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Oncotarget38959
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www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 25
Current perspectives between metabolic syndrome and cancer
Carla Micucci1, Debora Valli1, Giulia Matacchione1 and Alfonso Catalano1
1 Department of Clinical and Molecular Sciences, Polytechnic University of Marche, School of Medicine, Ancona, Italy
Correspondence to: Alfonso Catalano, email: a.catalano@univpm.it
Keywords: metabolic syndrome, cancer risk, visceral adiposity, hyperglycemia, inammation
Received: September 30, 2015 Accepted: February 20, 2016 Published: March 24, 2016
ABSTRACT
Metabolic syndrome is a cluster of risk factors that lead to cardiovascular
morbidity and mortality. Recent studies linked metabolic syndrome and several
types of cancer. Although metabolic syndrome may not necessarily cause cancer,
it is linked to poorer cancer outcomes including increased risk of recurrence and
overall mortality. This review tends to discuss the major biological and physiological
alterations involved in the increase of incidence and mortality of cancer patients
aected by metabolic syndrome. We focus on metabolic syndrome-associated visceral
adiposity, hyperinsulinemia, hyperglycemia, insulin-like growth factor (IGF-I)
pathway as well as estrogen signaling and inammation. Several of these factors
are also involved in carcinogenesis and cancer progression. A better understanding
of the link between metabolic syndrome and cancer may provide new insight about
oncogenesis. Moreover, prevention of metabolic syndrome – related alterations may
be an important aspect in the management of cancer patients during simultaneous
palliative care.
INTRODUCTION
Metabolic syndrome (MetS) is increasing in
incidence and lead to signicance cardiovascular disease
(CVD) and mortality. CVD includes all the disease of the
heart and circulation including coronary heart disease,
angina, heart attach and stroke. MetS can also raise the risk
of other diseases, including cancer. It’s thought that more
than 2 in 10 cancers in the UK are linked to being MetS.
The relationship between MetS and cancer is complex.
Individual components of the metabolic syndrome are
known as risk factors for incident cancer disease, but it is
not clear how the clustering of these components is linked
to the development and progression of tumors. It seems
self-evident that a condition characterized by multiple risk
factors, as the metabolic syndrome, will carry a greater
risk for adverse clinical outcomes than will a single risk
factor. Therefore, a better understanding of the relationship
between components of the metabolic syndrome and
whether and how these components contribute to
progression of cancer and its incidence could inform more
eective prevention strategies [1].
MetS rises with economic development, sedentary
lifestyle and associated overweight and obesity as seen
among populations in Asia, South and North America, and
Eastern Europe. As a result, the metabolic syndrome is
now both a public health and a clinical problem. MetS has
existed in various forms and denitions [2]; however the
most widely accepted denition was issued by the Adult
Treatment Panel III of the National Cholesterol Education
Program (NCEP-ATP III). According to the NCEP-ATPIII
denition, MetS is dened having three or more of the
following ve risk factors: 1) visceral obesity dened
by waist circumference (population and country specic
denitions); 2) triglycerides ≥ 150 mg/dL; 3) low high-
density lipoprotein (HDL) cholesterol levels (men ≤ 40
mg/dL; women ≤ 50 mg/dL ); 4) blood pressure ≥ 130
and/or 85 mmHg; and 5) fasting glucose ≥ 100 mg/dL [3] .
The third National Health and Nutrition
Examination Survey (NHANES III) criteria have shown
that about 47 million people have MetS [4]. Incidence
increases with age and it has been estimated that, in the
category over 50 years of age, MetS aects more than
40% of the population in the United States and nearly
30% in Europe [5, 6]. The reasons for this incidence vary
from person to person. It can sometimes be linked to genes
we were born with, or our environments, as well as our
individual behaviour and choices. And some drugs and
diseases can also contribute to weight gain.
Interestingly patients with MetS are at twice the
risk of developing CVD over the next 5 to 10 years as
individuals without the syndrome, whereas it has been
shown that metabolic syndrome confers a 5-fold increase
in risk for type 2 diabetes [3]. On the other hand, research
Review
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has shown that many types of cancer are more common
in people who have MetS, such as breast cancer, in
women after the menopause, bowel cancer, colon cancer,
esophageal cancer, gastric cancer, pancreatic, kidney and
liver cancer. This is probably due to harmful eects in
the body that can have MetS, like producing hormones
and growth factors that aect the way our cells work.
This review presents current perspectives on the relations
of metabolic syndrome with cancer risk, oering new
insights into potential biological mechanisms, and
suggesting some directions for future cancer treatment.
METABOLIC SYNDROME AND CANCER
Recently, Esposito et. al analyzed 38,940 patients
aected by cancer and MetS through a meta-analysis
and it has been shown that the MetS is associated with
an increased risk of several cancers including colorectal,
pancreas and liver cancers. However, many of the reported
associations might dier between sexes. In men, MetS
was strongly associated with liver (RR 1.43, P < 0.0001)
and colorectal (RR 1.25, P < 0.001) cancers and weakly
associated with bladder cancer (RR 1.10, P = 0.013).
While in women, the presence of metabolic syndrome
was associated with endometrial (RR 1.61, P = 0.001),
pancreas (RR 1.58, P < 0.0001), breast (in particular in
postmenopausal, RR 1.56, P = 0.017), colorectal (RR
1.34, P = 0.006) and ovary cancers (RR 1.26, P = 0.054)
[7].
The increasing prevalence of MetS worldwide and
the high incidence of some malignancies, imply that every
year many cases of cancer are attributable to metabolic
syndrome. Primary prevention and early detection of
cancer are recommended for patients aected by fully
developed diseases.
It’s important to underline how interventions to
reduce the prevalence of metabolic syndrome in adult
populations will reduce cancer risk [8] therefore patients
with the metabolic syndrome, even in absence of obesity
or diabetes, should be encouraged to undergo appropriate
cancer screenings, at least for some more frequently
involved sites [9] (Figure 1).
Figure 1: Association between metabolic syndrome and cancer risk. Risk ratio in dierent cancer sites both in men i. and in
women ii.
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Jaggers et al. have conducted a study to examine the
association between MetS and all-cause cancer mortality,
in which participants were only men enrolled in Aerobics
Center Longitudinal study (ACLS) (33,230 aged 20-
88 years) who, at the time of examination, were free of
known cancer. Using criteria of the NCEP-ATP III, men
have been divided into two groups according to have or
not MetS. The study has shown that men with MetS had a
56% higher risk of cancer mortality compared with those
with only one condition. Moreover, participants with
3 or more risk factors had an 83% higher risk of cancer
death compared to men without risk factors. With the
exception of high blood pressure, the only component that
did not increase cancer risk, it has been shown a positive
association between cancer mortality and each of the MetS
components. The presence of MetS was then signicantly
associated with increased risk of cancer mortality for lung
and colorectal cancer.
Features studies must be done to analyze the
connection between MetS and all cause cancer mortality
among female population, although previous studies have
shown lower risk of cancer mortality for woman with
MetS [10]. Recently Stebbing et al. reported through
prospective cohort study that woman aected by breast
cancer and MetS are non-responders to standard treatment
than those without MetS. So preventing or controlling the
risk factors of MetS would be one of the possible ways to
reduce cancer deaths in both sexes [11].
MetS can also represent a common long-term
complication after cancer treatment that aects life
expectancy and quality of life. For example, in childhood
sarcoma survivors who received chemotherapy, the
prevalence of the metabolic syndrome was 33% compared
with data in healthy population [12]; for adult survivors
of testicular cancer the prevalence of metabolic syndrome
was higher in those patients treated with chemotherapy
(26%) and surgery only (36%) compared with healthy
controls (9%) [13]. Finally, patients with prostate cancer
receiving androgen-deprivation therapy had a higher
prevalence of MetS (55%) than patients treated with
prostatectomy, radiotherapy, or both (22%) and healthy
controls (20%) [14]. The presence of MetS in cancer
survivors is associated with signs of early atherosclerosis
and may represent the connection between cancer
Figure 2: Mechanisms that increase the risk of cancer in patients with metabolic syndrome. Biological alterations associated
with MetS that inuence cancer development and progression such as visceral adiposity, hyperinsulinemia, IGF/IGF-R axis, inammation
and estrogen signaling.
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treatment and its severe late eects like cardiovascular
disease [15].
MECHANISMS THAT INCREASE THE
RISK OF CANCER IN METABOLIC
SYNDROME
Patients aected by MetS present several biological
and physiological alterations which may increase risk
of neoplastic transformation or increase progression of
existing cancer.
We desire to summarize the main aspects that link
MetS and risk of cancer (Figure 2).
Visceral adiposity
The high rates of obesity are a worldwide problem:
the International Obesity Taskforce estimates that 1.1
billion people are overweight (BMI, body mass index, of
25-29.9 kg/m2) and 312 million are obese (BMI ≥30 kg/
m2) [16].
There are two categories of adipose tissue:
brown adipose tissue (BAT) and white adipose tissue
(WAT), the last one is also divided in subcutaneous
and visceral. The visceral-adiposity stores energy as
triglycerides and protects organs from mechanical
stress. Several epidemiological studies conrmed the
relationship between visceral adiposity and an increased
risk of developing certain types of cancer [17-19]
including colorectal, breast (especially postmenopausal
women), endometrial, esophageal adenocarcinoma,
cholangiocarcinoma and gastric cardia cancers. The
American Cancer Society calculated that currently new
cancer cases are in order of 1.5 million with half a million
cancer deaths per year, nearly one in ve due to obesity
[20, 21].
WAT is an active endocrine organ secreting local
and systemic hormones (such as leptin and adiponectin),
cytokines (such as TNF-α and iterleukin-6) interacting
with the immune system and various growth factors:
insulin-like growth factor (IGF-1), insulin-like growth
factor-binding protein (IGFBPs) and transforming growth
factor (TGF-β) [22].
Adipokines (hormones, cytokines and other proteins
with signaling properties) are synthesized by adipocytes
and regulate many physiological processes, in particular,
appetite, angiogenesis, metabolism of glucose and fatty
acids, as well as inammatory and immune reactions [23].
Adiponectin is the most abundant hormone in
circulation (0.05% of serum proteins) secreted after
activation of the nuclear receptor Peroxisome Proliferator-
Activated Receptor-γ (PPAR-γ) in fat cells. It enhances
metabolism of glucose and fatty acids (reduction of
FFA concentration) in liver and muscle and increasing
insulin sensitivity [24, 25]. Adiponectin also has an anti-
inammatory character and it’s a negative regulator of
angiogenesis, so it is considered to have anticancer eect
[26].
A low level of adiponectin is due to adipose tissue
hypoxia and this is correlated to a higher risk to develop
breast, endometrial and gastric cancers [27].
Leptin is known as the hormone that reduces food
intake giving a feeling of satiety [28, 29] as increases
insulin sensitivity and lipolysis in adipose tissue The
major source of leptin is WAT, thus obese patients become
hyperleptinemic for the development of leptin resistance
and more susceptible to the risk factors of metabolic
syndrome [24]. It was observed that leptin may promote
neoplastic transformation, proliferation of cancer cells
and tumor angiogenesis [30], indeed high levels of leptin
in plasma are associated with prostate, colon, breast and
endometrial cancer patients.
Adipocytes, in addiction, secretes proangiogenic
factors; among them Vascular Endothelial Growth Factor
(VEGF), is one of the most important. VEGF is stimulated
by hypoxia and implicated in angiogenesis, fundamental
for tumor formation and metastasis [24]. One recent study
on obese patients demonstrated an increase in serum
VEGF and soluble VEGFR-2 [31], positively dependent
on accumulation of visceral adiposity [32].
WAT could be a source of mobilizable progenitor
cells [33]: adipose stem cells (ASC) that are WAT-derived
mesenchymal stem cells, with potential to dierentiate
into osteocytes, chondrocytes and adipocytes, may be a
possible link between obesity and cancer [34-36]. ASCs
can move in response to tumor signal like hypoxia and
inammation and can be use for tumor vasculogenesis.
Subsequently the recruitment by tumors, they can be
integrated in tumor stroma after transition into cancer
associated broblasts (CAFs).
Several studies have shown a higher mobilization
and recruitment of ASCs in obese patients that lead to
stimulation of tumor growth, promotion of angiogenesis
and increasing of cancer cells invasion. The great number
of circulating ASCs, dierentiates in perivascular cells
that provide oxygen and nutrient to tumor, inducing an
augment survival and limit apoptosis of cancer cells.
Vincenzo Eterno et al. have analyzed the role of
ASCs in breast recurrence, after surgery, in patients who
undergoing autologous fat graft for breast reconstruction
and have shown that ASCs are tumorigenic in presence
of breast cancer cells which express the tyrosine-kinase
receptor c-Met. Moreover the co-injection of ASCs and
breast cancer cells in nude mice produces a tumor more
vascularizated and increased in size [37].
Hyperinsulinemia and hyperglycemia
Insulin is the most potent anabolic hormone,
secreted by the pancreatic β-cells located in the islets of
Langherans. It has a signicant role in glucose, fat and
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protein metabolism [38]. Insulin enables liver cells, muscle
and adipose tissue to extract glucose from the bloodstream
and it increases glycogen synthesis in muscle and liver
cells, esterication of free fatty acids in adipocytes,
inhibits lipolysis and gluconeogenesis; stimulates also cell
growth and dierentiation [39, 40].
In healthy individuals, blood glucose concentrations
are maintained through a state of balance between insulin
production and insulin-mediated glucose uptake in
target tissues [41] determinate by glucose transporters.
Insulin resistance can be dened as a condition in which
the normal cellular response to insulin is reduced.
The pancreatic β-cells react by secreting more insulin,
leading to increased circulating insulin concentrations
(hyperinsulinemia) to maintain normal plasma glucose
concentrations [24]. A favorable niche for neoplastic tissue
survival and cancer stem cells development is created by
insulin resistance [42-44], through the abnormally high
levels of growth factors, adipokines, reactive oxygen
species, adhesion factors, and pro-inammatory cytokines
observed under this condition. Chronic hyperinsulinemia
is also associated with various types of cancer such as
colorectal, pancreatic, endometrial and breast cancer [45],
because it reduces the production of insulin-like growth
factor-binding protein IGFBP -I and -II, proteins that
normally bind to insulin-like growth factor IGF -1 and
inhibits its action. These leads to an increase of circulating
IGF-I and promotes tumor development through changes
in the cellular environment [46].
Metabolic syndrome is also characterized by
increased circulating glucose (hyperglycemia). Glucose
excess can be converted to macromolecular precursors
such as acetyl-CoA for fatty acids, glycolytic intermediates
for nonessential amino acids, and ribose for nucleotides
[47]. Considering that cancer cells require a lot of energy
and substrates to maintain their intensive, uncontrolled
proliferation, those cells have an enhanced ability to take
up and use glucose. In virtue of this, glucose transporter
proteins especially GLUT1 and GLUT3 [25, 48, 49], and
enzymes involved in glycolysis such as hexokinase-2
(HK2) have activity and/or expression increased in many
tumors.
Furthermore certain types of cancer have been
associated with some Tricarboxylic Acid Cycle (TCA)
enzymes mutations, including isocitrate dehydrogenase
(IDH1 and IDH2) [50], succinate dehydrogenase (SDH)
and fumarate hydratase (FH) [51, 52].
Malignant tumor growth is supported also by
altered activity of several glycolytic enzymes such as the
overexpression of hexokinase [53] and 6-phosphofructo-
2-kinase/fructose-2,6- bisphosphatase-4 (PFKFB-4) [54]
that enhanced the ux through glycolysis.
Several studies of patients with dierent tumor
types have conrmed that increased glucose uptake/
accumulation by tumors, correlates with a higher grade of
tumor, incremented metastatic potential, reduced response
to therapy and poorer survival. Data showed a statistically
signicant increase in risk of pancreas cancer, malignant
melanoma, and urinary tract cancers among subjects who
had elevated levels of fasting glucose. The relationship
of hyperglycemia with the risk of cancer overall and of
cancer at organ specic sites was emphasized by Stattin et
al. in a prospective study [55].
Recently our group showed that the hyperglycemic
state is sucient to accelerate lung cancer development in
an oncogene K-Ras mouse model.
Indeed, K-Ras-driven tumors exposed to
hyperglycemia in vivo, grew faster than euglycemic
hosts and showed a more malignant growth behavior.
Moreover, our current study provides compelling evidence
that hyperglycemia, after activation of oncogenic K-Ras,
exerts its pro-tumorigenic eects by maintaining a sub-
population of cancer tumor-initiating cells, namely lung
bronchio-alveolar stem cells (BASCs) [56].
Various signaling pathways that cooperate to
control cancer cell behavior are activated by high
glucose. Indeed several studies suggest that high glucose
induces cancer cell invasiveness and migration through
stimulation of epithelial-mesenchymal transition (EMT),
a complex process critical for the acquisition of migration,
invasiveness and pluripotent stem cell-like phenotype
[57].
Recently, Dong et al. [58] suggested that the EMT
phenotype and the expression of cancer stem cell markers
in basal luminal breast carcinoma are hyperglycemia-
induced; these conditions lead to reduce the generation
of reactive oxygen species (ROS) and to increase cell
survival. Hyperglycemia is also an important contributing
factor to support rapid proliferation [59].
So these data further support the hypothesis that
tumor-promoting activity of hyperglycemia can be
associated with several aspects of oncogenesis.
IGF-I pathway
The IGF system is a complex molecular network
that includes two ligands (IGF-I and IGF-II), two
receptors (IGF-IR and IGF-IIR), six high-anity-binding
proteins (IGFBP-I-IGFBP-VI) and several binding-
protein proteases [60, 61]. IGF-I expression is regulated
by insulin and growth hormone (GH) which stimulated
the production of IGF-I in liver, the main source of
circulating IGF-I. Diet, nutrition, age and sex aect levels
of circulating IGF-I and IGFBP-III. IGF-I stimulates cell
proliferation and inhibits apoptosis, interacting with its
specic receptor on cell membrane, IGF-IR, and with
insulin receptor (IR) even if with low anity [62]. These
interactions are regulated by IGFBPs. The IGFBPs can
promote stabilization in the circulation, regulation of the
eux from liver to target tissues and availability of IGF-I
for binding to its receptors and particularly most of the
circulating IGF-I (80%) is bound to IGFBP-III [46].
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IGF-I binding to IGF-IR activates two main
signaling pathways: phosphatidyloinositol 3-kinase
(PI3K)-AKT/protein kinase B (PKB) pathway and the
Ras-mitogen-activated protein kinase (MAPK) pathway.
Stimulation of PI3K pathway leads to activation of
several downstream substrates, including PKB. Its active
form (Akt/PKB) enhances proliferation, tumorigenesis
and self-renewal by activating mammalian target of
rapamycin (mTOR) and forkhead box O (FoxO), and
blocking glycogen synthase kinase 3β (GSK3β) that
result in accumulation of β-Catenin and in activation of its
downstream targets [41].
The same eects are also achieved through the
activation of Ras/MAPK/extracellular signal-related
kinase 1/2 (ERK-1/2) (21).
Cancer cells show signicant overexpression of
IGF-I and its receptor. High circulating levels of IGF-I,
are associated with increased risk for several cancers,
including breast [63], prostate [64], lung [65], and
colorectum [66]. Instead the level of IGFBP-III, which
suppresses the mitogenic action of IGF-I, is inversely
associated with risk of these cancers.
The involvement of IGF-I in cancer progression
is supported by several clinical and experimental
studies. A signicantly increased risk for prostate cancer
development is due to an augment of circulating IGF-I
as shown by Price et al. (2012) [67], others studies also
revealed a specically expression of IGF-I in tumor tissue
in prostate cancer suggesting that levels of IGF-I may be a
prognostic marker in predicting risk of death in men with
advanced prostate cancer [68-70].
In vitro studies on human colon cancer cells showed
cells proliferation promotion by IGF-I, an overexpression
of IGF-IR, and inhibition of tumor cell growth using its
monoclonal antibody [71]; moreover IGF-I serum levels
are increased in patients with locally advanced colorectal
cancer (pT3 and pT4), in comparison to less advanced
(pT2) [72].
In familial breast cancer an association between high
IGF-I levels and cancer development has been proved [73-
75] and in breast cancer survivors IGF-I can also predict
higher risk of recurrence [76].
Regarded cancer metastasis recently has been
documented a role for the IGF system in several human
cancer such as colorectal [77] and gastric cancer [78].
IGF-IR is also expressed by endothelial progenitor
cells from bone marrow (EPCs). BM-derived cells are
precursors for both hematopoietic and endothelial cells; in
particular EPCs represent the non-hematopoietic (CD45-)
BM derived cell population [79].
Exciting new data have shown that tumor
neovascularization, which supports growth and
dissemination of tumors, involves recruitment of EPCs.
An increased mobilization of EPCs has been associated
with cancer, vascular injury, and poor prognosis in patients
with lymphoma, thus establishing the signicance of these
cells in tumor progression.
BM-derived cells are thought to merge with the
wall of a growing blood vessel, where they dierentiate
into endothelial cells [80]. After treatment with vascular-
targeting therapies, the number of EPCs increases, and
they invade and colonize the viable rim of tumor that
remains, thereby contributing to the rapid regrowth [81].
Recently some insights have been obtained about the
role of IGF in progenitor cells relocalization, suggesting a
role of IGFs during BM-derived cell mobilization.
IGF has an important role in the angiogenic
processes, indeed tumor neovasculature is also inuenced
by IGF which promoting proliferation and migration of
endothelial cells, mobilization and colonization of tumor
niche by BM-derived cells.
Inammation
MetS is frequently associated with inammation.
Regarding hyperglycemia is well-known that an excess
of glucose promotes formation and accumulation of
advanced glycation end-products (AGEs) [23]. AGEs
bind to AGE receptors on macrophages, endothelial
and mesangial cells, causing receptor-induced Reactive
Oxygen Species (ROS) production. ROS can damage DNA
through dierent mechanisms such as DNA deletions,
modications and frame shifts [82]. DNA damage can
aect genes linked to cell survival or cell proliferation like
p53 and Ras respectively, and triggers cancer progression.
So these compounds cause degenerative changes in cells,
alter signaling pathways of their metabolism and may lead
to carcinogenic mutations.
Even inamed adipose tissue may play a critical role
in pathogenesis of several cancers, such as breast, colon,
pancreas, and kidney [83].
Visceral adipose tissue can release several cytokines
as tumor necrosis factor (TNF-α) and interleukin-6 (IL-6)
which are considered to form a link between inammation
and cancer. Indeed it has been shown, in obese women,
elevated circulating levels of TNF-α and IL-6 which are
associated with development and progression of breast
tumors [84]. These cytokines are known to promote
angiogenesis and they are positively correlated with
insulin resistance.
Particularly TNF-α activates two pathways: MAPK
and NF-kB pathway. NF-kB is a transcription factor that
activates the expression of genes which promote cell
proliferation, inhibit apoptosis and therefore enhance cell
survival. NF-kB also increases production of nitrogen
oxide (NO) and favors formation of ROS [85].
Another family of small cytokines is chemokines,
of which the circulating Monocyte Chemoattractant
Protein-1 (MCP-1) promotes the recruitment of monocytes
to adipose tissue, where the cells dierentiate and become
macrophages [86].
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Inltrated macrophages surround the adipocyte in a
histologically characteristic pattern known as crown-like
structures (CLS) [87] and eectively these inammatory
foci were rst observed in visceral fat of metabolic
syndrome patients.
Moreover, components of metabolic syndrome have
a positive correlation with C reactive-protein (CRP), an
acute phase protein synthesized and secreted by the liver
[85].
Particularly it has been shown a highly signicant
correlation between visceral adiposity and CRP, and also
patients with increasing number of metabolic syndrome
components presented a linear increase in CRP levels
[89]. This protein is also associated with an augmented
risk to developed many types of cancer such as colorectal,
cervical and ovarian cancer.
Hence CRP can probably be used as a marker of
chronic inammation in metabolic syndrome patients.
Estrogen signaling
Visceral adiposity regulates the synthesis of the
endogenous sex steroids such as estrogens, androgens and
progesterone through several mechanisms. In particular
in men and postmenopausal women, adipose tissue is the
principal site of estrogens synthesis [46].
In fertile women estrogens, of which oestradiol is the
major, are predominantly produced by the ovary. Whereas
in menopause, estrogens production decreases and remains
a peripheral conversion, primarily in the adipose tissue,
of androgens by the cytochrome P450 enzyme aromatase
located in adipocytes [86]. As a result, increasing adiposity
with age has been suggested to contribute to increase total
and free circulating estrogen levels [90].
Another consequence of increased visceral adiposity
is reduction in hepatic synthesis and blood concentrations
of sex-hormone binding globulin (SHBG), a plasmatic
binding protein with high specic anity for estradiol
[91] that generally brings out an increase in the fraction of
bioavailable estradiol.
Epidemiological studies have given several
evidence that this shift in circulating levels of sex steroids,
induced through adiposity, could in large part explain the
associations between anthropometric indices of excess
weight and risks of breast (postmenopausal women
only) and endometrial (both pre- and postmenopausal
women) cancers. Especially estrogens show a central
role in regulating cellular dierentiation, proliferation
and apoptosis induction [92-94] in these tissue types, as
indicated by a large amount of experimental and clinical
demonstrations.
Indeed in estrogen receptor-positive breast and
endometrial cancers, estradiol acts as a powerful growth
factor that supports tumor growth; estrogen activity
through dierent and complex mechanisms may promote
tumor development and progression.
Direct eects of estrogens include stimulation of
cellular proliferation and inhibition of apoptosis via ER-α
agonism as well as induction of vascular endothelial
growth factor and angiogenesis [95, 96]. Furthermore,
carcinogenesis is probably due to mutagenic eects of
estrogen via genotoxic metabolites [95].
Dierential eects of menopause on cancer
incidence observed in epidemiologic studies point to the
potential role of estrogen in development and progression
of these malignancies.
In postmenopausal women risk of estrogen
receptors-positive breast cancer development is inversely
related to blood levels of SHBG [97, 98], reply to
endometrial cancer in which was reported an increased
cancer risk among both pre and postmenopausal women
who have comparatively low plasma levels of SHBG [99,
100].
NEW THERAPEUTIC OPPORTUNITIES
Many therapeutic approaches are studied to face the
metabolic syndromes and its impact on development and
progression of certain types of cancer.
As described above, insulin is the most important
hormone in the metabolic syndrome and its binding with
receptors induces inhibition of apoptosis and promotes
cell proliferation. Cancer cells are characterized by an
overexpression of insulin receptors (IGF-R) suggesting
their important role in tumorigenesis and growth. In
addition, surrounding stromal tissue of tumor cells
produces IGF-I and IGF-II [101] suggesting that activation
of the IGF-IRs of tumor cells may be mediated by IGFs in
a paracrine and autocrine way [102]. Only recently tools
for targeting the IGF pathways are becoming available
for therapy. More than 10 IGF/IGF-IR inhibitors have
entered clinical trials and they can be divided in three
main classes: monoclonal antibodies against IGF-IR;
monoclonal antibodies against IGF-I and IGF-II ligands;
and IGF-IR tyrosine kinase inhibitors [103]. These
molecules, used in clinical trials of patients with tumors,
including non-small cell lung cancer, breast cancer, and
pancreatic cancer, failed to show clinical benet. Possible
reasons for failure include the complexity of the IGF-IR/
insulin receptor system, in fact the IGF-IR can cross-talk
with other receptor tyrosine kinase and their downstream
eectors and this situation can compensate the inhibition
of IGF-IR by a specic antibody. Moreover, the formation
of complexes between IGF-IR and specic antibodies lead
to an increase of soluble free IGF-I and IGF-II that can
leave the circulation to stimulate IGF receptors present
on cell surface of cancer cells [104]. Up to date it is still
necessary to make a successful IGF-IR target therapy.
Another condition of metabolic syndrome associated
with multiple cancers is obesity. This metabolic condition
is characterized by the deregulation of adipokines such
as leptin and adiponectin responsible of maintenance of
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metabolic homeostasis and inammation, angiogenesis,
proliferation and apoptosis modulation.
For therapeutic approach an important aspect should
be to consider that adiponectin can antagonize the actions
of leptin. If adiponectin has been shown to decrease
growth and proliferation, increase apoptosis, decrease
invasion and vessel density in murine cancer models,
leptin has been shown to increase proliferation, migration,
and invasion of cancer cells.
Elevated leptin levels have been reported in
hepatocellular carcinoma and prostate cancers whereas
levels are unchanged in breast cancer patients where leptin
receptor expression is instead enhanced. At the same time,
adiponectin single-nucleotide polymorphisms have been
shown to increase prostate, colon and breast cancer risk.
As therapeutic approach recent evidence suggests that
soluble leptin receptor can act to bind circulating leptin
attenuating its activity, although additional preclinical
studies are needed to test the real ecacy in vivo [105].
Moreover the use of adiponectin as a direct therapeutic
agent is not yet available because of its expensive
production and the diculty in converting the full size
adiponectin protein into a drug. Up to date an adiponectin-
based short peptide that mimics adiponectin action has
been synthesized and called ADP 355 and its test in vitro
cells reduced the proliferation in a dose-dependent manner
[106]. Alternately, targeting downstream adipokine
signaling mediators is likely to be a good choice.
PPAR-γ is highly expressed in adipose tissue
and it has high anity for thiazolidinediones (TZDs)
which induces insulin-sensitizing. TZDs which are
PPAR-γ agonists increase the secretion of adiponectin
from adipocytes altering tumor development but after a
long-term treatment. If glitazones (PPARγ agonists) are
important to induce antiproliferative or proapoptotic
eects in cancer cells taking advantage of the inhibition
of glycogen synthase kinase-3β (GSK-3β), a crucial
activator of nuclear factor-kappaB (NF-kB), at the same
time PPARγ agonists provoke several physiological
modications that inuence lipid metabolism, glucose
homeostasis and activation of inammation signaling
cascade (Figure 3). It has as consequence that PPARs
could have prognostic and/or therapeutic roles but there
is urgent need to better understand the real positive eects
on tumor treatments. Another controversial aspect of
TZDs therapy is that PPAR-γ activation may also aect
bone through an increase of bone marrow adiposity and
a decrease in osteoblastogenesis, resulting in reduced
Figure 3: Potential intracellular pathways directly linking MetS with cancer. Enzymatic proteins (involved in the Warburg
eect) which may represent potential target therapies in oncological patients are also represented (white circles). Drugs are shown in white
boxes.
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bone formation [107]. Another down-stream targeting of
the adiponectin can be the activation of AMPK through
metformin. Metformin inhibits mitochondrial complex
I in the liver to interfere with ATP production [108,
109]. This causes an energy stress with the consequent
activation of the AMP activated protein (AMPK) via an
LKB1-dependent mechanism; liver kinase B1 (LKB1) is a
protein threonine kinase that has tumor-suppressor activity
and it is frequently loss in human cancers (Figure 3).
Mechanisms to target the leptin pathway include the use of
common inhibitors such as signal transducer and activator
of transcription 3 (STAT3), Akt and Raf inhibitors to block
cell growth and survival. Dual target therapies directed
versus the decreasing response from leptin stimulation and
increasing the response from adiponectin pathways have
some potential for more ecacious cancer therapy.
Another approach to treat cancer is the one based
on targeting the genetic alterations that are known to
promote cancer such as the metabolic phenotype that
is characterized by cell-autonomous nutrient uptake
and reorganization of metabolic pathways to support
biosynthesis [110-112]. As described above cancer cells,
unlike their normal counterpart, metabolize glucose by
aerobic glycolysis. This phenomenon, known as Warburg
eect, is characterized by increased glycolysis and lactate
production regardless of oxygen availability. It is possible
to safely target metabolic pathways in patients. The small
molecule dichloroacetate (DCA) is used to treat patients
with lactic acidosis resulting from rare inborn errors of
mitochondrial metabolism but can be used also to target
pyruvate dehydrogenase kinase (PDK). This kinase
is expressed in many cancers as a result of increased
activation of the transcription factor hypoxia inducible
factor (HIF) [113, 114]. PDK is a negative regulator
of the pyruvate dehydrogenase complex (PDH) [115].
PDH catalyses oxidative decarboxylation of pyruvate to
acetyl CoA, which allows the entry of pyruvate into the
tricarboxylic acid (TCA) cycle and away from lactate
production. Thus, DCA mediated inhibition of PDK
leads to the activation of PDH, increased metabolism of
pyruvate to acetyl CoA and decreased lactate production.
Another therapeutic approach can be to target the
glucose transporters which are responsible of glucose
uptake. Most of glucose transporters such as GLUT3
and GLUT1 are not expressed in normal cells but they
can be expressed at high levels in cancer cells. Antibodies
specic for those transporters or analogues which bind
the receptor can be a way to block nutrient uptake and
starving cancer cells. Some enzymes which are involved
in glucose metabolism can be used as therapeutic
targets: the hexokinase 2 (HK2) which is responsible of
trapping and transforming glucose in glucose 6 phosphate
(G6P); the phosphofructokinase 2 (PFK2) which,
by generating fructose-2,6-bisphosphate (F-2,6-BP),
activates phosphofructokinase 1 (PFK1) to increase ux
versus glycolysis; the pyruvate kinase M (PKM2) which
promotes aerobic glycolysis etc.. but all these enzymes are
not so selective for tumoral cells and for most of them
the anticancer agent developed is still of limited ecacy
for the low tolerability in patients. Because lactate is
excreted from the cell, inhibiting lactate production or
lactate transport out of the cell are two strategies that
directly target the Warburg eect in cancer. The family
of monocarboxylate transporters (MCTs) comprises the
major proteins that are responsible for lactate export
in glycolytic cells, including cancer cells (Figure 3).
Considering that the target of MCTs by small molecules
also inhibits the proliferation of lymphocytes, this suggests
that impaired immune function is a side eect of targeting
lactate export in cancer [116].
CONCLUSIONS AND FUTURE
DIRECTIONS
Worldwide, the prevalence of MetS is increasing,
and in the United States, nearly two-thirds of adults are
either overweight or obese. Given the rising epidemic of
metabolic syndrome worldwide, especially in developing
countries, and the potential links among MetS, obesity,
androgen metabolism, diabetes, and inammation, it is
critical to better understand the complex relations between
MetS and cancer risk and the role of chronic inammation
in MetS and the pathogenesis of cancer.
Clearly, to dissect these interrelated factors, future
prospective studies should be suciently large, with better
assessment of overall and abdominal obesity and with
biochemical measures, such as insulin concentrations, sex
steroids, and IGFs, to clarify the complex interplays of
these factors on cancer risk. Etiologic heterogeneity should
be considered. Further renement of molecular cancer
classication, using biomarkers and genetic markers,
coupled with a clearer understanding of the cellular and
molecular pathways involved, should prove illuminating.
Factors such as grade, stage, and aggressiveness of tumors
should be assessed and incorporated into the analysis.
Methodological studies are also needed to gain a better
understanding of the determinants of these biomarkers,
including insulin, leptin, adipokines, IGFs, sex steroids,
and inammatory mediators, and to provide biological
data to help interpret the results.
A potential role for IGF-IR target therapy, PPARs
agonists, TZDs and metformin in the adjuvant treatment
of cancers is advisable, but further studies are warranted in
order to better clarify the impact of these drugs in cancer
therapy. At the time of writing, nearly 60 patents have
been led for small-molecule activators of AMPK, and
it is hoped that some of these may enter human clinical
trials soon. It seems likely that by the end of this decade
we will have a much clearer picture of whether drugs that
are selective for MetS will have a place in the treatment
of cancer.
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ACKNOWLEDGMENTS
We declare that all named as authors have made a
sucient contribution to the work.
Authors have obtained all necessary consent from
Grant support: Italian Ministry of Research (PRIN grant)
and RSA (ex 60%). C M was supported by fellowship
from University of Marche.
CONFLICTS OF INTEREST
There is no conict of interest.
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