Link Diabetes Cancer

C GARCÍA-JIMÉNEZ and others High glucose amplifies WNT 52:1 R51–R66
Review signaling in cancer
A new link between diabetes and

cancer: enhanced WNT/b-catenin
signaling by high glucose
Custodia Garcı́a-Jiménez, Jose Manuel Garcı́a-Martı́nez, Ana Chocarro-Calvo and

Antonio De la Vieja1
Correspondence
Departamento de Fisiologı́a y Bioquı́mica, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, should be addressed
28922 Alcorcon, Madrid, Spain to C Garcı́a-Jiménez
1
Unidad Funcional de Investigación en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Email
28220 Majadahonda, Madrid, Spain [email protected]
Abstract
Journal of Molecular Endocrinology
Extensive epidemiological studies suggest that the diabetic population is at higher risk of Key Words
site-specific cancers. The diabetes–cancer link has been hypothesized to rely on various " WNT
hormonal (insulin, IGF1, adipokines), immunological (inflammation), or metabolic " b-catenin
(hyperglycemia) characteristics of the disease and even on certain treatments. Inflammation " insulin
may have an important but incompletely understood role. As a growth factor, insulin directly, " diabetes
or indirectly through IGF1, has been considered the major link between diabetes and cancer, " glucose-dependent
while high glucose has been considered as a subordinate cause. Here we discuss the evidence insulinotropic peptide
that supports a role for insulin/IGF1 in general in cancer, and the mechanism by which " incretin
hyperglycemia may enhance the appearance, growth and survival of diabetes-associated " transcription
cancers. High glucose triggers several direct and indirect mechanisms that cooperate to " signaling
promote cancer cell proliferation, migration, invasion and immunological escape. In particular, " cancer
high glucose enhancement of WNT/b-catenin signaling in cancer cells promotes proliferation,

survival and senescence bypass, and represents a previously unrecognized direct mechanism
linking diabetes-associated hyperglycemia to cancer. Increased glucose uptake is a hallmark of
tumor cells and may ensure enhanced WNT signaling for continuous proliferation.
Mechanistically, high glucose unbalances acetylation through increased p300 acetyl transferase
and decreased sirtuin 1 deacetylase activity, leading to b-catenin acetylation at lysine K354, a
requirement for nuclear accumulation and transcriptional activation of WNT-target genes. The
impact of high glucose on b-catenin illustrates the remodeling of cancer-associated signaling
pathways by metabolites. Metabolic remodeling of cancer-associated signaling will receive
much research attention in the coming years. Future epidemiological studies may be guided
and complemented by the identification of these metabolic interplays. Together, these studies
Journal of Molecular
should lead to the development of new preventive strategies for diabetes-associated cancers. Endocrinology
(2014) 52, R51–R66
Introduction
Extensive epidemiological studies have revealed that the (Shikata et al. 2013). Increased cancer risk in the diabetic
diabetic population is at higher risk of suffering cancers population may be attributed to treatment for diabetes, to
of the liver, pancreas, endometrium, colon and others hormonal disorders, to the status of chronic inflammation
http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

DOI: 10.1530/JME-13-0152 Printed in Great Britain
Review C GARCÍA-JIMÉNEZ and others High glucose amplifies WNT 52:1 R52
signaling in cancer
and to metabolic alterations underlying the diseases associated increase in insulin-like growth factor 1 (IGF1)
(summarized in Fig. 1). Moreover, diabetes may also signaling. Hyperinsulinemia may arise in type 1 diabetes
develop following tumor establishment in certain pan- (T1D) from exogenous injection due to treatment, and in
creatic and liver cancers that progress very rapidly (Li et al. type 2 diabetes (T2D) it develops early in the disease as a
2012; Fig. 1, please note the double headed arrow physiological response to lower the increasingly high
representing the bidirectionality of the link). As, to our glucose levels in the blood. The mechanisms whereby
knowledge, there are very few studies that analyze this hyperinsulinemia could link diabetes and cancer have
point separately, we do not explore it in this review. The been extensively reviewed, and are thought to be mediated
impact of antidiabetic treatments on cancer risk is mainly by increased bioavailability of IGF1 (Novosyadlyy
discussed elsewhere (Bowker et al. 2006, Jonasson et al. & LeRoith 2010, Djiogue et al. 2013). However, recent
2009, Dowling et al. 2012, Bosetti et al. 2013). epidemiological studies demonstrate that circulating IGF1
The major hormonal disorders in diabetes are un- levels do not correlate with tumor progression and report
balanced adipokine secretion, reviewed in Khandekar et al. no relationship between IGF1 or IGF-binding protein levels
(2011), and most important hyperinsulinemia and the and cancer risk (Kaplan et al. 2012).
Diabetes Cancer
Treatments
Other associated factors
(not analyzed in this review)
Hormonal disorders Inflammation Metabolic alterations
Insulin/IGF-1 Adipokines TNFα IL-6 Others ROS Hyper- Others

glycaemia
(see
figure 3)
Proliferation
Cancer Invasion &

Survival
Hallmarks migration
DNA
mutations
Figure 1
Links between diabetes and cancer. Diabetes and cancer are linked by a inflammatory state and increased proliferation; iii) chronic inflammation
double headed arrow because the frequency of certain cancers is increased characterized by increased circulating levels of tumor necrosis factor a
in the diabetic population and conversely certain cancer patients develop (TNFa), interleukin 6 (IL6), and others which have been described to
diabetes (see the text). The diagram shows a summary of mechanisms that underlie the diabetic state; iv) metabolic disturbances are represented
may contribute to increased cancer risk in the diabetic population, that is mainly by hyperglycemia and accumulation of reactive oxygen species
i) some treatments which are not discussed in this review; ii) hormonal (ROS), both of which may induce secretion of proinflammatory cytokines
disorders such as increased circulating levels of insulin (endogenous or and hormonal disorders, such as increased insulin secretion, and therefore
exogenous), and subsequent increase in insulin-like growth factor 1 (IGF1) both lead to increased proliferation and mutations. The effects of
signaling. Altered balances of some adipokines may also contribute to an hyperglycemia are detailed in Fig. 3. For other details, see the text.

signaling in cancer
Another aspect of the pathophysiology of diabetes and considered as an adaptation or a consequence of such
cancer is a shared status of chronic inflammatory signaling mutations. As such, a number of oncogenes including RAS
leading to insulin resistance (Grivennikov et al. 2010, and MYC have been shown to alter the expression of many
Hummasti & Hotamisligil 2010, Nakagawa & Maeda genes encoding metabolic enzymes critical for glycolysis,
2012). Inflammatory cytokines signal through the mito- OXPHOS, etc. (Pylayeva-Gupta et al. 2011). Although
gen-associated protein kinase: MAPK or JAK/STAT this is undisputable, metabolic stress may also drive the
pathways, and contribute to cancer biology through acquisition of mutations for cancer promotion
increased proliferation, survival, accumulation of (Martinez-Outschoorn et al. 2013). Metabolic stress may
mutations (Hoffmann & Baltimore 2006, Parameswaran be caused by excess nutrients (Wellen & Thompson 2010) –
& Patial 2010), and suppression of host antitumor like hyperglycemia – in cells that are able to take them up
immunity (Yu et al. 2009). However, although it seems but are incapable of storing them (the vast majority of our
clear that inflammatory cytokines play an important role cells). In this respect, circulating levels of insulin or IGF1
in tumor growth and invasion, the inflammatory response will allow glucose uptake without the need for
may also have antitumor activity (Allavena & Mantovani mutations. In this review, we provide an overview of the
2012, Haabeth et al. 2012). More studies are needed to mechanisms that may link hyperglycemia to cancer with
clarify the contribution of the inflammatory response. a special focus on those related to remodeling cancer-
Diabetes-associated metabolic alterations such as associated cell signaling.
increased circulating levels of lipids and sugar represent
another link with cancer. Lipid metabolism and signaling
might play an important, though still incompletely

Hyperglycemia may feed cancer cells:
understood, role in cancer which has been recently
the sweet kiss of death
covered by Natter & Kohlwein (2013). The analysis of
the influence of lipids on diabetes-associated cancers is Over the last century, cancer patients have been reported
beyond the scope of this review. Hyperglycemia is the best to exhibit signs of early glucose intolerance and insulin
characterized metabolic alteration in all types of diabetes, insensitivity, most likely as a result of an acute phase
and we discuss in this review the evidence and molecular inflammatory response induced by the tumor (Marat et al.
mechanisms that may associate hyperglycemia with 1999, Klement & Kammerer 2011). On the other hand,
cancer (Giovannucci et al. 2010, Wang et al. 2013). enhanced glucose uptake is a well-known metabolic
Hyperglycemia links diabetes and cancer indirectly hallmark of cancer cells. Hyperglycemia could therefore
through the induction of increased circulating levels of ensure a high glucose supply for cancer cells favoring
growth factors (insulin/IGF1) and inflammatory cyto- anabolic cancer metabolism to fuel tumor growth and
kines, but hyperglycemia also acts directly upon tumor thereby explain the increased cancer risk associated with
cells. Among the direct actions on cancer cells, a relatively diabetes. Thus the relationship between hyperglycemia
unexplored aspect is the influence of high glucose levels and cancer appears bidirectional: cancer can cause
on cancer signaling. In this context, high glucose has been hyperglycemia, and hyperglycemia may facilitate cancer
shown to be essential for WNT/b-catenin signaling, a key appearance and growth.
cancer-associated pathway (Anagnostou & Shepherd Increased glucose flux and metabolism, maintained by
2008, Chocarro-Calvo et al. 2013). As such, amplified angiogenesis, promotes cell cycle progression, excessive
WNT/b-catenin signaling represents a previously unrecog- proliferation, and anti-apoptotic signaling in cancer cells.
nized link that may contribute to the higher frequencies of In vitro, in tumor cell lines from several organs (breast,
cancer in the diabetic population. Other examples of colon, others), diabetogenic glucose concentrations alter
metabolic remodeling of cancer-related signaling are the expression of genes that promote cell proliferation,
illustrated by enhanced MAPK and AKT cancer-related migration, and adhesion (Masur et al. 2011). In vivo, in
signaling through increased production of reactive oxygen tumor-bearing animals, blood glucose levels strongly
species (ROS) via increased oxidative phosphorylation correlate with tumor growth. Certain experimental cancers
(OXPHOS) (Ray et al. 2012). behave more aggressively when animals overeat, and less
Mutations toward constitutive oncogene activation or aggressively when animals are calorically restricted (Algire
loss of tumor suppressors have been viewed as initiating et al. 2008, Kalaany & Sabatini 2009, Park et al. 2010),
steps in cancer promotion (Hsu & Sabatini 2008, Jones & providing evidence that diet may influence neoplasia
Thompson 2009), while metabolic changes have been (Pollak 2009). Indeed, animals fed a calorie-restricted diet

signaling in cancer
show a strong reduction in plasma glucose levels and In vitro, activation of the receptors for insulin or IGF1 (IR
prolonged survival (Santisteban et al. 1985). and IGF1R respectively) increases proliferation and blocks
In humans, high sugar intake and elevated blood apoptosis. This, together with the observation that cancer
glucose levels are associated with increased cancer risk, cells over express IRs and IGF1Rs supports the idea that
with hyperglycemia being a predictor of poor survival insulin and IGF1 are important drivers of cancer cell
(Krone & Ely 2005, Derr et al. 2009). In large cohort growth. However these receptors appear to be over
studies, hyperglycemia is positively correlated to an expressed in most solid and hematopoeitic tumors and
increased risk of developing cancers associated with the are not specifically increased in those cancers associated
gastrointestinal tract (Jee et al. 2005, Stattin et al. 2007, with diabetes (Belfiore et al. 2009, Gallagher & LeRoith
Ikeda et al. 2009). A diet which repeatedly elevates blood 2011). Furthermore, targeting IGF1R with different
glucose levels due to a high glycemic load has been inhibitors has been helpful only in small subsets of
suggested to provide additional growth stimuli for patients, reviewed in Chen & Sharon (2013), although
neoplastic cells (Mulholland et al. 2008, Masur et al. 2011). the failure of the treatment could be attributed in some
Increased demands for glucose by cancer cells and the cases to constitutive activation of the pathway. On the
positive correlation between cancer risk and hyperglyce- other hand, increased circulating levels of insulin or IGF1
mia, as in T1D and T2D, may not be a coincidence. Thus, have been reported in prostate cancer (Hellawell et al.
hyperglycemia should not be neglected as a potential 2002, Rowlands et al. 2012). Nevertheless, prostate cancer
underlying factor facilitating cancer growth and/or is less frequent in the diabetic than in the nondiabetic
establishment. population (Kasper & Giovannucci 2006). Moreover, some
authors have reported decreased tumor growth after

insulin treatment in diabetic animals (Fisher et al. 1995)
Hyperglycemia vs hyperinsulinemia as
or the successful treatment of some patients with
a cancer–diabetes link
metastatic tumors by an insulin-induced hypoglycemic
Although impaired glucose tolerance, without diabetes, is coma (Koroljow 1962). Some authors even propose
associated with increased cancer risk (Dankner et al. 2007), that insulin may help in antitumoral treatment by
hyperglycemia inexorably induces increased insulin increasing membrane permeability to other drugs
secretion unless there is a defect in insulin production (Lasalvia-Prisco et al. 2004).
or secretion. Hyperinsulinemia develops early in T2D In contrast, high glycemic index or high glycemic load
patients in response to hyperglycemia and may also be does correlate with the site-specific cancers associated with
present in T1D patients after exogenous injection of diabetes (Gnagnarella et al. 2008, Mulholland et al. 2009).
insulin. As insulin acts as a growth factor, hyperglycemia Cancer cells upregulate glucose transporters (GLUTs)
has been classically considered as a subordinate and independently of insulin (Pollak 2008, Szablewski 2013),
hyperinsulinemia as the primary causative factors for although insulin may further increase the exhibition of
cancer (Giovannucci 2001). Early attempts to clarify this glucose transporter GLUT1 and glucose uptake with it in
point showed that tumor growth was retarded in animals some cells (Cifuentes et al. 2011). The importance of high
with T1D (Heuson & Legros 1972), suggesting that tumor glucose for cancer growth and survival is supported by
growth relies on insulin and not on high glucose. results obtained after glucose starvation. Malignant cells
However, the autoimmune nature of T1D may complicate in vitro quickly lose ATP when starved of glucose
the interpretation of this result, because the immune (Demetrakopoulos et al. 1978, Priebe et al. 2011). Glucose
system plays a pivotal role in cancer cell surveillance starved cells commit apoptosis after toxic accumulation of
(Allavena & Mantovani 2012, Haabeth et al. 2012). In vitro ROS that results from a positive feedback loop including
studies also showed that adding insulin to the medium increased tyrosine kinase signaling (Graham et al. 2012). In
containing high glucose promoted the sequential acti- animals bearing tumors (Zhou et al. 2007), and in human
vation of PI3K, AKT, and mTOR leading to the increased patients (Seyfried et al. 2009), lowering blood glucose with
anabolic activity in cancer cells and subsequent 20–40% ketogenic diets to force mitochondrial use of ketones as
enhanced proliferation rates (Klement & Kammerer 2011, energy sources restricts the amount of glucose available to
Ward & Thompson 2012). However, in these experiments, cancer cells and improves or prolongs survival. Moreover,
the effects of hyperinsulinemia and hyperglycemia could treatment with metformin, which decreases hepatic gluco-
not be disentangled as both were present and the neogenesis and reduces glucose release to the blood, impro-
tissue culture medium contained high levels of glucose. ves cancer outcome (El-Mir et al. 2000, Dowling et al. 2012).

signaling in cancer
However, metformin also has direct actions on cancer glycolysis as a mechanism to maximize the accumulation
cells, some of them through induction of the metabolic of anabolic intermediaries required to sustain proliferation
sensor AMPK (Dowling et al. 2012, Hardie 2013). (Lunt & Vander Heiden 2011, MacIver et al. 2013).
Better-controlled experiments might help evaluate the An increase in glucose availability that is not contested
relative importance of insulin and glucose. For example, by storage or the Warburg effect will generally speed up the
tumor appearance and growth may be tested in animals metabolism, including OXPHOS. This leads to an increase
with hyperglycemia induced in the absence of hyperin- in ROS production, through the mitochondrial respiratory
sulinemia or inflammation. In this respect, it is interesting complexes (Balaban et al. 2005) that results in increased
to highlight that association of T1D with the diabetes- DNA damage and cell death (Wellen & Thompson 2010).
specific cancers is stronger than in T2D, even though Cancer cells increase their glucose uptake and utilization
hyperinsulinemia may play a more prominent role in T2D but keep a reduced OXPHOS rate. Increasing glycolysis
(Garcı́a-Jiménez et al., manuscript in preparation). flux allows enhanced uptake of carbon sources and
Nevertheless, if exogenous administration of insulin in accumulation of anabolic intermediaries. Decreasing
T1D is associated with cancers, it should be considered OXPHOS flux declines ROS production which leads to
among the cancers associated with treatments for diabetes increased cell survival and contributes to sustain
which appear to be even more site-restricted, for example pluripotency. Potential mechanisms to decrease ROS in
to the bladder, kidney, and breast, but not to gastrointes- cancer cells and maintain pluripotency are discussed in the
tinal tumors which are more strongly linked to T1D. next section on ‘mechanisms for hyperglycemia increased
cancer’. Nevertheless, cancer cells do not completely
switch off OXPHOS. The enzymatic machinery is only

Hyperglycemia contributes to the abnormal
less efficient due to differential expression of specific
glucose metabolism in cancer cells
enzymatic variants (Balaban et al. 2005).
Cancer cells originate from noncancer cells and exhibit The apparent paradox that a cancer cell with high
very distinctive metabolic hallmarks (Hanahan & energy demands switches toward glycolysis may be
Weinberg 2011). Senescence and apoptosis bypass coupled interpreted as the adaptation of tumor cells to supply
to higher proliferation rates and migratory capacity must the anabolic intermediates required for rapid proli-
be fed. Enhanced angiogenesis in response to factors feration. Therefore, the poor energetic pay off of glycolysis
secreted by the tumor drives the genesis of new blood needs to be compensated by a high glucose supply from
vessels that increase the supply of energetic substrates and angiogenesis-derived new blood vessels, high glucose
building blocks needed to make new cells. Proliferative uptake through the upregulation of GLUTs, and increased
and resting cells differ more in their demands for anabolic glycolytic flux through changes in critical enzymes
substrates than in their ATP requirements (Locasale & (summarized in Fig. 2).
Cantley 2011, Chocarro-Calvo et al. 2013). However, the To keep pace with the increased demand for energy
anabolic urge of tumor cells drives them to adapt with and anabolic intermediates, glucose uptake is enhanced in
profound metabolic changes, among which the most cancer cells independently of insulin. This is exploited in
remarkable is the switch from OXPHOS toward aerobic clinical practice to detect residual tumor activity after
glycolysis, known since 1956 as the ‘Warburg effect’ after surgery through [18F]fluorodeoxyglucose positron emission
its discoverer, the Nobel prize-winner Otto Warburg. tomography (FDG-PeT).
Glycolysis maximizes the production of building blocks GLUTs, and especially GLUT1 whose expression is
at the cost of diminished energy production compared insulin-independent, are upregulated in many cancer cells
with OXPHOS. Through glycolysis, cancer cells convert (Tennant et al. 2009). GLUTs expression is upregulated by
each mole of glucose into 2 mol pyruvate obtaining 2 mol oncogenes such as RAS, hypoxia (via increased activity of
ATP. Via OXPHOS, 36 mol ATP are obtained from each the hypoxia inducible factor transcription regulator,
mole of glucose. The advantage of glycolytic metabolism is HIF1a), accumulation of ROS, and other factors charac-
the production of glycolytic intermediaries that can be teristic of tumor cells (Cushman & Wardzala 1980, Suzuki
used in anabolic pathways that allow synthesis of proteins, & Kono 1980). Additionally, HIF1a cooperates with
nucleic acids, and lipids needed for proliferation. activated AKT, downstream of PI3K signaling, to enhance
Although the Warburg effect was initially observed in the expression of critical glycolytic enzymes (see Fig. 2)
rapidly proliferating cancer cells, normal liver cells and such as hexokinase (HK), phospho fructo kinase isoform B
highly proliferative T lymphocytes also exhibit increased (PFKB) (Deprez et al. 1997, Majewski et al. 2004) and lactate

signaling in cancer
Glucose
In cancer cells:
Glucose
HK Upregulated
G6P
F6P
Nucleotide
PFK Isoform B,
F1,6P
Glycolysis
upregulated
GADP/
Biosynthesis
DHAP NAD+
NADH
Lipid
3PG
Amino acids
PKM1 Expression of
Pyruvate isoform M2
NADH
LDH Upregulated
NADH OAA NAD+
Acetyl-
TCA cycle
Malate Lactate
CoA
Citrate Cytoplasm
FADH2
NADH NADH Nucleus

ATP
αKG
Figure 2
Gluco-addiction and recycling of glucose into macromolecules to feed fulfill the increasing demands of proliferating cancer cells which adapt
proliferation. Of the metabolic adaptations of cancer cells the most through upregulation of several critical enzymes such as hexokinase (HK),
remarkable are the increased glycolytic and decreased oxidative phospho fructo kinase isoform B (PFKB), and lactate dehydrogenase (LDH)
phosphorylation (OXPHOS) rates. Although other substrates such as which regenerates the NADC to be used in the next glycolysis cycle and
glutamine provide a source of nitrogen and carbon, glucose is the main through the expression of characteristic isoform of others like pyruvate
carbon source and as such uptake of glucose is enhanced by several kinase, isoform M2 (PKM2) that facilitates the use of glycolytic
adaptations. When glucose enters glycolysis, it renders ATP (blue cylinders), intermediates in various anabolic pathways. For other details, see the text.
redox power (NADH), and, most important for highly proliferating cells, AA, amino acid; aKG, a-ketoglutarate; DHAP, dihydroxyacetone
anabolic intermediaries (black dots) ready to use as precursors to synthesize phosphate; F1,6P, fructose-1,6-biphosphate; F6P, fructose-6-phosphate;
nucleotides (red boxes), amino acids (green boxes), and lipids (purple G6P, glucose-6-phosphate; GADP, glyceraldehyde-3-phosphate;
boxes), which are the building blocks for nucleic acids, proteins, and OAA, oxaloacetate; 3PG, 3-phosphoglycerate.
membranes during proliferation. Increased glycolytic flux is necessary to
dehydrogenase (LDH). LDH reduces pyruvate to lactate Effects of hyperglycemia at the level
and regenerates NADC. Lactate fuels hepatic gluconeo- of the organism and their impact on
genesis and NADC regeneration is critical for continued cancer development
flux through glycolysis as well as for the deacetylase
Hyperglycemia may increase cancer through several
activity of sirtuins that are critically involved in cancer
cooperative mechanisms, summarized in Fig. 3. We have
and longevity. Other glycolytic steps differ in cancer cells
due to differential expression of enzyme isoforms. For divided the effects of hyperglycemia on cancer as ‘direct’
example, the M2 isoform of pyruvate kinase (PKM2) when the effect is exerted directly on tumor cells and
expressed in cancer cells facilitates diversion of glycolytic ‘indirect’ when the action takes place at other organs that
intermediates into biosynthetic pathways in contrast will later on influence tumor cells. Indirect mechanisms
with the isoform PKM1, expressed in noncancer cells include the induction of i) increased circulating levels of
(Hamanaka & Chandel 2012). insulin and bioavailability of IGF1, ii) increased secretion

signaling in cancer
Hyperglycemia
Direct effects Indirect effects

(at tumor site) (through soluble factors)
WNT/ Cell Insulin/ Inflammatory

↑
↑ GF
↑ROS ↑attractant
Chemo- ↑β-catenin cycle ↑ IGF1 ↑ cytokines
Ascorbic
transport
signaling ↑
(e.g. EGFR) ROS (e.g. GDNF) immune
(see figure 5) function
(see figure 1)
Decreased
↑ Proliferation immunological
surveillance
Invasion and Cancer
↑ migration hallmarks ↑ Survival
DNA
↑ mutations
Figure 3
The many mechanisms by which hyperglycemia may feed cancer cells. antisenescence and invasion. The mechanisms used for high glucose to
Hyperglycemia may have direct effects on the tumor site, or indirect effects enhance this pathway are summarized in Fig. 5. Indirect effects of
through soluble factors. Direct effects promote: i) increased growth factor hyperglycemia on cancer cells are mediated through i) increased levels of
signaling (GF) and accelerated cell cycle. ii) An initial accumulation of ROS insulin/IGF1 and/or ii) inflammatory cytokines as well as iii) a diminished
enhances mutagenesis and leads to the secondary selection of clones with immunological surveillance. The reduced immune response is achieved
diminished ROS production to ensure survival. Alternatively, some cancer through the reduction in ascorbic acid transport in critical immune cells
cells also export ROS to neighboring cells to ensure their own survival (see that diminishes their phagocytic and proliferation capabilities. Both direct
the main text). iii) The upregulation of chemo-attractants for invasion, such and indirect effects converge on cancer hallmarks (increased proliferation,
as glial cell line-derived neurotrophic factor (GDNF). iv) An increase in the survival, invasion, and migration and accumulation of mutations in the
WNT/b-catenin signaling pathway which favors proliferation, DNA). For other details, see the main text.
of inflammatory cytokines and adipokines, and iii) increases circulating glucose levels and, consistently,
decreased immune surveillance. removal of the tumor improves glucose clearance (Permert
First, high plasma glucose concentrations induce et al. 1993, Yoshikawa et al. 1994). In summary, high
insulin secretion and elevate the levels of circulating glucose and inflammation feed each other as high glucose
insulin and free IGF1 (Rajaram et al. 1997), two potent triggers inflammation while inflammation induces insulin
anti-apoptotic growth factors for most cancer cells (Pollak resistance and hepatic gluconeogenesis, both leading to
2008). In addition, insulin also stimulates the release of increased glycemia in a positive feedback loop.
the proinflammatory cytokine interleukin 6 (IL6) from Third, high glucose alters immune function because
human adipocytes (LaPensee et al. 2008). glucose competitively impairs the transport of ascorbic acid
Second, high plasma glucose in vitro and in vivo into immune cells (Krone & Ely 2005). As ascorbic acid is
activates monocytes and macrophages to produce the needed for effective phagocytosis, mitosis and for proper
inflammatory cytokines tumor necrosis factor alpha function of lymphocytes, the immune response
(TNFa) and IL6 (Devaraj et al. 2005, Gonzalez et al. 2012). to malignant cells diminishes with hyperglycemia. It stands
Interestingly, circulating TNFa and IL6 levels are also to reason that all these mechanisms may act synergistically.
increased through a tumor-induced acute phase inflam- Thus, at the level of the organism not only does
matory response (McCall et al. 1992) and trigger insulin hyperglycemia enhance tumor growth through several non
resistance in cancer patients (Makino et al. 1998). exclusive mechanisms, but there are also a number of
Additionally, the inflammatory process leads to increased mechanisms by which the tumor induces metabolic adap-
gluconeogenesis in the liver of cancer patients, which is tations in other organs to favor hyperglycemia. The supply of
further enhanced by lactate secreted from the tumor high glucose to the ‘parasite’ cancer cells is thus increased.
(Waterhouse et al. 1979; Fig. 4). Hepatic gluconeogenesis These bidirectional relationships are summarized in Fig. 4.

signaling in cancer
Cancer Hyper-
glycemia
Lactate
↑ production
Cancer ↑ gluconeo-
Hepatic Glucose
↑ supply to
genesis blood
Inflammation
↑ TNFα, IL6
Hyper-
glycemia Insulin/
↑ IGF1
↑
Glucose
Insulin
consumption by
resistance
noncancer cells
Figure 4
Cancer cells ensure high glucose supply through enhanced hyperglycemia from the liver contribute to hyperglycemia. Cancer supports and enhances
and hyperglycemia favors tumor growth: the strategy of a parasite. hyperglycemia in various ways: i) the metabolic switch in cancer cells
Hyperglycemia favors tumor growth at the organism level – as depicted in drives increased glycolytic flux and lactate production. Lactate induces
‘indirect mechanisms’ in Fig. 3 – by increased secretion of the growth glyconeogenesis at the liver contributing to hyperglycemia. ii) Tumor
factors, insulin and IGF1, reduced immune surveillance, and increased growth also induces an acute inflammatory response with increased
circulating inflammatory cytokines. This causes insulin resistance that production of inflammatory cytokines TNFa and IL6, known to cause insulin
diminishes glucose consumption (by noncancer cells) and increased hepatic resistance and induce hepatic gluconeogenesis. Both of these processes
glyconeogenesis. Reduced uptake from the blood and increased supply contribute to hyperglycemia.
Mechanisms for hyperglycemia increased the mitochondrial electron transport chain (Brownlee
cancer risk: direct effects on cancer cells 2001). Unrestricted glucose availability may accelerate the
metabolic rate and lead to increased oxygen consumption
The direct effects of high glucose on tumor cells include
and ROS generation in a first phase. High ROS will cause
i) increased proliferation, ii) induced mutations,
mutations first at the mitochondrial DNA (where ROS are
iii) augmented invasion and migration and iv) rewiring produced through OXPHOS) and then in nuclear encoded
of cancer-associated signaling pathways. genes, see Wellen & Thompson (2010). As most
First, high glucose accelerates the cell cycle through mitochondrial DNA encode for proteins, there will be a
changes in the expression of critical genes such as E2F and high probability that enzymes for OXPHOS will be altered
cyclins A and E (Masur et al. 2011). Proliferation is also leading to a subsequent decrease in ROS generation. From
induced through increased expression of epidermal the generated mutants, those that allow for efficient
growth factor (EGF) and enhanced EGF receptor signaling diversion of captured glucose toward anabolism will be
in pancreatic cancer cells (Li et al. 2011). rapidly selected. These include those mutants that render
Second, high glucose induces mutations through constitutive activation of the AKT signaling pathway and
upregulated oxidative stress-responsive genes (like independence of insulin for glucose uptake. Reduction in
thioreodoxin-interacting protein) that in turn increase ROS production will ensure survival and pluripotency of
the levels of ROS (Turturro et al. 2007). ROS facilitate those clones. That is, a switch from high to low ROS
mutations and cell death through increased DNA damage, production in cancer cells may develop temporarily.
impaired repair, accumulation of advanced glycation end Alternatively, ROS produced by cancer cells may be
products (Sindhu et al. 2004) and, as reported in diabetic exported to neighboring cells, enabling cancer cells to
individuals, through the overproduction of superoxide by survive by keeping a low oxidative potential as reported by

signaling in cancer
Martinez-Outschoorn et al. (2013), who used oncogene- transformation (Ward & Thompson 2012). Oncogenic
transformed cancer cells cocultured with fibroblasts and mutations may dictate increased glucose uptake, which
demonstrated that oxidative stress imposed by oncogene may itself dictate distinct phenotypes inside the tumor,
activated cancer cells induces metabolic reprograming allowing the coexistence of cancer stem and migratory
toward glycolysis in surrounding fibroblasts, which in turn cells as well as highly proliferative cells. Some tumors have
exported lactate toward cancer cells. Fibroblasts were been described as symbiotic associations of cells that
nesting and protecting the oncogenic cancer cells in a secrete and cells that import lactate to be used as energy
very interesting model of metabolic symbiosis, where the sources (Kennedy & Dewhirst 2009). The diversity of
tumor behaves as a parasite (Martinez-Outschoorn et al. tumor cells may rely on metabolic differences and on the
2013). Further research on metabolic interrelationships relationships between tumor cells and their surrounding
between cancer and neighboring cells is needed. cells. These are very promising research avenues that will
Third, high glucose induces invasiveness and advance our understanding of tumor pathophysiology
migration. Masur et al. (2011) demonstrated that diabeto- and may empower therapeutic strategies.
genic glucose concentrations decrease E-cadherin and Fourth, high glucose enhances cancer-associated
increase protein kinase Ca signaling leading to increased WNT signaling (see below) by allowing nuclear retention
cell motility. E-cadherin maintains cell–cell adhesion and and accumulation of transcriptionally active b-catenin
plays a pivotal role in epithelial–mesenchymal transition independently of hyperinsulinemia, adipokines, or
(EMT), a multifaceted developmental program critical for inflammation (Chocarro-Calvo et al. 2013). b-catenin is a
the acquisition of migration and invasion capabilities and potent transcriptional coactivator targeted to genes involved
for the maintenance of stem cells. EMT might be activated in proliferation (Niehrs & Acebron 2012, Anastas & Moon
transiently and to different degrees by carcinoma cells 2013) and senescence bypass (Larue et al. 2009) among others.
during metastasis, reviewed in Hanahan & Weinberg Nuclear b-catenin is a well-known tumor marker of bad
(2011). Acquisition of EMT phenotype and expression of prognosis, and therefore the requirement for high glucose by
cancer stem markers were induced in basal luminal breast WNT signaling to promote nuclear accumulation of
carcinoma by high glucose consumption which reduced b-catenin is likely to have a major impact on cancer biology.
ROS production (Dong et al. 2013) allowing survival. Dong
et al. first observed that high glucose induced epigenetic
WNT signaling links hyperglycemia and
silencing of a critical gluconeogenesis enzyme through the
diabetes to cancer
EMT-related transcriptional repressor Snail. Lack of this
gluconeogenic enzyme on its own increased glycolysis and The WNTs comprise a large family of secreted cys-rich
the NADPH produced via pentose phosphate pathway glycoprotein ligands that coordinate cell fate decision-
(ensuring anabolic intermediates for proliferation) and making in a broad range of developmental and homeo-
reduced OXPHOS. Both reduced OXPHOS and increased static contexts (Clevers & Nusse 2012). WNT proteins bind
NADPH (used by enzymes that detoxify H2O2) contributed to their membrane receptors and activate a number of
to lower ROS production, and correlated with pathways, including planar cell polarity pathway, Ca2C
expression of cancer stem cell markers dependent on signaling, and the canonical WNT/b-catenin pathway
b-catenin/transcription factor 4 (TCF4) activation, see also which is the best known and the most deeply involved
comment by Schieber & Chandel (2013). in cancer. Functional WNT/b-catenin signaling is tran-
In addition to the previous direct effects of high siently activated to maintain stem cells in the intestinal
glucose on migration, several diffusible mediators of high crypts (Korinek et al. 1998). However, constitutive WNT
glucose also increase migration in the pancreatic cells. For signaling was believed to lead to nuclear accumulation of
example, high glucose induces the expression of urokinase the WNT effector b-catenin (a well-known tumor marker)
plasminogen activator. This enhances invasive and and promotion of aberrant cell growth, senescence bypass
migratory activities (Li et al. 2011) and also upregulates (Delmas et al. 2007), and cancer (Clevers 2006). Notably,
chemo-attractant glial cell line-derived neurotrophic aberrant WNT signaling is present in 40–90% gastrointes-
factor (GDNF) expression and its interaction with the tinal cancers (White et al. 2012), which are the specific
RET tyrosine kinase receptor, a critical step for tumor cancer sites more tightly associated with diabetes.
progression, migration, and invasion (Liu et al. 2011). WNT signaling is also tightly associated with diabetes.
Thus, cancer cell hallmarks concerning glucose Indirect links are illustrated by WNT-regulated control of
metabolism may be consequences and also a cause of adipocyte differentiation and obesity (Lu et al. 2013),

signaling in cancer
a major risk factor for diabetes. Direct links are illustrated Traditionally, it was understood that the resulting
by the mutations reported in its effector, the transcription pool of stabilized cytosolic b-catenin delocalized from the
factor TCF7L2 (previously known as TCF4), which membrane and entered the nucleus. Once there, it was
represent the strongest genetic link with diabetes in all thought to bind as a potent coactivator to transcription
ethnicities (Saxena et al. 2006, Lyssenko 2008). The role of factor members of the T cell factor/lymphoid enhancer
the TCF7L2 intronic mutations associated with diabetes factor (TCF/LEF) family such as TCF7L2 and LEF1,
has remained elusive, but since their discovery, WNT/ activating target genes which include those of critical
b-catenin signaling has been shown to increase the factors for proliferation and prosurvival such as those
expression of incretin hormones (Garcia-Martinez et al. encoding MYC and Cyclin D1. However, there is now new
2009) that are global regulators of metabolism and are and solid evidence that demonstrates that WNT stimu-
required for normal glucose-dependent insulin secretion. lation alone is not enough to promote nuclear accumu-
As such, WNT-mediated induction of incretin production lation of b-catenin, but that this process requires and
established a new link between WNT and diabetes. This depends on high glucose to increase its nuclear retention
has been reinforced by the findings that WNT also induces in a variety of human tumor-derived cell lines related to
incretin receptor expression and signaling in the pancreas cancers associated with hyperglycemia and diabetes
as well as insulin expression and secretion, reviewed in (Chocarro-Calvo et al. 2013). As nuclear accumulation of
Garcia-Jimenez (2010). In other tissues, WNT induces the b-catenin is a well-known tumor marker of bad prognosis,
expression of the receptors for insulin and IGF1 (Singh constitutive WNT signaling in cancer on one side, and
et al. 2013). Recently, Savic et al. (2011) have demonstrated increased glucose uptake by tumor cells on the other,
that the diabetes-associated TCF7L2 intronic mutations reveals a previously unrecognized requisite for WNT
had a gain of expression effect and a role on glucose signaling in cancer, namely its amplification by high
metabolism. Next, Boj et al. (2012) demonstrated that glucose (Chocarro-Calvo et al. 2013). The ability of high
most of the genes controlled by TCF7L2 in the liver are glucose to amplify WNT/b-catenin signaling provides a
metabolic regulators. In fact, the hepatic response to link between cancer and hyperglycemia which is inde-
fasting critically relies on TCF7L2. Consistently, hepatic pendent of inflammation, hyperinsulinemia, or ROS
gluconeogenesis is diminished in animals whose TCF7L2 induced mutations. As cancer cells are a well-characterized
loci have been silenced. Reintroduction of the gene source of autocrine WNT signaling (Bafico et al. 2004),
restores glucose production by the liver in concordance high glucose uptake may be critical to maintaining
with the high blood glucose levels found during fasting in nuclear accumulation of b-catenin and subsequent
human carriers of the TCF7L2 mutation. tumor growth and progression, a notion reinforced by
Thus, a growing number of genes involved in the strong dependence of tumor cells on glucose avail-
metabolism have to be added to the classical WNT/ ability as highlighted above.
b-catenin targets that are mostly involved in proliferation
and prosurvival (see below). This suggests that WNT may
High glucose enhances cancer-associated
serve as a new factor that links enhanced cancer risk with
WNT signaling through targeted acetylation
metabolic diseases such as hyperglycemia, obesity, and
of b-catenin
diabetes. This link becomes especially relevant because
TCF7L2 mutations associated with diabetes increase basal High glucose remodels cancer-associated WNT/b-catenin
circulating glucose levels, and because WNT increases signaling to promote the formation and nuclear entry of
insulin production, secretion, and signaling trough a LEF1–b-catenin complex which binds to promoters
enhanced receptor expression. marked by poised TCF7L2, replacing it and leading to
Excellent and extensive reviews focused on WNT increased expression of WNT target genes (Chocarro-
signaling have recently been published (Clevers & Nusse Calvo et al. 2013). The model depicted in Fig. 5 sum-
2012, Anastas & Moon 2013), but here we will draw a very marizes the findings that support this idea. In the absence
simple outline. In the ‘cannonical’ WNT/b-catenin of WNT and high glucose (left panel), WNT target genes
signaling pathway, WNT binds to frizzled and lipoprotein are bound by TCF7L2 and a corepressor complex that
receptor-related protein LRP5/6 coreceptors. This leads silences their expression, while b-catenin remains associ-
to inactivation of glycogen synthase kinase 3b (GSK3b), a ated with the cytoplasmic membrane. High glucose alone
kinase that constitutively phosphorylates cytosolic (up-right panel) does not increase or de-localize b-catenin,
b-catenin to trigger its degradation. despite a small increase in p300 levels and WNT-target

signaling in cancer
Cytoplasm p300 Nucleus

p300
β-Cat
Co
repressor
Lef1 β-Cat
TCF7L2
Sirt1 Sirt1 WNT target genes
β-Cat
+ WNT
+ Hyperglycemia
Cytoplasm
p300 p300 Nucleus
β-Cat p300 p300
Cytoplasm β-Cat β-Cat
Nucleus
Sirt1 + Hyper-
p300 p300
Sirt1 glycemia
β-Cat
Lef1 β-Cat β-Cat

Co 1 Ac Ac
repressor + WNT Lef1 Lef1 β-Cat
2 3
TCF7L2 Lef1
1 LEF1–β-catenin/p300 interaction
WNT target genes Sirt-1 WNT target genes
2 Nuclear accumulation of
β-Cat
LEF1–β-catenin/p300. Inhibition of SIRT1
3 TCF7L2 replacement at target genes
+ Hyperglycemia
+ WNT
Cytoplasm p300 Nucleus

p300
β-Cat Co
repressor
β-Cat β-Cat Sirt1 TCF7L2
Sirt1 WNT target genes
Figure 5
High glucose enhances cancer-associated WNT/b-catenin signaling: a new there is accumulation of cytosolic b-catenin, but nuclear accumulation does
link between hyperglycemia and cancer. In the absence of high glucose and not occur and there is no induction of WNT target genes. Upon coincidence
WNT signals (left panel), WNT target genes remain silenced through of both WNT and high glucose (mid-right panel), the expression of
targeted binding of TCF7L2–corepressor complexes, and b-catenin is WNT target genes is induced by LEF1–b-catenin complexes that displace
located at specific plasma membrane sites. Stimulation with high glucose, TCF7L2–corepressor complexes. Hyperglycemia acts on cytosolic b-catenin
WNT, or both, is depicted on the right panels. Upon exposure to high accumulated via WNT induction to promote three effects: (1) acetylation of
glucose (upper-right panel) there is a small accumulation of p300 in the b-catenin that favors formation of LEF1–b-catenin/p300 complex,
nucleus and cytoplasm, but b-catenin remains at the membrane and WNT (2) inhibition of SIRT1 activity required for nuclear accumulation of
target genes remain silenced. If only WNT signals are present instead of LEF1–b-catenin/p300, and (3) replacement TCF7L2 by LEF1–b-catenin
high glucose (bottom-right panel), there is a small increase in p300 and complex inducing the transcriptional activity of target genes of WNT.
genes remain silenced. Stimulation by WNT proteins only nuclear localization signal and specific DNA-binding
(bottom-right panel) allows b-catenin release from the domain (both absent in b-catenin). In this context, the
degradation complex and accumulation in the cytosol but interactions of b-catenin with TCF7L2 in breast cancer
not in the nucleus. Coincidence of both signals (right-mid cells have been recently shown to rely on the oxidative
panel) allows high glucose to cooperate with WNT by state (Dong et al. 2013). High ROS production led to the
inducing acetylation of lysine residues in the armadillo accumulation of b-catenin–FOXA3 complexes in detri-
repeats of b-catenin by p300 (whose levels are ment of b-catenin–TCF7L2 complexes and using the
cooperatively upregulated by WNT and high glucose). antioxidant N-acetylcystein or lowering ROS production
This acetylation event is a requirement for LEF1–b-catenin displaced b-catenin from FOXA3 toward TCF7L2. In
complex formation, a step that facilitates b-catenin gastrointestinal cancer cells high glucose enhances bind-
nuclear entry and specific DNA targeting by LEF1–b- ing of b-catenin–TCF7L2 complexes to target genes but the
catenin relying on the exhibition by LEF1 of classical presence of WNT signaling displaces TCF7L2 and favors

signaling in cancer
b-catenin–LEF1 complexes (Chocarro-Calvo et al. 2013). It absence of a WNT signal would be insufficient to activate
would be interesting to investigate, in individuals who are gene expression even in the presence of glucose as it would
carriers of the mutation related to diabetes (that leads to not outcompete SIRT1–LEF1 interactions. However, it can
increased expression of TCF7L2 and increased blood be argued that interactions may depend more on protein
glucose), how b-catenin partnership evolves to adapt to conformation or exposure of the right domains than on
metabolic challenges posed by high glucose and ROS. levels, otherwise the most abundant proteins would
Also, as acetylation of both histone and non-histone exhibit the most interactions. A clear example is that
proteins is regulated by nutrients (Wang et al. 2010, Zhao upon WNT signaling cytosolic b-catenin increases but its
et al. 2010) it would be interesting to explore whether interactions with E-cadherin are not increased.
changes in ROS production alters the interactions of Taken as a whole the results by Chocarro-Calvo et al.
b-catenin with LEF1 and p300. (2013) suggest that the ability of LEF1 to bind p300 may
Earlier studies suggested that overexpressed p300–CBP depend more on stabilizing a conformation through the
interacted with the C-terminus of b-catenin (Hecht et al. LEF1–b-catenin complex (that requires both WNT and
2000), leading to lysine acetylation. Binding to TCF–LEF glucose), rather than simply relying on p300 levels.
factors (Lévy et al. 2004) and nuclear entry of b-catenin Interactions promoted by high glucose upon WNT
(Wolf et al. 2002) followed and correlated with increased stimulation (LEF1–b-catenin with p300) differ from those
oncogenic potential (Ma et al. 2005). However, the promoted in its absence (LEF1–SIRT1 and b-catenin–
evidence for a definitive role for p300-mediated acetyl- SIRT1), which may appear logical if we consider that
ation of b-catenin was inconclusive as mutation of the WNT imposes dramatic and well-known increases in the
identified lysine (K345) targeted by p300–CBP did not availability of b-catenin. Thus, the combined effect of
significantly alter b-catenin-driven transcriptional acti- glucose and WNT on p300 levels and SIRT activity
vation. The nature of the pathophysiological stimulus that are crucial to shift the balance of acetylation and allow
increased acetylation and oncogenic potential also the formation of the LEF1–b-catenin complex that
remained unknown. Under WNT signaling, high glucose accumulates inside the nucleus.
has been revealed as a pathophysiological stimulus whose The catalytic activity of SIRT1 is important to prevent
combined action, inducing p300 acetyltransferase and LEF1–b-catenin nuclear accumulation and may interfere
inhibiting sirtuin deacetylase activities, targets b-catenin with LEF1–b-catenin interactions, or with exposure of the
acetylation. High glucose induced acetylation of lysine nuclear localization signals, or with nuclear export. Inhi-
K354 in b-catenin, which induces nuclear retention and bition of sirtuin deacetylase activity mimics glucose-driven
transcriptional activation through enhanced p300–LEF1– nuclear retention of b-catenin and transcriptional activation
b-catenin interactions (Chocarro-Calvo et al. 2013). in cells where cytosolic b-catenin has accumulated through
Interestingly, interaction of SIRT1 with both b-catenin WNT-induction (Chocarro-Calvo et al. 2013). Thus, high
and LEF-1 is favored by high glucose in the absence of glucose not only increases p300 levels and acetylase activity
WNT signaling, even though the levels of SIRT1 remain but also inhibits sirtuin deacetylase activity, and therefore
unchanged. During caloric restriction, sirtuin levels are results in excess acetylation with the consequent transcrip-
upregulated (Mantel & Broxmeyer 2008), likely facilitating tional activation. A possible mechanism for high glucose
formation of SIRT1–b-catenin and SIRT1–LEF1 complexes inhibition of sirtuin activity in the presence of WNT
and outcompeting LEF1–b-catenin complex formation signaling may be given by enhanced glycolysis in tumor
which is associated with proliferation. In addition, under cells. Increased glycolytic flux leads to rapid turnover of the
caloric restriction, there is enough supply of NADC, as a NADC obtained by lactic acid production from pyruvate.
cofactor needed for sirtuin activity favoring de-acetylation NADC is necessary for the next round of glycolysis, but it is
of b-catenin K354, which diminishes its interaction with also an essential sirtuin cofactor. Depletion of NADC then
LEF1 and transcriptional activity. This hypothetical limits its availability for sirtuins and consequently their
mechanism would explain the decreased cancer risk deacetylase activity. In this respect, it would be interesting
associated with calorie-restricted diets. In this scenario, to determine the location and activity of sirtuins and of
accumulation of b-catenin in response to WNT signaling b-catenin in the subpopulations of cells belonging to the
and high glucose may outcompete SIRT1 and provide tumor (or the surroundings) that release lactate (generating
enough b-catenin to form LEF1–b-catenin complexes, NADC) and those that consume lactate (see Martine-
which will ensure the nuclear accumulation of LEF1–b- z-Outschoorn et al. (2013)). Importantly, high glucose-
catenin. The low levels of b-catenin observed in the mediated amplification of cancer-associated WNT

signaling in cancer
signaling cannot be attributed to nonspecific changes in and cancer-associated signaling pathways (such as MAPK
energy supplies or to a general nutrient requirement because or PI3K, see Ray et al. (2012)) is widely recognized, little is
both diabetogenic and physiological glucose concentrations known about how the metabolic intermediates (for
render similar increases in ATP levels having opposite effects example NADC levels) may alter cancer pathways such
on b-catenin and the use of an alternative carbon source had as WNT/b-catenin.
no effect (Chocarro-Calvo et al. 2013). We hope that this review will remind the reader
that metabolism may drive cancer cell reprograming.
Concluding remarks and future perspectives During the last international meeting on Prediabetes,
much attention was given to the fact that early
The World Health Organization (WHO) predicts that the detection of hyperglycemia and policies that change
obese and diabetic population will double from the year life style may prevent T2D; perhaps also some cancers
2000 to 2030 and the epidemiological data clearly establish might be prevented through the same policies. High
a link between diabetes and cancer. This represents an glucose amplification of WNT signaling is an example of
enormous emotional and financial cost for society and how metabolism can remodel a cancer-associated
knowledge should guide new policies that maximize signaling pathway. Identifying the molecules and under-
prevention and find new treatments at low cost. A close
standing the processes underlying metabolic remodeling
cooperation between epidemiologists, who establish the
of cancer-associated signaling will empower new
correlations, and basic scientists, who uncover the
preventive, diagnostic, and therapeutic approaches
mechanisms, may provide the clues to refine and confirm
toward curing cancer.
the epidemiological findings and help to implement new

policies based on prevention.
There are still many unanswered questions. For
Declaration of interest
example, which WNT signals are required for incretin The authors declare that there is no conflict of interest that could be
expression, which WNT signals are released in cancer, and perceived as prejudicing the impartiality of the research reported.
which cooperate with high glucose? When or where is the
cancer-related WNT signal released? Are there other
signals such as other nutrients, hormones, or cytokines Funding
that cooperate with high glucose to induce nuclear This work was financed by FIS (PI12/01201). C G-J is professor in Universidad
Rey Juan Carlos, J M G-M, and A C-C were supported by teaching contracts
accumulation of b-catenin? Can we find natural meta- from Universidad Rey Juan Carlos (URJC, Madrid). A D V is a researcher and
bolites, hormones, etc., that oppose the effects of high head of Endocrine tumor Unit in the Instituto de Salud Carlos III.
glucose on WNT signaling? And if so, would it be possible
to direct these signals specifically toward cancer cells and
not toward healthy cells? How does glucose alter SIRT1
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Received in final form 15 September 2013

Accepted 18 September 2013
Accepted Preprint published online 18 September 2013


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C GARCÍA-JIMÉNEZ and others High glucose amplifies WNT 52:1 R51–R66

Review signaling in cancer

A new link between diabetes and

Custodia Garcı́a-Jiménez, Jose Manuel Garcı́a-Martı́nez, Ana Chocarro-Calvo and

high glucose enhancement of WNT/b-catenin signaling in cancer cells promotes proliferation,

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

(not analyzed in this review)

Hormonal disorders Inflammation Metabolic alterations

Insulin/IGF-1 Adipokines TNFα IL-6 Others ROS Hyper- Others

Cancer Invasion &

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

might play an important, though still incompletely

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

authors have reported decreased tumor growth after

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

switch off OXPHOS. The enzymatic machinery is only

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

NADH NADH Nucleus

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

Direct effects Indirect effects

WNT/ Cell Insulin/ Inflammatory

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

Cytoplasm p300 Nucleus

Lef1 β-Cat β-Cat

Cytoplasm p300 Nucleus

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

the epidemiological findings and help to implement new

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Dominguez D, Medina RA & Nualart F 2011 Insulin regulates GLUT1-

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

Received in final form 15 September 2013

http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd.

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