeping enzyme complex necessary for oxidative pyruvate metabolism via the TCA cycle. On the
surface, this objective of inducing pyruvate oxidation to repress metabolism through the aerobic
glycolysis pathway appears to match the problem faced in cancer.

The need for metabolic stimulation of pyruvate oxidation in the context of cardiovascular disorders
has led to the development of dichloroacetate (DCA), a pharmacological inhibitor of pyruvate de-
hydrogenase kinase (PDK), which increases the cellular activity of PDC causing a shift towards OX-
PHOS [46–49] (Figure 3). DCA has the ability to promote a metabolic shift away from aerobic glycol-
ysis and towards OXPHOS in preclinical models [50]. Thus, preclinical studies in the context of
cardiovascular disease have shown DCA to have beneficial effects on myocardial function [51].
DCA has even reached clinical trials as a treatment for congestive heart failure, although it has
shown mixed results thus far [52,53]. Due to the overlapping metabolic profiles of cardiovascular
disorders and cancer, interest in DCA as a potential therapeutic approach in cancer was quickly
ignited. Within a short period of time, DCA progressed to Phase II clinical trials in patients with
metastatic breast cancer and non-small cell lung cancer (NSCLC) [54]. However, two patients
died during the treatment period [54]. These negative clinical outcomes could be due to the
late stage of cancer or could be explained by the fact that cancer cells utilize both aerobic

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Figure 3. Metabolic Crossroads between Cancer and Cardiovascular Diseases.

Pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) via dichloroacetate (DCA) causes an increase
in the activity of the pyruvate dehydrogenase complex (PDC). PDC is composed of three parts: pyruvate
dehydrogenase, which releases CO2 from pyruvate; dihydrolipoyl transacetylase, which produces acetyl-CoA
from CoA-SH; and dihydrolipoyl dehydrogenase, which converts NAD+ to NADH. The acetyl-CoA produced
from pyruvate, then enters the TCA cycle. Subsequently, NADH generated from the TCA cycle leads to
increased oxidative phosphorylation (OXPHOS). Cancers (pink circle) also exhibit aerobic glycolysis in addition
to OXPHOS. Metabolites are shown in purple. Enzymes are shown in black.

glycolysis and OXPHOS [43] to support their growth. Therefore, pharmacologically promoted meta-
bolism through OXPHOS, a feature still present in cancer cell metabolism, may not be a good
approach (Figure 3). Thus, while the approach of using DCA as a possible cancer therapy initially
appeared promising, researchers must remain extremely cautious when translating pharmacolog-
ical approaches from one disease to another.

Glutamine Metabolism: The Driving Engine of Neurological Diseases Also

Provides the Building Blocks of Cancer
While glutamine catabolism provides cancers with a source of nitrogen for protein and nucleotide
synthesis as well as the carbon skeleton for TCA cycle components [55], elevated levels of glutamate,
the immediate catabolic product of glutamine, have been shown to have neurodegenerative
properties in the human brain [56]. The dependency of cancer cells on glutamine (also called
‘glutamine addiction’ [20]) has become one of the most promising therapeutic targets in recent years
[10]. One of the explanations for the vital role of glutamine metabolism in cancer is to provide an
important fuel for the TCA cycle in cancers when glucose is sparse [43]. Similarly, neurological dis-
eases have shown a strong association with the upregulation of glutamine metabolism, with gluta-
mate having a neurodegenerative effect contributing to the onset and progression of Alzheimer’s
disease (AD) [57,58]. Glutamate-induced neuronal excitotoxicity has also been demonstrated to
contribute to the pathogenesis of a number of other neurological diseases, including ischemic stroke
and epilepsy [56].

The pathogenic overlap of neurological diseases and cancers not only offers new insights into the
shared aspects of glutamine metabolism underpinning these diseases, but also provides novel op-
portunities for future cancer therapy (Figure 4). Specifically, the action of glutamate through the N-
methyl-D-aspartate receptor (NMDAR), which is identified as an important contributor in the

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Figure 4. Glutamate Is a Metabolic Axis Connecting Several Diseases.

Glutamate metabolism is a common feature of cancers, neurological diseases, and hyperammonemic diseases.
Glutamate can be produced from g-aminobutyric acid (GABA) (green semicircle) through coupled
transamination of a-ketoglutarate (a-KG) via GABA transaminase. This reaction also produces succinate
semialdehyde (green arrow). Succinate semialdehyde can then be converted to succinate by succinic
semialdehyde dehydrogenase (SSADH), which can produce glutamate via the TCA cycle coupled with an a-KG-
linked aminotransferase such as aspartate aminotransferase (AAT/GOT) or through glutamate dehydrogenase
(GDH). Glutamate can also be produced through the hydrolysis of N-acetyl-aspartyl-glutamate (NAAG) (yellow
semicircle) catalyzed by glutamate carboxypeptidase II (GCPII) (brown arrow). NAAG can be produced from
glutamate and NAA via N-acetylaspartylglutamate synthetase A and B. NAA can be produced from aspartate
and acetyl-CoA through aspartate N-acetyltransferase. Glutamine (red full circle) also acts as an important
source of glutamate via direct conversion through glutaminase (GLS), or through the glutaminase II pathway
intermediates – a-ketoglutaramate (KGM) and a-KG – initially catalyzed by glutamine transaminases (e.g., GTK)
(red arrows). The N-methyl-D-aspartate receptor (NMDAR), shown in purple, is a receptor connected to cancer
and neurological diseases. Metabolites are shown in black. Diseases are shown in blue. Enzymes are shown in red.

pathogenesis of AD [59], has now garnered great interest for cancer therapy due to its role in promot-
ing cancer growth [60–62]. Inhibition of this receptor has led to decreased tumor growth in in vivo
models [61], suggesting NMDAR as a new target of glutamine metabolism for cancer therapy.

It is well known that the conversion of glutamine to glutamate and ammonia is upregulated in cancers
[20]. In other fields unrelated to cancer, a-ketoglutaramate (KGM), a direct product of glutamine
catabolized by glutamine transaminases [63] via the glutaminase II pathway, is a biomarker for primary
and secondary hyperammonemic diseases, such as hepatic encephalopathy and inborn errors of the
urea cycle [63]. While the pathogenic role for the glutaminase II pathway through KGM in the context
of hyperammonemic diseases has been developed over the past half-century, the relevancy of this
biochemical pathway was largely overlooked in the field of cancer metabolism. The study of these
two diseases has remained separated over the past few decades. Only one recent study has identified
the role of the glutaminase II pathway as a source of glutamate in cancer [64] (Figure 4). Importantly,
blocking the first step of the glutaminase II pathway, glutamine’s conversion to KGM, led to complete
inhibition of pancreatic tumorigenesis in vivo [64]. It turns out that the metabolic mechanisms under-
lying hyperammonemic diseases and cancers share some common metabolic characteristics. Thus,
the intersection between cancers and other diseases provides great potential opportunities to enrich
our understanding of the metabolism of cancer, as well-known metabolic reactions in one disease
could occur in the other.

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N-Acetyl-aspartyl-glutamate (NAAG) Metabolism: From Neuropeptide in

Neurological Diseases to a Glutamate Reservoir for Cancer
Previous studies of glutamine metabolism were confined to glutaminolysis, resulting in a somewhat
limited view of the vast metabolic network of tumors. Recent work has breached this boundary in
search of new sources of glutamate production beyond glutaminolysis [65]. Preliminary work had de-
tected NAAG, a peptide-based neurotransmitter found in the mammalian central nervous system
(CNS) [66], as an active metabolite in cancers. However, the specific mechanism of action of NAAG
in cancer remained unresolved [67]. By contrast, there is an abundance of literature documenting
the role of NAAG in the neurological system [66]. A recent study revealed a strong inverse association
between tumor or plasma NAAG concentration versus survival time in patients with brain tumors [65].
Since NAAG is a neurotransmitter/neuromodulator, there is the possibility that the source of this
neurotransmitter could be released by nerves in the tumor microenvironment [68,69]. To test whether
NAAG was produced by cancer cells, the authors used stable isotope-resolved metabolomics [70]
and observed abundant production of NAAG from 13C515N2-labeled glutamine especially in MYC-
ON compared with MYC-OFF lymphoma cancer cells grown in vitro, indicating endogenous forma-
tion of NAAG in cancer cells [65]. They further found significantly increased production of glutamine-
derived NAAG in higher-grade ovarian cancer in vivo. These findings indicated that the neurotrans-
mitter NAAG can be found in nonglial tumors. These findings led to further investigation into the spe-
cific role of NAAG in cancer [65]. Specifically, NAAG hydrolysis through glutamate carboxypeptidase
II (GCPII), a known enzymatic target in neurological diseases [71], was demonstrated to play a crucial
role in glutamate production in cancer [65]. This glutamate can then be catabolized to provide can-
cers with the carbon and nitrogen necessary to support elevated nucleotide and protein synthesis
[55]. Hence, the role of NAAG, the most abundant peptide-based neurotransmitter in the mammalian
CNS [66], in promoting cancer growth was discovered for the first time [65] (Figure 4). The glutamine
addiction phenomenon in cancer was established several years ago [20]. The hydrolysis of NAAG to
glutamate through GCPII, which was already well known in neurological diseases, might have been
discovered in cancer much earlier had metabolic overlap between cancers and other diseases
been more avidly pursued as a strategic approach. Hence, the GCPII inhibitor 2-phosphonomethyl
pentanedioic acid (2-PMPA), which was extensively investigated as a pharmacotherapeutic approach
for a number of neurological diseases including stroke, amyotrophic lateral sclerosis, and schizo-
phrenia [71,72], is now being investigated for cancer therapy [65,73]. Preclinical study of GCPII inhi-
bition through the pharmacological inhibitor 2-PMPA has shown success in decreasing tumor growth
in mice bearing patient-derived recurrent ovarian and pancreatic tumors [65]. Furthermore, combina-
tion therapy with GCPII and the current clinical trial glutaminase inhibitor 2-(pyridin-2-yl)-N-{5-[4-(6-
{2-[3-(trifluoromethoxy)phenyl]acetamido}pyridazin-3-yl)butyl]-1,3,4-thiadiazol-2-yl}acetamide (CB-
839), accentuated tumor reduction more than either treatment alone [65]. Of note, the oral form of
the GCPII inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), has passed a Phase I clinical
trial for other diseases [74]. Thus, 2-MPPA could potentially move into clinical trials for cancer therapy
quickly. The metabolic interplay between cancers and other diseases is an invaluable key to unlocking
new therapeutic opportunities for one disease from existing knowledge of another.

GABA Metabolism: From the Master Inhibitory Neurotransmitter to a

Succinate Precursor for Cancer
g-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian brain [75]
and is formed by decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD) (Fig-
ure 4). GABA is metabolized by transamination to form succinic semialdehyde. Succinic semialde-
hyde, in turn, is converted to succinate, an intermediate metabolite of the TCA cycle [76]. Due to
the prominent role of GABA as an inhibitory neurotransmitter, dysregulation of GABA metabolism
has been implicated in a large number of neurological diseases including epilepsy and schizophrenia
[77]. The role of GABA metabolism in neurological diseases, coupled with the biochemical role of
GABA as a precursor to succinate, prompted the exploration of the potential role of GABA in cancers.
The rapid rates of proliferation and reprogrammed metabolism of cancers readily necessitate the
additional source of carbon from the incorporation of succinate (derived from GABA) into the TCA
cycle [78] (Figure 4). Although GABA is present at only nano- or micromolar concentrations in the

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blood [79] and cerebrospinal fluid [80], it is surprising to see that GABA supplementation at low
micromolar concentrations was sufficient to increase cellular proliferation in HER2+ breast-to-brain
metastatic cancer cells [81]. Takehara et al. also demonstrated that GABA increases cancer cell
proliferation [82]. These findings are consistent with the notion that cancer cells may utilize these
alternative sources of metabolic precursors when access to the primary metabolic pathways
(e.g., glycolysis, glycogen breakdown, glutaminolysis) is limited. Furthermore, several studies found
elevated GABA and GAD levels in colon, breast, prostate, and gastric cancers and glioma [83]. The
metabolic role of GABA in cancers was demonstrated, as cancers have the ability to break down
GABA into succinate as a TCA intermediate for bioenergy metabolism [78,81,84]. The increased
GABA uptake in the progression of neurological disease and cancers has stimulated the uncovering
of a new, unexpected source of metabolic precursors in cancers and has provided a potential meta-
bolic target for the next generation of pharmacotherapeutic inhibitors.

From Obesity to Cancer: The Unexpected Ways Obesity Can Contribute to

Carcinogenesis
While the causative link between obesity and T2D or cardiovascular diseases is known, only recently
have epidemiological studies provided ample evidence to demonstrate an association between
obesity and the risk of developing a number of cancers, including colorectal, breast, endometrial, kid-
ney, esophageal, liver, bladder, pancreatic, thyroid, and liver cancers [85,86]. Specifically, a study by
Calle et al. revealed that 14.2% of cancer deaths in men and 19.8% in women can be attributed directly
to obesity [86].

One of the main characteristics of obesity is the presence of high levels of adipose tissue [87]. Inter-
estingly, studies have demonstrated the collaborative role of adipocytes in helping cancer cell growth
[88,89]. Excess lipogenesis and decreased fatty oxidation could lead to hepatic steatosis as a conse-
quence of surpassing the normal storage capacity of the liver. Steatosis eventually leads to liver dam-
age and often to hepatocellular carcinoma at later stages. Moreover, a growing number of studies
have demonstrated obesity to contribute directly to insulin resistance [90,91] through the harmful
secretion of triglycerides, leptin, resistin, cytokines, and free fatty acids from adipose tissues. Chronic
insulin resistance, and consequently prolonged exposure to a high-glucose environment, can lead to
oncogenic alterations as discussed in the section on T2D. In addition, a study by Yu et al. demon-
strated hyperglycemia to induce mitochondrial dysfunction and promote reactive oxygen species
(ROS) accumulation [92]. ROS accumulation, in turn, can directly promote cellular damage and
thereby drive the formation of malignant phenotypes through redox-sensitive transcription factors,
DNA mutations, and epigenetic changes [93]. Changes in redox homeostasis result in not only the
activation of a number of known oncogenes, such as Ras, Bcr-Abl, and c-MYC, but also the promotion
of the PI3K/Akt and MAPK/ERK pathways involved in cell proliferation [94]. Hence, the ability of
metabolic perturbation to induce genetic and epigenetic changes is an underlying mechanistic link
between obesity and cancer (Figure 5). The metabolic mechanisms of obesity and cancer are funda-
mentally intertwined and the development of a better understanding of this association may provide
new insights into the etiology of cancer.

From Aging to Cancer: Why Does the Risk of Developing Cancer Increase with
Age?
Is it because our genes change over time or due to changes in our lifestyle, diet, and metabolism? To
distinguish between the environmentally driven and genetically driven effects observed with aging,
Vinuela et al. assessed the RNA sequence of several types of samples from 855 human adult female
twins [95]. They identified over 100 genes with age-related changes in variance and around 40 genes
with age-related discordance between co-twins, implying that the latter were driven by environ-
mental effects [95]. The way we live our lives over time can affect metabolic pathways and ROS pro-
duction, which in turn can regulate immune responses, epigenetic control, and DNA repair (Figure 5).

Metabolism slowing down with age is arguably the most universal contributor to metabolic changes,
including T2D, which in turn increase risk factors for cancer [96] (Figure 5). However, the discoveries of

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Figure 5. Alterations in Metabolism Associated with Obesity and Aging Could Lead to Cancer.
Metabolism is depicted directionally from young and healthy (upper) to obese (lower left) and aged (lower right).
Metabolism decrease in older adults is commonly accompanied by an increase in reactive oxygen species (ROS).
Accumulation of ROS over time, a common feature of aging and obesity, can lead to oncogenic mutations,
epigenetic changes, and mitochondrial dysfunction via HIF-1a stabilization, subsequently increasing the risk of
cancer. Acetyl-CoA, a product of glucose, is involved in histone acetylation. Methylation and histone acetylation
are epigenetic changes. Decreased activity of AMP-activated protein kinase (AMPK) with age facilitates cancer
cell proliferation and promotes lipid production, through increased activity of acetyl-CoA carboxylase and
HMG-CoA reductase. ROS-related metabolites, such as superoxide, hydrogen peroxide, and hydroxyl radicals,
are shown in red. Metabolic precursors for epigenetic changes are shown in purple. Enzymes are shown in blue.

gene mutations causing cancer should not overshadow other consequences of metabolic distur-
bances. The formation of cancer involves not only alterations in genetics (oncogene, tumor suppres-
sor activation or deactivation) but also epigenetics (e.g., alterations in DNA methylation, histone
modifications) accompanied by chromosomal instability and DNA repair deficiency. Age can also
lead to dysregulated hepatic gluconeogenesis, adipose lipogenesis, and defective glycogen synthe-
sis and glucose uptake in muscle. The accumulation of cofactors, byproducts, and proteins plays a
crucial role in post-translational modifications [97]. These factors can lead to changes in epigenetic
regulation, which form the basis for a potential causational link between aging and cancer. In addition
to the increase in the acquisition of somatic nuclear mutations as aging progresses [98], the meta-
bolism also changes dramatically with age. Key metabolic proteins such as the mechanistic target
of rapamycin (mTOR) [99] and the insulin-like growth factor (IGF)-I and -II were found to be upregu-
lated in cancer [100], while AMP-activated protein kinase (AMPK) was found to be downregulated in
cancer [101]. Since AMPK activation is a negative regulator of cell proliferation and lipid synthesis, its
lack of activation facilitates tumor growth and enables lipid production [97]. Specifically, AMPK acti-
vation leads to phosphorylation and inhibition of the essential enzymes acetyl-CoA carboxylase and
HMG-CoA reductase involved in lipid production [102,103]. Therefore, metabolism is believed to be a
main link between aging and cancer risk.

In 2005, Douglas Wallace hypothesized that mitochondrial dysfunction plays a central role in various
forms of cancer [104], which echoed Otto Warburg’s suggestion from 50 years prior that mitochon-
drial dysfunction is the origin of cancer [1,2]. Wallace proposed that the accumulation of somatic mu-
tations in mitochondrial DNA (mtDNA) with age would lead to the dysfunction of energy homeostasis

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and consequently to an increase in ROS. Increased ROS, in turn, increases the oxidation of ferrous
Outstanding Questions
ions which consequently inactivates prolyl hydroxylases (PHDs), as oxidation of ferrous ions is essen-
What strategy should we use to
tial for this catalytic mechanism. The inactivation of PHDs leads to HIF-1a stabilization, thereby upre-
screen the possible metabolic
gulating glycolysis and decreasing mitochondrial respiration [105]. Stemming from this vicious cycle
overlaps between cancer and other
of increased ROS and mitochondrial dysfunction, several researchers have proposed the free radical diseases more effectively for thera-
theory of aging and cancer [106,107]. Is the increased risk of cancer with increased age, which is peutic potential?
accompanied by evidence of increased oxidative stress, a causative or correlative relationship? While
ROS are endogenous products of normal metabolic processes (predominantly occurring in the mito- Would applying knowledge from
other diseases to cancer sooner
chondria), excess accumulation over time can lead to protein and DNA damage, which is a precon-
have resulted in more effective
dition for the development of cancer and other age-related diseases. While cancer cells have the abil-
therapeutic approaches for cancer?
ity to deal with ROS accumulation [19,108,109], most experts accept that the free radicals produced
during aging remain one of the causes, or at least a facilitator, of cancer [107]. Metabolite intermedi- Why are there very few studies thus
ates and ROS can act as second messengers regulating signaling pathways and genetic and epige- far examining the metabolic over-
netic mechanisms and form the foundation for cancer development. For example, compounds lap between cancer and other
diseases?
directly essential to the function of epigenetic enzymes are produced during metabolism, such as
S-adenosylmethionine (SAM, which is the product of methionine and ATP via methionine adenosyl- Why have well-established biochem-
transferase, Figure 5) for methylation. Researchers have established that there is an epigenetic drift to ical pathways in other diseases been
indicate the methylation changes in aging [110]. Another link between metabolism and epigenetics is largely overlooked in the field of can-
through acetyl-CoA. Acetyl-CoA regulates histone acetylation. Acetyl-CoA itself is regulated by cer metabolism?
glucose availability. Glucose availability also affects O-GlcNAcylation, which requires UDP-GlcNAc
as a donor substrate, a product of the hexosamine biosynthesis pathway that uses 2-5% of imported
glucose. O-GlcNAcylation is found to be upregulated in cancer [111] and is often used as a tumor
grade and prognostic marker [112].

Another aspect to consider in the metabolism of aging is provided by Goodrick et al. and others, who
have discovered that calorie restriction together with a steady sleep and circadian cycle resulted in
health benefits, lifespan extension, reduced inflammation, and reduced cancer in rodent models
[113,114]. Excess or lack of metabolites and substrates from nutrient uptake can disrupt the energy
balance, as reflected by the ATP:AMP or NAD+:NADH ratio, and compromise cellular function and
biological systems as a whole [115]. Mitochondria, the factories for respiratory energy production,
are also major sources of ROS production and the common place for multiple metabolic pathway in-
tersections. Thus, the continued uncovering of new metabolic pathways in a wide range of different
diseases yields new opportunities for sharing knowledge between cancer and other fields.

Concluding Remarks
Although recent studies in cancer metabolism have shown that metabolic aspects from other dis-
eases can readily occur in tumors, there remain a number of unresolved questions (see Outstanding
Questions). The converging metabolic profiles of other diseases and cancer may therefore be a key to
unlocking new therapeutic insights for the treatment of cancer. Metabolite intermediates, and other
products of metabolic processes such as ROS, hold the ability to directly influence cancer initiation
and progression by damaging cellular genetic and epigenetic processes. Thus, aberrant metabolism
itself can trigger carcinogenesis and maintain cancer growth. This can thereby form a vicious cycle in
which metabolic perturbations can promote the acquisition of one disease, which in turn can increase
the risk of the generation of another disease. Despite these challenges, given the new interest and
knowledge in the study of cancer metabolism, the opportunity to utilize existing knowledge to
combine with recent findings provides a bright future for cancer therapy.

Acknowledgments
This review article was made possible by the members and alumni of the Le Cancer Metabolism
Research Laboratory (http://pathology.jhu.edu/lelab/index.cfm). We thank Dr. Arthur Cooper for
his helpful editing and scientific expertise. This work was supported by National Institutes of Health
(NIH) grants R01-CA193895, R01-CA112314, 1S10OD025226-01, and UL1 TR001079, the Hopkins-Al-
legheny Health Network Cancer Research Fund, and the Doris M. Weinstein Pancreatic Cancer
Research Fund. Special thanks to Michel Soudée for his helpful editing.

818 Trends in Cancer, December 2019, Vol. 5, No. 12

Trends in Cancer
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