Content uploaded by Horatiu Silaghi
Author content
All content in this area was uploaded by Horatiu Silaghi
Content may be subject to copyright.
www.wjgnet.com
Online Submissions: wjg.wjgnet.com World J Gastroenterol 2009 November 7; 15(41): 5141-5148
wjg@wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
doi:10.3748/wjg.15.5141 © 2009 The WJG Press and Baishideng. All rights reserved.
ORIGINAL ARTICLES REVIEW
Metabolic syndrome and risk of subsequent colorectal cancer
Raluca Pais, Horatiu Silaghi, Alina Cristina Silaghi, Mihai Lucian Rusu, Dan Lucian Dumitrascu
Raluca Pais, Mihai Lucian Rusu, Dan Lucian Dumitrascu,
2nd Department of Internal Medicine, University of Medicine
and Pharmacy (Iuliu Hatieganu), Str Clinicilor 2-4, Cluj-Napoca
400006, Romania
Horatiu Silaghi, 2nd Department of Surgery, University of
Medicine and Pharmacy (Iuliu Hatieganu), Cluj-Napoca 400006,
Romania
Alina Cristina Silaghi, Department of Endocrinology, University
of Medicine and Pharmacy (Iuliu Hatieganu), Cluj-Napoca
400006, Romania
Author contributions: Pais R designed the research and wrote
the paper; Silaghi H and Silaghi AC performed the literature
review; Rusu ML and Dumitrascu DL suggested the subject and
revised the paper.
Supported by CNCSIS project number 1342 of Romanian
Ministry of Education
Correspondence to: Dan Lucian Dumitrascu, Professor, 2nd
Department of Internal Medicine, University of Medicine and
Pharmacy (Iuliu Hatieganu), Str Clinicilor 2-4, Cluj-Napoca
400006, Romania. ddumitrascu@umfcluj.ro
Telephone: +40-264-593355 Fax: +40-264-593355
Received: August 22, 2009 Revised: September 11, 2009
Accepted: September 18, 2009
Published online: November 7, 2009
Abstract
The metabolic syndrome and visceral obesity have an
increasing prevalence and incidence in the general
population. The actual prevalence of the metabolic
syndrome is 24% in US population and between
24.6% and 30.9% in Europe. As demonstrated by
many clinical trials (NAHANES Ⅲ, INTERHART) the
metabolic syndrome is associated with an increased
risk of both diabetes and cardiovascular disease. In ad-
dition to cardiovascular disease, individual components
of the metabolic syndrome have been linked to the de-
velopment of cancer, particularly to colorectal cancer.
Colorectal cancer is an important public health prob-
lem; in the year 2000 there was an estimated total of
944 717 incident cases of colorectal cancer diagnosed
world-wide. This association is sustained by many epi-
demiological studies. Recent reports suggest that indi-
viduals with metabolic syndrome have a higher risk of
colon or rectal cancer. Moreover, the clusters of metabolic
syndrome components increase the risk of associated
cancer. The physiopathological mechanism that links
metabolic syndrome and colorectal cancer is mostly
related to abdominal obesity and insulin resistance.
Population and experimental studies demonstrated that
hyperinsulinemia, elevated C-peptide, elevated body
mass index, high levels of insulin growth factor-1, low
levels of insulin growth factor binding protein-3, high
leptin levels and low adiponectin levels are all involved
in carcinogenesis. Understanding the pathological
mechanism that links metabolic syndrome and its
components to carcinogenesis has a major clinical sig-
nicance and may have profound health benets on a
number of diseases including cancer, which represents
a major cause of mortality and morbidity in our societies.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Metabolic syndrome; Colorectal cancer;
Insulin resistance; Obesity; Adipokines; Inammatory
cytokines
Peer reviewer: Chakshu Gupta, MD, FCAP, Heartland
Regional Medical Center, St. Joseph 64506, United States
Pais R, Silaghi H, Silaghi AC, Rusu ML, Dumitrascu DL.
Metabolic syndrome and risk of subsequent colorectal cancer.
World J Gastroenterol
2009; 15(41): 5141-5148 Available
from: URL: http://www.wjgnet.com/1007-9327/15/5141.asp
DOI: http://dx.doi.org/10.3748/wjg.15.5141
INTRODUCTION
The concept of metabolic syndrome has existed for at
least 80 years and was rst described by Kylin[1], a Swedish
physician, as a clustering of hypertension, hyperglycemia
and gout, and later on by Vague[2] who added to the
previous description the presence of abdominal obesity.
While the concept of metabolic syndrome has been
accepted for a long time, there was no largely recognized
international denition until 1998.
The rst proposal came in 1998 from a consultation
group for the definition of diabetes for World Health
Organisation. This definition was then modified by
the European Group for Study of Insulin Resistance
in 1999, the National Cholesterol Education Program
Adult Treatment Panel Ⅲ (ATP Ⅲ) in 2001 and revised
in 2005, and the International Diabetes Foundation
(IDF) in 2005. These denitions agree on the different
components of metabolic syndrome but differ in details
(Table 1)[3].
More recently, the use of the term of “metabolic
sy ndrome” has been questione d by the American
www.wjgnet.com
Diabetes Association and the European Association for
the Study of Diabetes for several reasons: (1) Criteria are
ambiguous or incomplete (for example it is unclear if the
blood pressure definition is systolic blood pressure ≥
130 mmHg and diastolic ≥ 85 mmHg or whether it
is either ≥ 130 mmHg or > 85 mmHg); (2) The value
of including diabetes in the definition is questionable
and the role of insulin resistance as unifying etiology is
uncertain. Furthermore it is still unclear the extent to
which an elevated cardiovascular (CVD) risk is due to
insulin resistance itself vs isolated hyperinsulinemia; (3)
There is no clear basis for including/excluding other
CVD risk factors; the CVD risk associated with the
syndrome appears to be no greater than the sum of its
parts; (4) The treatment of the syndrome is not different
from the treatment for each of its components.
A recent review of the ATP Ⅲ denition broadened
the etiological basis of the syndrome from insulin
resistance alone to include “obesity and disorders of
adipose tissue”[4].
The actual prevalence of obesity is 30.5% and that
of associated metabolic syndrome is 24% in the US
population[3,5].
In Europe, the age- and sex-adjusted prevalence of
metabolic syndrome was 24.6% using the 2005 ATP Ⅲ
definition and 30.9% using the International Diabetes
Federation denition, according to the MADRIC study
(MADrid Rlsego Cardiovascular Study) performed on
1344 participants[6]. In this study, the authors found a
good overall agreement between the ATP Ⅲ and IDF
denitions, much closer in women than in men (κ = 0.92
± 0.07 vs κ = 0.66 ± 0.06). The prevalence of metabolic
syndrome was greater according to the IDF denition
than according to ATP Ⅲ, because the former denition
has a lower threshold of abdominal obesity.
A cross-sectional analysis of 10 206 participants aged
20-89 years in the Nord-Trøndelag Health Study 1995-97
(HUNT 2) in Norway, found a prevalence of IDF-dened
metabolic syndrome of 29.6%, compared to 25.9% using
the 2005 ATP Ⅲ criteria[7].
In a meta-analysis, Cameron et al[8] found a variable
prevalence of metabolic syndrome in urban populations
from 8% (India) to 24% (USA) in men, and from 7%
(France) to 43% (Iran) in women.
It is well known that the metabolic syndrome is
associated with an increased risk of both diabetes and
cardiovascular disease.
Many clinical studies outlined the interrelation between
the metabolic syndrome and cardiovascular risk[9].
Applying the ATP Ⅲ criteria to 10 537 NHANES Ⅲ
participants resulted in a signicant association between the
metabolic syndrome with prevalent myocardial infarction
and stroke in a multivariate analysis: myocardial infarction
[OR: 2.01, 95% condence intervals (CI): 1.53-2.64], stroke
(OR: 2.16, 95% CI: 1.48-3.16), and myocardial infarction/
stroke (OR: 2.05, 95% CI: 1.64-2.57)[10].
The INTERHART study performed on 15 152 cases
and 14 820 controls in nearly 52 countries found a sig-
nificant association between abnormal lipids, smoking,
hypertension, diabetes, abdominal obesity, psychosocial
factors, consumption of fruits, vegetables, and alcohol,
and regular physical activity and the risk of myocardial
infarction. Collectively, these nine risk factors accounted
for 90% of the population risks in men and 94% in
women[11].
In addition to CVD, individual components of the
metabolic syndrome have been linked to the development
of cancer[12].
Colorectal cancer is an important health problem since
one million new cases are diagnosed world-wide each
year with half million related deaths[13]. The incidence
rate of colon cancer according to Five Continents cancer
registries varies from 3% in Africa (Algeria) up to 40% in
North America. In Europe the incidence of colon cancer
ranges from 12.1% in Belarus up to 30.5% in Italy[14].
There is evidence that body composition and hor-
monal factors contribute to colorectal cancer etiology. In
this paper we will highlight this association supported by
epidemiological data and pathophysiological mechanisms
arising from prospective human research studies.
EPIDEMIOLOGY
In an analysis of nearly 58 000 individuals who par-
ticipated in the Nat ional Health Interview Sur vey
(2002-2003), Garow et al[1 5] identified 1200 individuals
with metabolic syndrome, 350 of them being diagnosed
with colorectal cancer. After controlling for age, race,
gender, obesity, smoking and alcohol use the individuals
with metabolic syndrome had a 75% increased risk for
colon or rectal cancer.
In a large prospective study of more than 900 000 US
adults (404 576 men and 495 477 women) conducted by
Calle et al[16], there were 57 145 deaths from cancer during a
follow up period of 16 years. The authors also studied the
relationship between the relative risk (RR) of death and
body mass index (BMI). For all cancer there was a trend
in increasing death rate with BMI. For colorectal cancer
the RR of death varied from 1.34 (95% CI: 0.94-1.34) for
a BMI of 25-29.9, to 1.90 (95% CI: 1.46-2.47) and 4.52
(95% CI: 2.94-6.94) for an BMI between 30.0-34.9 and
35.0-39.9, respectively[16].
Recent studies also provide information concerning
the association between colorectal cancer incidence
and the number of metabolic syndrome components,
especially BMI, waist circumference (WC), lipid levels,
plasma glucose and glycosylated hemoglobin (HbA1c). In
an analysis of 14 109 participants from the ARIC study
(Atherosclerosis Risk in Communities), 194 incident
colorectal cancers were identied. In this study baseline
metabolic syndrome (> 3 components vs 0 components)
had a positive association with age-adjusted and gender-
adjusted colorectal cancer incidence (RR: 1.49, 95% CI:
1.0-2.4). There was a dose-response association between
colorectal cancer incidence and the number of metabolic
syndrome components present at baseline (P for trend =
0.006) after multivariate adjustment[17].
In another study, Trevisan et al[18], used information
5142 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
www.wjgnet.com
from the Risk Factors and Life Expectancy study, which
pooled data from nine epidemiological studies conducted
in Italy between 1978 and 1987, including 21 311 men and
15 991 women. In this study, low high density lipoprotein
(HDL) and high triglyceride levels, hypertension and
plasma glucose levels were also analyzed as individual
components of the metabolic syndrome. For the presence
of the cluster of metabolic abnormalities, the calculated
hazard ratios and 95% CIs were 2.99 (1.27-7.01) when
both sexes were combined. When analyzing the individual
components, only glucose level was associated with an
increased risk of death from colorectal cancer, and only in
men and women combined (RR: 1.8, 95% CI: 1.05-3.09).
The results of this study suggest that the effects of
the individual components of metabolic syndrome
are additive, because the RR of death from colorectal
cancer was increased in cluster analysis compared with
glucose alone.
The association between plasma glucose levels re-
ected by HbA1c and the incidence of colorectal cancer
was outlined in a prospective analysis from the European
Prospective Investigation into Cancer and Nutrition
(EPIC) study[19]. Among 9605 participants in this study,
aged between 45 and 79 years, there were 67 incident
colorectal cancers. In this study population, the RR of
colorectal cancer for men and women combined was 2.94
(95% CI: 0.80-10.85), age and sex adjusted for an HbA1c
≥ 7%, compared with RR, 1.13 (95% CI: 0.56-2.30),
for HbA1c of 5.0%-5.9%. For the same HbA1c levels
of > 7%, the age adjusted RR was higher in men than
in women [RR: 4.94 (95% CI: 0.89-27.35) in men, and
1.58 (95% CI: 0.19-13.14) in women]. The association of
higher HbA1c levels and increased colorectal cancer risk
was also present in the CLUE Ⅱ cohort[20].
Conversely, to evaluate the association between meta-
bolic syndrome and colorectal cancer, Stocks et al[21] eval-
uated the presence of metabolic syndrome components
(C-peptide, HbA1c, leptin, adiponectin, BMI, hyperten-
sion and fasting glucose) in 306 individuals with known
colorectal cancer. The presence of hypertension, obesity
and hyperglycemia, correlated with a RR for three vs null
factors of 2.57 (95% CI: 1.20-5.52, P trend = 0.00021).
The relationship between BMI and colon cancer
was also studied in the recent EPIC study[22], which was
based on 984 cases of colon cancer. A 55% increased
risk of colon cancer was observed between the high
and low quintiles of BMI in men, but no significant
association was observed in women.
Some recent studies considered anthropometric
measures of adipose distribution in addition to BMI in
relation to the risk of colon cancer of adenoma. In most
of these studies, the association between WC or waist-
to-hip ratio and colon cancer risk was stronger than that
between BMI and cancer risk. Moore et al[23], in a retro-
spective analysis of 7566 subjects from the Framingham
cohort, found 306 cases of incident colorectal cancer.
The authors demonstrated a two-fold increased risk of
colorectal cancer for a WC of > 99 cm in women and
101 cm in men; the risk increased linearly with increas-
ing WC[23]. One Japanese study[24] of 51 consecutive
patients aged ≥ 40 years, suggests that visceral adipose
tissue rather than whole body adipose tissue correlates
better with the risk of colorectal adenoma. Furthermore,
in this study, low adiponectin level is a factor associ-
ated with the development of colorectal adenoma. It is
known that adiponectin levels decrease in obesity, espe-
cially abdominal obesity in association with insulin resis-
tance; thus, the results of this study offer an insight to
understanding the relationship of colorectal carcinogen-
esis with abdominal obesity and insulin resistance which
will be discussed later on this paper.
The fact that the metabolic syndrome is a risk factor
for both CVD and colorectal cancer raised the question
if there is any association between CVD and colorectal
cancer. This correlation was found to be positive in several
studies. In a pilot study of 63 patients with colorectal
cancer, Hamoudi and Dumitrascu demonstrated a
statistical association between CVD and colorectal cancer
in men[25].
The relationship between individual components of
metabolic syndrome and the risk of colorectal cancer
was also separately analyzed by several studies. Colangelo
et al[26] found a 35% increased risk of colorectal cancer
associated with high blood pressure. The results were
co nfirmed by anothe r study[1 7]. Bot h studi es also
underlined that the clustering of metabolic syndrome
components signicantly increased the risk of associated
colorectal cancer.
High circulating triacylglycerols were associated in
a large prospective study with a non-significant two-
Table 1 Comparison of denitions of metabolic syndrome
WHO 1999 ATP Ⅲ 2001 IDF 2005
Diabetes or impaired fasting glycemia or impaired
glucose tolerance or insulin resistance
Three or more of the following:
Central obesity: waist circumference
> 102 cm (male), > 88 cm (female)
Hypertriglyceridemia: triglycerides
> 150 mg/dL
Low HDL cholesterol: < 40 mg/dL (male),
< 50 mg/dL (female)
Hypertension: blood pressure
> 130/85 mmHg
Fasting plasma glucose > 100 mg/dL
Increased waist circumference > 94 cm cm in men
and > 80 cm in women plus any 2 of the following:
Hypertriglyceridemia: triglycerides > 150 mg/dL
Low HDL cholesterol: < 40 mg/dL (male),
< 50 mg/dL (female)
Hypertension: blood pressure > 130/85 mmHg
Fasting plasma glucose > 100 mg/dL
Plus 2 or more of the following:
Obesity: BMI > 30 or waist-to-hip ratio
> 0.9 (male) or 0.85 (female)
Dyslipidemia: triglycerides > 150 mg/dL or HDL
cholesterol < 35 mg/dL (male) or
< 39 mg/dL (female)
Hypertension: blood pressure > 140/90 mmHg
Microalbuminuria: albumin excretion > 20 μg/min
Pais R
et al
. Metabolic syndrome and colorectal cancer 5143
www.wjgnet.com
fold elevation in risk of colorectal cancer in men, but no
clear association was observed in women[17]. In another
prospective study, there was a 40% increased risk of
colorectal cancer for men and women in the top quartile
of triacylglycerol levels, although this association was
not signicant[27].
The association between C-peptide levels as a marker
of hyperinsulinemia and colorectal cancer risk was also
examined by several studies. In a case control study in the
Physicians’ Health Study, an increased concentration of
plasma C-peptide was statistically signicantly associated
with an increased risk of colorectal cancer in men (RR
for the highest vs lowest quintile of plasma C-peptide =
2.7, 95% CI: 1.2-6.2, P trend = 0.047), after adjusting
for age, smoking status, fasting, BMI and alcohol
consumption. The results of this study also suggest
that elevated insulin production, as reected by elevated
concentrations of plasma C-peptide, may predict the
risk of developing colorectal cancer, independently of
BMI, factors related to insulin resistance, or levels of
insulin growth factor (IGF)-1 and insulin growth factor
binding protein (IGFBP)-3[28]. The interrelation between
a high concentration of plasma C-peptide and colorectal
adenoma was also demonstrated in women in a series of
380 patients with a multivariable relative risk (MVRR)
top vs bottom quartile, 1.63, 95% CI: 1.01-2.66, P = 0.01,
even after including BMI and physical activity in the
statistical model[29].
The findings of all these studies suggest that the
clusters of the metabolic syndrome components may
be predictors for developing colorectal cancer and for
colorectal cancer mortality. The understanding of the
underlying physiopathology that links the metabolic
syndrome and cancer may play a key role in developing
new strategies for prevention and treatment.
PHYSIOPATHOLOGICAL LINKS
BETWEEN METABOLIC SYNDROME AND
COLORECTAL CANCER
Obesity, insulin resistance and insulin growth factors
and binding proteins
It has been hypothesized that insulin resistance is the
most important underlying mechanism of the metabolic
syndrome in close relationship to abdominal obesity.
Insulin has been shown to affect growth of normal
and neoplastic epithelial cells and to have mitogenic ac-
tions in vitro and in experimental models, either directly
or indirectly through IGF-1[17]. At high concentrations,
insulin can bind to IGF-1 receptors (IGF1Rs) or can
act directly to promote IGF-1 biosynthesis, enhancing
IGF-1 bioavailability and inhibiting the production of
IGFBP-1, IGFBP-2 and IGFBP-3[30].
IGF-1 is an important mitogen required for the
progression through the cell cycle and has autocrine,
paracrine and endocrine actions on cell proliferation
and apoptosis[31], increasing the risk of cellular transfor-
mation by enhancing cell turnover. In addition, IGF-1
increases the production of vascular endothelial growth
factor (VEGF), an angiogenic factor that can support
cancer growth[32].
It has been shown that normal colorectal epithelia
and colon cancer cells have both insulin and IGF1Rs[17].
Tissue homeostasis in the normal colonic crypt relies on
a balance between proliferation, differentiation and apop-
tosis, with apoptosis occurring at the top of the colonic
crypt as the culmination of a differentiation pathway.
The link between IGF-1 and IGFBP-3 levels and the
increased risk of colorectal adenoma and cancer came
rst to attention in acromegalic patients, characterized by
chronically elevated growth hormone (GH) levels. GH
excess leads to hepatic and peripheral insulin resistance
and thus to hyperinsulinemia, a common feature of
acromegaly and metabolic syndrome, that causes IGF-1
hypersecretion and low IGFBP-3 levels[33].
The relationship between IGF-1 and IGFBP-3 levels
and colorectal cancer was examined by Giovannucci
et al[34] on 32 826 women from Nurses’ Health Study.
Controlling for IGFBP-3 level, relative to women in the
lowest tertile of IGF-1, those in the highest tertile were
at elevated risk of intermediate/late-stage colorectal
neoplasia adenoma (MVRR: 2.78, 95% CI: 0.76-9.76)
and cancer (RR: 2.18, 95% CI: 0.94-5.08). Controlling
for IGF-1 level, relative to women in the lowest tertile
of IGFBP-3, women in the highest tertile of IGFBP-3
were at lower risk of intermediate/late-stage colorectal
adenoma (RR: 0.28, 95% CI: 0.09-0.85) and cancer
(RR: 0.28, 95% CI: 0.10-0.83). Neither IGF-1 nor
IGFBP-3 had any appreciable relation with early-stage
adenoma. These analyses indicate that high levels of
circulating IGF-1 and particularly low levels of IGFBP-3
are associated independently with an elevated risk of
large or tubulo-villous/villous colorectal adenoma and
cancer. These results are concordant with those obtained
previously in Physicians’ Health Study[35].
The role of IGFBP-3 in colorectal cancer was in-
dependently analyzed by Williams et al[36] IGFBP-3 has
been shown to enhance p53-dependent apoptosis after
DNA damage. Therefore, loss of IGFBP-3 could con-
tribute to the development of colonic adenomas that
retain wild-type p53 function through suppression of
p53-dependent apoptotic signals, allowing aberrant cell
survival and tumor formation. Furthermore there is dis-
ruption in both adenoma and carcinoma tissue. This pat-
tern is similar to that of TGF-β distribution in normal,
adenoma and carcinoma tissue[37]. Because it is known
that TGF-β is a potent growth inhibitor for colonic
epithelium[36], this similarity suggests that IGFBP-3 may
have an important role in the regulation of differentia-
tion and apoptosis in human colonic epithelium[37].
The role of insulin resistance and hyperinsulinemia
in colorectal cancer was directly assessed by Schoen
et al [27] in a study performed on 5849 participants in
the Cardiovascular Health Study cohort. The authors
identied 102 cases of colorectal cancer. Fasting insulin
was not related to an increased risk (RR = 1.2), whereas
2 h insulin was related to a signicantly increased risk
(RR = 2.0).
Giovannucci et al[38] found that BMI was not signicantly
5144 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
www.wjgnet.com
associated with an increased risk of distal colon ad-
enoma irrespective of size, while WC and waist hip ratio
were strong risk factors for large distal colon adenomas
with diameter ≥ 1 cm but were unrelated to small ad-
enomas with diameter < 1 cm. The association of WC
with an increased risk of cancer has been reported to be
slightly stronger for distal colon cancer.
There are also several studies which determined
the relationship between C-peptide (an indicator of
insulin production) and the risk of colorectal cancer. As
mentioned before, in the Physicians’ Health Study, men
with C-peptide in the top vs the bottom quintile had a
2.7-fold significantly higher risk of colorectal cancer
after control for BMI and exercise; this RR increased
to 3.4 after the analysis was controlled for indicators of
the metabolic syndrome[28]. In a prospective study of
14 275 women in New York State, a 3-fold higher risk of
colorectal cancer was observed in those in the top quartile
of C-peptide, and a 4-fold higher risk was observed for
colon cancer alone[39].
Adipokines and inammatory cytokines
Adipose tissue is a complex endocrine organ, responsible
for the secretion and synthesis of hormones, cytokines
and other signaling proteins, collectively termed as
adipokines. Adipokines are a diverse group of signaling
molecules that play roles in such processes as appetite
and energy balance, inflammation, insulin resistance/
sensitivity, angiogenesis, lipid metabolism, cell proliferation
and atherosclerosis. Many of these functions are related
to either the metabolic syndrome or cancer, and they may
serve as a link between these two pathologies[40].
Adiponectin
Adiponectin, a 30-kDa complement C1q-related protein,
is a key regulator of insulin sensitivity and inammation
and modulates several physiologic processes, such as me-
tabolism of glucose and fatty acids. In contrast to other
adipokines such as leptin, adiponectin circulating levels
are decreased in obese individuals and in those with dia-
betes[41]. Decreased plasma adiponectin concentrations
are associated with insulin resistance, type 2 diabetes and
atherosclerosis. In addition, it was recently shown that
adiponectin may play a role in the development and pro-
gression of various types of malignancies. Accumulating
evidence suggests that adiponectin is an important regu-
lator of cell proliferation. Adiponectin may act either
directly on cancer cells or indirectly by regulating whole-
body insulin sensitivity[42].
Mechanisms that may link adiponectin with
carcinogenesis
In obesity, reduced adiponectin levels lead to the devel-
opment of insulin resistance and compensatory, chronic
hyperinsulinaemia. Increased insulin levels results in in-
creased levels of bioavailable IGF-1. Insulin and IGF-1
signal through the insulin receptors and IGF1R, pro-
mote cellular proliferation and inhibit apoptosis in many
tissue types up-regulating the secretion of VEGF, con-
tributing thus to carcinogenesis[39]. Adiponectin has also
been shown to inhibit both the production of TNF-α
in macrophages and its action in endothelial cells, thus
promoting carcinogenesis through the altered effect of
TNF-α on tumor cell proliferation and angiogenesis[43].
Adiponectin can also protect from carcinogenesis
through more direct effects.
Specifically, adiponectin has been found to be an
important negative regulator of hematopoiesis and the
immune system. Moreover, adiponectin may inhibit
activation of nuclear factor-κB (NF-κB), a transcription
factor that upregulates VEGF[44].
Several signalling molecules such as 50-AMP-activated
protein kinase (AMPK), NF-κB, peroxisome proliferators
activated receptor (PPAR)-α and p38 mitogen-activated
protein kinase are known to mediate adiponectin-induced
metabolic effects. AMPK might inhibit th e growth
and/or survival of cancer cells[45]. Finally, adiponectin
may also regulate angiogenesis negatively (independently
of AMPK) through induction of apoptosis in vascular
endothelial cells by activating the caspase cascade, a group
of apoptotic enzymes[46].
The relationship between circulating adiponectin
levels and colorectal cancer was demonstrated by several
clinical and experimental studies.
Ferroni et al[47] demonstrated in a study involving 60
patients with non metastatic colorectal cancer that low
adiponectin levels are inversely correlated with increases
in tumor stage and were independent predictors of
recurrent disease. Low adiponectin levels were found in
52% of relapsing patients, compared with 26% of non-
relapsing patients[47].
Similar results were obtained by Wei et al[48] in a
prospective case-control study of 18 225 men enrolled
in the Health Professional Follow-up Study. Over the
approximately 8 years of follow-up, the authors noted 25
cases of colorectal cancer in the 3645 men in the highest
category of adiponectin compared with 54 cases of
colorectal cancer in the 3645 men in the lowest quintile
of adiponectin.
Leptin
Leptin is a 16 kDa glycoprotein which is expressed
almost exclusively (> 95%) by adipocytes. Initial interest
in leptin focused on its role in obesity but recently leptin,
has been associated with the inflammatory response,
insulin signaling, and carcinogenesis.
Insulin and leptin interact at multiple levels within a
complex network of adipose tissue signaling pathways,
providing several mechanisms that could link leptin to
colon cancer.
Of particular importance for cancer is the inuence
of leptin on suppressors of cytokine signaling 1 and 3
which in turn limits insulin signaling[49].
Although data directly linking leptin to colon cancer
are limited, some studies have shown increased risk
of colon and colorectal cancer with high serum leptin
levels.
Data from a cohort study in Norway detected an
almost 3-fold increased risk of colon cancer among
people with high leptin levels, independently of BMI[50].
Pais R
et al
. Metabolic syndrome and colorectal cancer 5145
www.wjgnet.com
Another study found that men in the highest tertile
of leptin concentrations had a 3.3-fold (95% CI: 1.2-8.7)
increased adenoma risk compared with those in the lowest
tertile[51]. The association between leptin concentration
and colorectal cancer was also evaluated in women, in a
case-control study conducted in Japan, suggesting that
leptin increases substantially the risk of female colorectal
cancer, independent of BMI[52].
Inammatory cytokines and colorectal cancer
Accumulating evidence suggests that systemic inflam-
mation might be a plausible mechanism for colon carci-
nogenesis. Studies have shown that genetic variations in
inflammation-related genes, such as interleukin (IL)-6,
IL-8, and IL-10, are associated with susceptibility to
colorectal cancer and adenomas.
IL-6 appears to enhance tumorigenesis by a paracrine
and autocrine mechanism, to stimulate cell growth and
inhibit apoptosis. Also IL-6 concentrations reflected
disease status and were commonly associated with
metastatic disease[53].
TNF-α activates NF-κB (by phosphorylation of its
inhibitor IκB), which increases production of NO, a
substrate for reactive oxygen species (ROS) formation,
and stimulates other inflammatory cytokines[54]. With
respect to cancer, ROS can damage DNA by several
processes including DNA base modication, deletions,
frame shifts, strand breaks, DNA-protein cross-links,
and chromosomal rearrangements. DNA damage can
occur in genes that are important in cell proliferation
(such as ras), or cell survival (such as p53), which can
then trigger cancer progression[55].
There are several studies which demonstrated the
correlation between high levels of IL-6, TNF-α, C-reac-
tive proteins (CRP) and colorectal carcinogenesis. More-
over, a Greek study demonstrated that high levels of
serum IL-6, TNF-α and CRP were correlated with larger
tumor size. The relation to tumor size could be related
to the fact, that larger tumors may trigger a more potent
immunological response manifested by the circulation of
proinammatory cytokines such as TNF-α[56].
PPAR-
γ
PPAR-γ, a ligand-activated transcription factor, is a key
regulator of adipogenic differentiation and glucose
homeostasis. PPAR-γ ligands have recently been dem-
onstrated to affect proliferation and differentiation in
cancer cell lines. A gradually increasing number of stud-
ies demonstrated the association between PPAR-γ and
colorectal cancer[57].
A recent study demonstrated a positive PPAR-γ
immunostaining in 48 of 86 cases of colon cancer (56%).
No association was found for PPAR-γ positivity with
different Dukes’ stages, histological grade of differentiation,
tumor locatio n, presence o f lymph node and liver
metastasis, venous invasion, or tumor cell proliferating
capacity assessed as Ki-67 overexpression. On the contrary,
PPAR-γ expression was statistically significant correlated
with the expression of cell cycle-related molecules[58].
Another recent study demonstrated that PPAR-γ
agonists have inhibitory effects on the proliferation of
colon cancer cell lines associated with G1 cell cycle arrest
and invasive activity. The latter effect is demonstrated
in certain cell lines through the down-regulation of
metalloproteinase-7 synthesis[59].
CONCLUSION
The association between metabolic syndrome and
colorectal cancer is now supported by a large number
of epidemiological studies[14,16,17,19,26]. The components
of metabolic syndrome appear to have an additive ef-
fect on colon cancer development acting through dif-
ferent pathophysiological pathways. This evidence is
based on studies of determinants of the metabolic
syndrome (obesity, abdominal distribution of adiposity,
physical inactivity), clinical consequences (type 2 diabe-
tes, hypertension) of this syndrome, plasma or serum
components of the definition of metabolic syndrome
(hypertriglyceridemia, hyperglycemia, low HDL choles-
terol), markers of hyperinsulinemia or insulin resistance
(insulin, C-peptide), and serum inammatory cytokines
levels in relation to colon cancer or adenoma risk. High
insulin and insulin resistance are common features of
industrialized societies characterized by a large preva-
lence of overweight individuals and obesity, a diet rich in
energy intake, and a lifestyle characterized by low calorie
expenditure. Understanding the pathological mechanism
that links metabolic syndrome and its components to
carcinogenesis has a very important clinical signicance.
Controlling even one or two of the components of the
metabolic syndrome may result in a longer, healthier and
cancer-free life. Public health efforts aimed at reducing
lifestyle patterns and dietary habits associated with this
imbalance on insulin metabolism may have profound
health benets on a number of diseases including can-
cer, that represent major causes of mortality and mor-
bidity in our societies.
REFERENCES
1 Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J.
The metabolic syndrome: a global public health problem
and a new denition. J Atheroscler Thromb 2005; 12: 295-300
2 Vague J. La differenciation sexuelle, facteur determinant
des formes de l’obesite. Presse Med 1947; 55: 339
3 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel
RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith
SC Jr, Spertus JA, Costa F. Diagnosis and management of
the metabolic syndrome: an American Heart Association/
National Heart, Lung, and Blood Institute Scientific
Statement. Circulation 2005; 112: 2735-2752
4 Ka hn R, Buse J, Ferrannini E, Stern M. The metabolic
syndrome: time for a critical appraisal: joint statement
from the American Diabetes Association and the European
Association for the Study of Diabetes. Diabetes Care 2005; 28:
2289-2304
5 Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence
and trends in obesity among US adults, 1999-2000. JAMA
2002; 288: 1723-1727
6 Martínez MA, Puig JG, Mora M, Aragón R, O'Dogherty P,
Antón JL, Sánchez-Villares T, Rubio JM, Rosado J, Torres
5146 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
www.wjgnet.com
R, Marcos J, Pallardo LF, Banegas JR. Metabolic syndrome:
prevalence, associated factors, and C-reactive protein: the
MADRIC (MADrid RIesgo Cardiovascular) Study. Metabolism
2008; 57: 1232-1240
7 Hildrum B, Mykletun A, Hole T, Midthjell K, Dahl AA.
Age-specic prevalence of the metabolic syndrome dened
by the International Diabetes Federation and the National
Cholesterol Education Program: the Norwegian HUNT 2
study. BMC Public Health 2007; 7: 220
8 Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome:
prevalence in worldwide populations. Endocrinol Metab Clin
North Am 2004; 33: 351-375, table of contents
9 Ninomiya JK, L'Italien G, Criqui MH, Whyte JL, Gamst A,
Chen RS. Association of the metabolic syndrome with history of
myocardial infarction and stroke in the Third National Health
and Nutrition Examination Survey. Circulation 2004; 109: 42-46
10 Eckel RH, Grundy SM, Zimmet PZ. The metabolic
syndrome. Lancet 2005; 365: 1415-1428
11 Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F,
McQueen M, Budaj A, Pais P, Varigos J, Lisheng L. Effect of
potentially modiable risk factors associated with myocardial
infarction in 52 countries (the INTERHEART study): case-
control study. Lancet 2004; 364: 937-952
12 Kreger BE, Splansky GL, Schatzkin A. The cancer experience
in the Framingham Heart Study cohort. Cancer 1991; 67: 1-6
13 Boyle P, Leon ME. Epidemiology of colorectal cancer. Br
Med Bull 2002; 64: 1-25
14 Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue
M, Boyle P, editors. Cancer Incidence in Five Continents, Vol.
IX. IARC Scientic Publications No. 160, Lyon, IARC, 2007.
Available from: URL: http://www-dep.iarc.fr/CI5_IX_frame.
htm
15 Garow D. Metabolic syndrome is a risk factor for
colorectal cancer in the United States. American College of
Gastroenterology 2008 Annual Scientific Meeting. October 6,
2008
16 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ.
Ov er weight, o besity, a nd morta lit y from ca ncer in a
prospectively studied cohort of U.S. adults. N Engl J Med
2003; 348: 1625-1638
17 Ahmed RL, Schmitz KH, Anderson KE, Rosamond WD,
Folsom AR. The metabolic syndrome and risk of incident
colorectal cancer. Cancer 2006; 107: 28-36
18 Trevisan M, Liu J, Muti P, Misciagna G, Menotti A, Fucci F.
Markers of insulin resistance and colorectal cancer mortality.
Cancer Epidemiol Biomarkers Prev 2001; 10: 937-941
19 Khaw KT, Wareham N, Bingham S, Luben R, Welch A,
Day N. Preliminary communication: glycated hemoglobin,
diabetes, and incident colorectal cancer in men and women:
a prospective analysis from the European prospective
investigation into cancer-Norfolk study. Cancer Epidemiol
Biomarkers Prev 2004; 13: 915-919
20 Saydah SH, Platz EA, Rifai N, Pollak MN, Brancati FL,
Helzlsouer KJ. Association of markers of insulin and glucose
control with subsequent colorectal cancer risk. Cancer
Epidemiol Biomarkers Prev 2003; 12: 412-418
21 Stocks T, Lukanova A, Johansson M, Rinaldi S, Palmqvist
R, Hallmans G, Kaaks R, Stattin P. Components of
the metabolic syndrome and colorectal cancer risk; a
prospective study. Int J Obes (Lond) 2008; 32: 304-314
22 Pischon T, Lahmann PH, Boeing H, Friedenreich C, Norat
T, Tjønneland A, Halkjaer J, Overvad K, Clavel-Chapelon F,
Boutron-Ruault MC, Guernec G, Bergmann MM, Linseisen
J, Becker N, Trichopoulou A, Trichopoulos D, Sieri S, Palli
D, Tumino R, Vineis P, Panico S, Peeters PH, Bueno-de-
Mesquita HB, Boshuizen HC, Van Guelpen B, Palmqvist
R, Berglund G, Gonzalez CA, Dorronsoro M, Barricarte
A, Navarro C, Martinez C, Quirós JR, Roddam A, Allen
N, Bingham S, Khaw KT, Ferrari P, Kaaks R, Slimani N,
Riboli E. Body size and risk of colon and rectal cancer in
the European Prospective Investigation Into Cancer and
Nutrition (EPIC). J Natl Cancer Inst 2006; 98: 920-931
23 Moore LL, Bradlee ML, Singer MR, Splansky GL, Proctor
MH, Ellison RC, Kreger BE. BMI and waist circumference
as predictors of lifetime colon cancer risk in Framingham
Study adults. Int J Obes Relat Metab Disord 2004; 28: 559-567
24 Otake S, Tak ed a H, Suz uki Y, Fukui T , W at anabe S,
Ishihama K, Saito T, Togashi H, Nakamura T, Matsuzawa
Y, Kawata S. Association of visceral fat accumulation and
plasma adiponectin with colorectal adenoma: evidence for
participation of insulin resistance. Clin Cancer Res 2005; 11:
3642-3646
25 Hamoudi WTY, Dumitrascu DL. Is there an association
between coronary heart disease and colorectal carcinoma?
Results from a pilot study. Rom J Gastroenterol 1997; 6: 13-16
26 Colangelo LA, Gapstur SM, Gann PH, Dyer AR, Liu K.
Colorectal cancer mortality and factors related to the insulin
resistance syndrome. Cancer Epidemiol Biomarkers Prev 2002;
11: 385-391
27 Schoen RE, Tangen CM, Kuller LH, Burke GL, Cushman
M, Tracy RP, Dobs A, Savage PJ. Increased blood glucose
and insulin, body size, and incident colorectal cancer. J Natl
Cancer Inst 1999; 91: 1147-1154
28 Ma J, Giovannucci E, Pollak M, Leavitt A, Tao Y, Gaziano
JM, Stampfer MJ. A prospective study of plasma C-peptide
and colorectal cancer risk in men. J Natl Cancer Inst 2004; 96:
546-553
29 Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, Hankinson
SE, Giovannucci E. C-peptide, insulin-like growth factor
binding protein-1, glycosylated hemoglobin, and the risk
of distal colorectal adenoma in women. Cancer Epidemiol
Biomarkers Prev 2006; 15: 750-755
30 Sandhu MS, Dunger DB, Giovannucci EL. Insulin, insulin-
like growth factor-I (IGF-I), IGF binding proteins, their
biologic interactions, and colorectal cancer. J Natl Cancer Inst
2002; 94: 972-980
31 Grimberg A, Cohen P. Role of insulin-like growth factors and
their binding proteins in growth control and carcinogenesis.
J Cell Physiol 2000; 183: 1-9
32 Warren RS, Yuan H, Matli MR, Ferrara N, Donner DB.
Induction of vascular endothelial growth factor by insulin-
like growth factor 1 in colorectal carcinoma. J Biol Chem
1996; 271: 29483-29488
33 Jenkins PJ. Acromegaly and cancer. Horm Res 2004; 62
Suppl 1: 108-115
34 Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer
MJ, Majeed N, Colditz GA, Speizer FE, Hankinson SE. A
prospective study of plasma insulin-like growth factor-1
and binding protein-3 and risk of colorectal neoplasia in
women. Cancer Epidemiol Biomarkers Prev 2000; 9: 345-349
35 Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y,
Hennekens CH, Stampfer MJ. Prospective study of colorectal
cancer risk in men and plasma levels of insulin-like growth
factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst
1999; 91: 620-625
36 Williams AC, Collard TJ, Perks CM, Newcomb P, Moorghen
M, Holly JM, Paraskeva C. Increased p53-dependent
apoptosis by the insulin-like growth factor binding protein
IGFBP-3 in human colonic adenoma-derived cells. Cancer
Res 2000; 60: 22-27
37 Barnard JA, Beauchamp RD, Coffey RJ, Moses HL.
Regulation of intestinal epithelial cell growth by transforming
growth factor type beta. Proc Natl Acad Sci USA 1989; 86:
1578-1582
38 Giovannucci E, Ascherio A, Rimm EB, Colditz GA,
Stampfer MJ, Willett WC. Physical activity, obesity, and risk
for colon cancer and adenoma in men. Ann Intern Med 1995;
122: 327-334
39 Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy
C, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore RE,
Riboli E. Serum C-peptide, insulin-like growth factor (IGF)-I,
IGF-binding proteins, and colorectal cancer risk in women. J
Natl Cancer Inst 2000; 92: 1592-1600
40 Cowey S, Hardy RW. The metabolic syndrome: A high-risk
Pais R
et al
. Metabolic syndrome and colorectal cancer 5147
www.wjgnet.com
state for cancer? Am J Pathol 2006; 169: 1505-1522
41 Vona-Davis L, Howard-McNatt M, Rose DP. Adiposity,
type 2 diabetes and the met abo lic synd rom e in bre ast
cancer. Obes Rev 2007; 8: 395-408
42 Ba rb D, Williams CJ, Neuwirth AK, Mantzoros CS.
Adiponectin in relation to malignancies: a review of existing
basic research and clinical evidence. Am J Clin Nutr 2007; 86:
s858-s866
43 Rose DP, Komninou D, Stephenson GD. Obesity, adipo-
cytokines, and insulin resistance in breast cancer. Obes Rev
2004; 5: 153-165
44 Wang Y, Lam KS, Xu JY, Lu G, Xu LY, Cooper GJ, Xu A.
Adiponectin inhibits cell proliferation by interacting with
several growth factors in an oligomerization-dependent
manner. J Biol Chem 2005; 280: 18341-18347
45 Goldstein BJ, Scalia R. Adiponectin: A novel adipokine
linking adipocytes and vascular function. J Clin Endocrinol
Metab 2004; 89: 2563-2568
46 Bråkenhielm E, Veitonmäki N, Cao R, Kihara S, Matsuzawa
Y, Zhivotovsky B, Funahashi T, Cao Y. Adiponectin-induced
antiangiogenesis and antitumor activity involve caspase-
mediated endothelial cell apoptosis. Proc Natl Acad Sci USA
2004; 101: 2476-2481
47 Ferroni P, Palmirotta R, Spila A, Martini F, Raparelli V,
Fossile E, Mariotti S, Del Monte G, Buonomo O, Roselli M,
Guadagni F. Prognostic significance of adiponectin levels
in non-metastatic colorectal cancer. Anticancer Res 2007; 27:
483-489
48 Wei EK, Giovannucci E, Fuchs CS, Willett WC, Mantzoros
CS. Low plasma adiponectin levels and risk of colorectal
cancer in men: a prospective study. J Natl Cancer Inst 2005;
97: 1688-1694
49 Slattery ML, Wolff RK, Herrick J, Caan BJ, Potter JD. Leptin
and leptin receptor genotypes and colon cancer: gene-
gene and gene-lifestyle interactions. Int J Cancer 2008; 122:
1611-1617
50 Stattin P, Lukanova A, Biessy C, Söderberg S, Palmqvist R,
Kaaks R, Olsson T, Jellum E. Obesity and colon cancer: does
leptin provide a link? Int J Cancer 2004; 109: 149-152
51 Chia VM, Newcomb PA, Lampe JW, White E, Mandelson
MT, McTiernan A, Potter JD. Leptin concentrations, leptin
receptor polymorphisms, and colorectal adenoma risk.
Cancer Epidemiol Biomarkers Prev 2007; 16: 2697-2703
52 Tamakoshi K, Toyoshima H, Wakai K, Kojima M, Suzuki K,
Watanabe Y, Hayakawa N, Yatsuya H, Kondo T, Tokudome
S, Hashim oto S, Suzuki S , Kawado M, Oza sa K, Ito Y,
Tamakoshi A. Leptin is associated with an increased female
colorectal cancer risk: a nested case-control study in Japan.
Oncology 2005; 68: 454-461
53 Chung YC, Chang YF. Serum interleukin-6 levels reflect
the disease status of colorectal cancer. J Surg Oncol 2003; 83:
222-226
54 Sonnenberg GE, Krakower GR, Kissebah AH. A novel
pathway to the manifestations of metabolic syndrome. Obes
Res 2004; 12: 180-186
55 Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of
oxygen radicals in DNA damage and cancer incidence. Mol
Cell Biochem 2004; 266: 37-56
56 Nikiteas NI, Tzanakis N, Gazouli M, Rallis G, Daniilidis
K, Theodoropoulos G, Kostakis A, Peros G. Serum IL-6,
TNFalpha and CRP levels in Greek colorectal cancer patients:
prognostic implications. World J Gastroenterol 2005; 11:
1639-1643
57 Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated
receptor-gamma: from adipogenesis to carcinogenesis. J Mol
Endocrinol 2001; 27: 1-9
58 The ocharis S, Giaginis C, Parasi A, Margeli A, Kakisis
J, Agapitos E, Kouraklis G. Expression of peroxisome
pro liferator-activated rece ptor-gamma in colon cancer:
correlation with histopathological parameters, cell cycle-
related molecules, and patients' survival. Dig Dis Sci 2007;
52: 2305-2311
59 Sh en D, De ng C, Zhang M . Perox isome p ro lifer at or-
activated receptor gamma agonists inhibit the proliferation
and invasion of human colon cancer cells. Postgrad Med J
2007; 83: 414-419
S- Editor Li LF L- Editor O’Neill M E- Editor Zheng XM
5148 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
