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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 affected 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 inflammation. 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.
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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, inammation
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
aected 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 inammation. 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 signicance 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
eective 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 denitions [2]; however the
most widely accepted denition was issued by the Adult
Treatment Panel III of the National Cholesterol Education
Program (NCEP-ATP III). According to the NCEP-ATPIII
denition, MetS is dened having three or more of the
following ve risk factors: 1) visceral obesity dened
by waist circumference (population and country specic
denitions); 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 aects 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 eects in
the body that can have MetS, like producing hormones
and growth factors that aect the way our cells work.
This review presents current perspectives on the relations
of metabolic syndrome with cancer risk, oering 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
aected 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 dier 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 aected 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 dierent 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 signicantly
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 aected 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 aects 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 inuence cancer development and progression such as visceral adiposity, hyperinsulinemia, IGF/IGF-R axis, inammation
and estrogen signaling.
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treatment and its severe late eects like cardiovascular
disease [15].
MECHANISMS THAT INCREASE THE
RISK OF CANCER IN METABOLIC
SYNDROME
Patients aected 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 conrmed 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 inammatory 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-
inammatory character and it’s a negative regulator of
angiogenesis, so it is considered to have anticancer eect
[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 dierentiate
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
inammation 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, dierentiates 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 signicant 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, esterication of free fatty acids in adipocytes,
inhibits lipolysis and gluconeogenesis; stimulates also cell
growth and dierentiation [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 dened 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-inammatory 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 dierent tumor
types have conrmed 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
signicant 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 specic sites was emphasized by Stattin et
al. in a prospective study [55].
Recently our group showed that the hyperglycemic
state is sucient 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 eects 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-anity-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 aect levels
of circulating IGF-I and IGFBP-III. IGF-I stimulates cell
proliferation and inhibits apoptosis, interacting with its
specic receptor on cell membrane, IGF-IR, and with
insulin receptor (IR) even if with low anity [62]. These
interactions are regulated by IGFBPs. The IGFBPs can
promote stabilization in the circulation, regulation of the
eux 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 eects are also achieved through the
activation of Ras/MAPK/extracellular signal-related
kinase 1/2 (ERK-1/2) (21).
Cancer cells show signicant 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 signicantly 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 specically 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 signicance of these
cells in tumor progression.
BM-derived cells are thought to merge with the
wall of a growing blood vessel, where they dierentiate
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 inuenced
by IGF which promoting proliferation and migration of
endothelial cells, mobilization and colonization of tumor
niche by BM-derived cells.
Inammation
MetS is frequently associated with inammation.
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 dierent mechanisms such as DNA deletions,
modications and frame shifts [82]. DNA damage can
aect 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 inamed 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 inammation
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 dierentiate and become
macrophages [86].
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Inltrated macrophages surround the adipocyte in a
histologically characteristic pattern known as crown-like
structures (CLS) [87] and eectively these inammatory
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 signicant
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 inammation 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 specic anity 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 dierentiation, 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 dierent and complex mechanisms may promote
tumor development and progression.
Direct eects 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 eects of
estrogen via genotoxic metabolites [95].
Dierential eects 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 benet. 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
eectors and this situation can compensate the inhibition
of IGF-IR by a specic antibody. Moreover, the formation
of complexes between IGF-IR and specic 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 inammation, 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 ecacy in vivo [105].
Moreover the use of adiponectin as a direct therapeutic
agent is not yet available because of its expensive
production and the diculty 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 anity 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
eects 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
modications that inuence lipid metabolism, glucose
homeostasis and activation of inammation 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 eects
on tumor treatments. Another controversial aspect of
TZDs therapy is that PPAR-γ activation may also aect
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
eect) 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 ecacious 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
eect, 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
specic 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 ecacy
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 eect 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 eect 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 inammation, it is
critical to better understand the complex relations between
MetS and cancer risk and the role of chronic inammation
in MetS and the pathogenesis of cancer.
Clearly, to dissect these interrelated factors, future
prospective studies should be suciently 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 renement of molecular cancer
classication, 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 inammatory 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
sucient 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 conict of interest.
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... MS is associated with a 1.5-fold increase in the risk of all-cause mortality [5]. Recent studies have examined MS and its components with cancer recurrence and overall mortality [6,7]. The relationship between MS and cancer is complex; individual components of the MS are known 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, including cancer mortality. ...
... The relationship between MS and cancer is complex; individual components of the MS are known 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, including cancer mortality. It seems self-evident that a condition characterized by multiple risk factors, like MS, will carry a greater risk for adverse clinical outcomes than will a single risk factor [6] The more components of MS present, the higher the mortality in cancer patients [8]. Contrarily, a study from Li W et al [9]. ...
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This study examines remaining life expectancy (RLE) after a cancer diagnosis, focusing on age, sex, cancer type, and metabolic syndrome (MS) components, using data from the SIDIAP database in Catalonia (2006–2017). RLE was analyzed for 13 cancer types, stratified by sex and MS components. The cohort study includes 183,364 individuals followed from diagnosis until death, transfer, or study end (December 2017). RLE at age 68 (median diagnosis age) was calculated based on MS components (0, 1, 2, and ≥ 3). Men aged 68 with 0 MS components had an RLE of 13.2 years, compared to 8.9 years for those with ≥ 3 MS. Women had an RLE of 15.9 years with 0 MS components versus 11.4 years with ≥ 3 MS. RLE varied by cancer type, with the highest RLE in men seen in prostate cancer and in women in non-Hodgkin lymphoma. The lowest RLE for both sexes was in pancreatic cancer. The largest differences between 0 and ≥ 3 MS components were observed in non-Hodgkin lymphoma and the smallest in pancreatic cancer. Increased MS components were associated with reduced RLE in at least 8 cancer types for men and 9 for women. Prevention strategies targeting MS components could increase RLE in cancer patients.
... Recent research has indicated an additional potential relationship between MetS and cancer [4,5]. Various cancer types, such as stomach, oesophageal, and colon, have been shown to be more prevalent in individuals with MetS, and more than two in ten cancers in the UK are thought to be linked to MetS [6,7]. By identifying potential biomarkers and targeting modifiable risk factors common to MetS and cancer, healthcare professionals can empower individuals with MetS to take proactive measures to reduce their cancer risk and improve overall health outcomes. ...
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Background The relationship between serum urea concentration and cancer in patients with metabolic syndrome (MetS) remains unclear. This study aimed to investigate the association between serum urea concentration and 16 site-specific cancers, overall cancer incidence, and cancer mortality in individuals with MetS. Methods We analysed the data of 108,284 individuals with MetS obtained from the UK Biobank. The Cox proportional hazards model was used to determine the association between serum urea concentration at recruitment and cancer. The Benjamini–Hochberg correction was used to account for multiple comparisons. Results Over the median follow-up period of 11.86 years, 18,548 new incident cases of cancer were documented. There were inverse associations of urea concentration with overall cancer incidence, and the incidence of oesophageal and lung cancers, with respective hazard ratios (95% confidence intervals) [HR (95% CI)] for the highest (Q4) vs lowest (Q1) urea quartiles of 0.95 (0.91–0.99), 0.68 (0.50–0.92), and 0.76 (0.64–0.90). However, high serum urea concentrations increased the male prostate cancer risk (HR 1.15; 95% CI 1.02–1.30). Although the Cox model indicated a protective effect of higher urea levels against stomach (HR 0.67; 95% CI 0.45–0.98; p = 0.040; FDR 0.120) and colorectal cancer (HR 0.86; 95% CI 0.74–0.99; p = 0.048; FDR 0.123), no strong evidence of association was found after applying the Benjamin-Hochberg correction. Moreover, across the median follow-up period of 13.77 years for cancer mortality outcome, 5034 cancer deaths were detected. An “L-shaped” nonlinear dose–response relationship between urea concentration and cancer mortality was discovered (p-nonlinear < 0.001), and the HR (95% CI) for urea concentration Q4 vs Q1 was 0.83 (0.77–0.91). Conclusions Serum urea concentration can be considered as a valuable biomarker for evaluating cancer risk in individuals with MetS, potentially contributing to personalised cancer screening and management strategies.
... It is important to mention that there is no significant link between polycystic ovary syndrome and ovarian or breast cancer [13]. On the other hand, metabolic syndrome is connected to a higher probability of developing endometrial cancer and an increased incidence of postmenopausal breast cancer, pancreatic cancer, and colorectal cancer [14,15]. The combined risks of PCOS and MS are the same as above. ...
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Women with polycystic ovary syndrome (PCOS) have a high prevalence of metabolic syndrome (MS), with rates up to 33%. This is associated with long-term consequences such as cardiovascular diseases, type 2 diabetes mellitus (T2DM), cancer, sleep apnea, and psychological issues. The prevalence of MS worldwide is often associated with obesity and T2DM, yet regional variations are reported. In this study, 122 women consulting general practice and family medicine physicians were evaluated, revealing a BMI exceeding 30 kg/m². Among MS criteria, the most common diagnoses were T2DM in 29 patients, insulin resistance (IR) in 36, arterial hypertension (AH) in 51, reduced HDL levels in 53, and elevated triglycerides in 39. Further analysis revealed 16 unique combinations of MS components in these patients, with 75% of PCOS cases exhibiting three MS components and 25% having four. Additionally, research indicated that most women with PCOS face persistent, treatment-resistant obesity, with a notably higher BMI (ρ=0.87; r=0.76). These findings highlight the multifactorial nature of PCOS and MS etiology.
Chapter
The book focuses on a new interdisciplinary understanding of the metabolic syndrome (MetS) for better health maintenance. It provides an updated understanding of the underlying principles, possible targets, implementation approaches and the effectiveness of various avoidance strategies in MetS. The chapters cover a wide range of topics, including major advances in general aspects of metabolic syndrome, functional changes, new diagnostic methods, genotype-phenotype associations, the effect of exercise and multitarget pharmacotherapeutic strategies for MetS and perspectives on personalized medicine. It also discusses epigenetic mechanisms underlying MetS-related processes and epigenetic strategies to prevent related diseases. The book also presents summarized information about the associated factors and mechanisms linking cancer and MetS and to identify potential targets for the treatment of these patients. A better understanding of the various linkages will provide greater insight into the management of cancer patients by preventing MetS and related alterations. Key Features - Comprehensive information focused on the biological factors and physiological changes associated with metabolic syndrome - Updates on metabolic syndrome diagnosis and management - Summarized information on clinical implications for cancer therapy - Thoroughly referenced chapters with summaries and discussions for quick understanding The book is an informative resource for interdisciplinary scientists and researchers in life sciences and medicine. Furthermore, it, including the insulin-like growth factor (IGF-1) pathway, estrogen signaling, visceral adiposity, hyperinsulinemia, hyperglycemia, aromatase activity, adipokinase production, angiogenesis, oxidative stress, DNA damage and pro-inflammatory cytokines, and their clinical implications in cancer therapy.
Chapter
The book focuses on a new interdisciplinary understanding of the metabolic syndrome (MetS) for better health maintenance. It provides an updated understanding of the underlying principles, possible targets, implementation approaches and the effectiveness of various avoidance strategies in MetS. The chapters cover a wide range of topics, including major advances in general aspects of metabolic syndrome, functional changes, new diagnostic methods, genotype-phenotype associations, the effect of exercise and multitarget pharmacotherapeutic strategies for MetS and perspectives on personalized medicine. It also discusses epigenetic mechanisms underlying MetS-related processes and epigenetic strategies to prevent related diseases. The book also presents summarized information about the associated factors and mechanisms linking cancer and MetS and to identify potential targets for the treatment of these patients. A better understanding of the various linkages will provide greater insight into the management of cancer patients by preventing MetS and related alterations. Key Features - Comprehensive information focused on the biological factors and physiological changes associated with metabolic syndrome - Updates on metabolic syndrome diagnosis and management - Summarized information on clinical implications for cancer therapy - Thoroughly referenced chapters with summaries and discussions for quick understanding The book is an informative resource for interdisciplinary scientists and researchers in life sciences and medicine. Furthermore, it, including the insulin-like growth factor (IGF-1) pathway, estrogen signaling, visceral adiposity, hyperinsulinemia, hyperglycemia, aromatase activity, adipokinase production, angiogenesis, oxidative stress, DNA damage and pro-inflammatory cytokines, and their clinical implications in cancer therapy.
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The rapid increase in metabolic syndrome (MetS) as a major public health problem may be attributed to changes in population behavior patterns in modern society, including nutritional habits and physical activity. Therefore, this study was conducted to investigate the association between dietary diversity score (DDS) and metabolic syndrome in adults. In this cross-sectional study, 9,990 participants aged 35–70 years from the Rafsanjan Cohort Study (RCS) were included. Demographic, medical, and habitual histories were collected. DDS was calculated using a food frequency questionnaire (FFQ). All analyses were performed using Stata 14, with p-values < 0.05. In total, 9,990 subjects (46.6% men and 53.4% women) with a mean age of 35–70 years were included in this study. Based on the DDS, subjects were divided into four groups (quartiles). The multivariate-adjusted model showed that the risk of MetS increased by 18% in the third quartile and by 25% in the fourth quartile (OR: 1.18; 98% CI: 1.02–1.36 and OR: 1.25; 98% CI: 1.06–1.48, respectively). Additionally, an increased risk of high serum triglyceride levels was observed in the third quartile (OR: 1.19; 98% CI: 1.05–1.35). The results suggest that there is a relationship between DDS and metabolic syndrome, although this relationship changed after adjusting for confounders.
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Metabolic disorders have long been a challenge for medical professionals and are a leading cause of mortality in adults. Diabetes, cardiovascular disorders (CVD), renal dysfunction, and ischemic stroke are the most prevalent ailments contributing to a high mortality rate worldwide. Reactive oxygen species are one of the leading factors that act as a fundamental root cause of metabolic syndrome. All of these disorders have their respective treatments, which, to some degree, sabotage the pathological worsening of the disease and an inevitable death. However, they pose a perilous health hazard to humankind. Cysteine, a functional amino acid shows promise for the prevention and treatment of metabolic disorders, such as CVD, Diabetes mellitus, renal dysfunction, and ischemic stroke. In this review, we explored whether cysteine can eradicate reactive oxygen species and subsequently prevent and treat these diseases.
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Gastric cancer (GC), a prevalent disease in Asian countries, presents a substantial global health challenge. The risk factors for GC include Helicobacter pylori infection, diet, smoking, alcohol, and metabolic syndrome (MetS). This review meticulously examines the intricate connections between MetS and GC, focusing on visceral adipocytes, hormonal factors, obesity, and their impact on survival outcomes. Visceral adipocytes, which secrete inflammatory cytokines and hormones, play a pivotal role in influencing cancer development. Hormonal factors demonstrate nuanced associations with specific GC subtypes, underscoring the complexity of their impact. Large-scale studies exploring obesity-related factors reveal sex-specific nuances and underscore the importance of considering overall weight and body composition. Furthermore, the review explores the impact of eradication therapy for H. pylori infection, which is the most significant factor in the onset of GC, on the components of MetS. Additionally, the influence of MetS on postoperative outcomes and survival in GC patients highlights the interplay between therapeutic interventions and lifestyle factors. This comprehensive exploration sheds light on the multifaceted relationship between MetS and GC, providing valuable insights for future research and preventive strategies.
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The IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons why IGF-I R targeted therapy fails to inhibit growth of human cancers. It has become clear that intracellular signaling pathways are highly interconnected and complex instead of being linear and simple. One of the most potent candidates for failure of IGF-IR targeted therapy is the insulin receptor isoform A (IR-A). Activation of the IR-A by insulin-like growth factor-II (IGF-II) bypasses the IGF-IR and its inhibition. Another factor may be that anti-cancer treatment may reduce IGF-IR expression. IGF-IR blocking drugs may also induce hyperglycemia and hyperinsulinemia, which may further stimulate cell growth. In addition, circulating IGF-IRs may reduce therapeutic effects of IGF-IR targeted therapy. Nevertheless, it is still possible that the IGF-IR may be a useful adjuvant or secondary target for the treatment of human cancers. Development of functional inhibitors that affect the IGF-IR and IR-A may be necessary to overcome resistance and to make IGF-IR targeted therapy successful. Drugs that modify alternative downstream effects of the IGF-IR, so called “biasing agonists,” should also be considered.
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Both metabolic syndrome (MetS) and chronic kidney disease (CKD) are increasing in incidence and lead to significant cardiovascular morbidity and mortality. The relationship between these two entities is complex. Individual components of the MetS are known risk factors for incident kidney disease, but it is not clear how the clustering of these components is linked to the development and progression of kidney disease. Cross-sectional studies show an association of the MetS and prevalent CKD; however, one cannot draw conclusions as to which came first – the MetS or the kidney disease. Observational studies suggest a relationship between MetS and incident CKD, but they also demonstrate the development of MetS in patients with established CKD. These observations suggest a bidirectional relationship. A better understanding of the relationship between components of the MetS and whether and how these components contribute to progression of CKD and incident cardiovascular disease could inform more effective prevention strategies.
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Background: Metabolic syndrome is known to predispose to atherosclerosis. C-reactive protein, a marker of systemic inflammation is significantly associated with the atherosclerotic process. Methods: We prospectively studied the relationship between high-sensitivity C-reactive protein (hs-CRP) with various components of metabolic syndrome in 91 patients with metabolic syndrome at our tertiary care centre in South India. Results: The mean age of patients was 57.5 ± 9.8 years; there were 67 (73.6%) males. On univariate analysis, hs-CRP was found to be significantly increased in patients with diabetes mellitus (p < 0.021) and those with abnormal waist circumference (p<0.003). There was no significant association between hs-CRP and high triglycerides, hypertension, and reduced high density lipoprotein cholesterol. Further, hs-CRP increased significantly with increasing number of components of metabolic syndrome (p< 0.008). Conclusions: Measurement of hs-CRP can be used as a surrogate marker of chronic inflammation in patients with metabolic syndrome.
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Purpose The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men. Patients and Methods We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone– binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine. Results Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FSH were higher, and inhibin B and total and free testosterone were lower in chemotherapy patients than controls. Adrenal and thyroid hormone production were unaffected. Chemotherapy patients with the metabolic syndrome (n 22; 26%) had a higher body mass index (BMI) pretreatment, a larger BMI increase during follow-up, lower total testosterone, and higher urinary cortisol metabolite excretion than those patients without the metabolic syndrome. BMI and insulin were associated with the metabolic syndrome, while total testosterone and urinary cortisol metabolite excretion were associated with BMI. Conclusion We found gonadal dysfunction, but normal adrenal and thyroid function. Through its association with BMI, testosterone may play a role in the development of the metabolic syndrome in long-term TC survivors.
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Aberrant activation of the androgen receptor (AR) may be one of the mechanisms which contribute to progression of prostatic carcinoma to an androgen-independent stage. We investigated effects of growth factors on stimulation of the AR-mediated gene transcription in human prostatic tumor cell lines. DU-145 cells, which do not contain endogenous AR, were cotransfected with an androgen-inducible chloramphenicol acetyltransferase (CAT) reporter gene and an AR expression vector. The reporter gene (CAT) was driven either by artificial promoters consisting of one or two androgen-responsive elements in front of a TATA box or by the promoter of the prostate-specific antigen (PSA) gene, a naturally occurring androgen-inducible promoter. Insulin-like growth factor-I (IGF-I), at a concentration of 50 ng/ml, stimulated AR-mediated reporter gene transcription to the same extent as the synthetic androgen methyltrienolone. This growth factor was effective irrespective of the nature of the androgen-inducible promoter. Keratinocyte growth factor (KGF) and epidermal growth factor (EGF), at concentrations of 50 ng/ml, activated CAT reporter gene transcription only in experiments in which the artificial promoter with two androgen-responsive elements was used. Insulin-like growth factor-II and basic fibroblast growth factor displayed no effect on AR-mediated gene transcription. None of the growth factors stimulated reporter gene activity in control experiments when added to cells cotransfected with the CAT gene and an empty expression vector. AR activation by IGF-I, KGF, and EGF was completely inhibited by the pure AR antagonist casodex, showing that these effects are AR mediated. Activation of endogenous AR by growth factors was studied in the LNCaP cell line by determination of PSA secretion. IGF-I, at a concentration of 50 ng/ml, increased the PSA level in the supernatant of this cell line 5-fold. Again, the IGF-I effect on PSA secretion was blocked by casodex. Our results provide evidence that IGF-I, KGF, and EGF directly activate the AR in the absence of androgens, which means that the androgen-signaling chain may be activated by growth factors in an androgen-depleted environment. These findings may have implications for endocrine therapy for metastatic prostatic carcinoma.
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Obesity is a leading modifiable risk factor for the development of several epithelial malignancies. In addition to increasing risk, obesity also confers worse prognosis for many cancers. Obesity represents an overall state of energy imbalance frequently associated with systemic effects including insulin resistance, altered hormone signaling, and high circulating levels of proinflammatory mediators. In addition to its systemic effects, obesity causes subclinical white adipose inflammation including increased tissue levels of proinflammatory mediators. Both local and systemic effects are likely to contribute to the development and progression of cancer. An understanding of the interplay between local and systemic alterations involved in the obesity-cancer link provides the basis for developing interventions aimed at mitigating the protumorigenic effects.