ORCP-711; No.

of Pages 13 ARTICLE IN PRESS

Obesity Research & Clinical Practice (2018) xxx, xxx—xxx

REVIEW

The mechanisms linking obesity to colon

cancer: An overview
Aleksandra Tarasiuk, Paula Mosińska, Jakub Fichna ∗

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Poland

Received 28 October 2017 ; received in revised form 19 January 2018; accepted 26 January 2018

KEYWORDS Summary Obesity, characterised as a chronic low-grade inflammation is a crucial

Obesity; risk factor for colon cancer. The expansion of the adipose tissue is related to elevated
Colon cancer; triglyceride and low-density lipoprotein (LDL) levels and hyperinsulinemia, which
Proinflammatory all are presumed mediators of the tumour development. Obesity is also believed to
cytokines; support carcinogenesis by activating the insulin/IGF-1 pathway. Moreover, obesity
Adipose tissue increases the level of proinflammatory cytokines (e.g. TNF-␣, IL-1, and IL-6) and has
a significant impact on selected adipokines.
This paper briefly outlines the latest evidence of the linkage between the obe-
sity and colon cancer and discusses its possible implication for the improvement of
anticancer prevention and treatment strategies connected with nutrition.
© 2018 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd.
All rights reserved.

Abbreviations: AP-1, activator protein 1; AT1 , type 1 receptors for angiotensin II; ATMs, adipose tissue macrophages; BAT, brown
adipose tissue; CLSs, crown-like structures; CRC, colorectal cancer; DGK␨, diacylglycerol kinase ␨; DHA, docosahexaenoic acid; DHEA,
docohexaenoylethanolamine; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; GPR120, G protein—coupled
receptor 120; HNF-1, hepatocyte nuclear factor 1 alpha; HNF-4␣, hepatocyte nuclear factor 4-alpha; IBD, inflammatory bowel
disease; IFN-␥, interferon gamma; IGF-1, insulin-like growth factor 1; IL-1, interleukin-1; IL-6, interleukin-6; iNOS, nitric oxide
synthase; IR, insulin receptor; IRS1-4, insulin receptor substrate protein; JAK-2, Janus kinase 2; LC-PUFAs, polyunsaturated omega-3
fatty acids; LDL, low-density lipoprotein; LR, leptin receptor; M1, macrophage type I; M2, macrophage type II; MAPK, mitogen-
activated protein kinases; MCP-1, monocyte chemoattractant protein 1; MMR, macrophage mannose receptor 1; mTOR, mammalian
target of rapamycin; NF-␬B, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; Ob-Re, soluble form
of the leptin receptor; Ob-Rb, Ob-RL, long isoform of the leptin receptor; Ob-Ra, Ob-Rs, short form of the leptin receptor; PAI-1,
plasminogen activator inhibitor-1; PGE2, prostaglandin E2; PI3K-Akt, phosphatidylinositol-4,5-bisphosphate 3-kinase; PPAR, peroxi-
some proliferator-activated receptor; PPAR␥, peroxisome proliferator-activated receptor-␥; PRL, prolactin; PRLR, prolactin receptor;
PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SAT, subcutaneous adipose tissue; SHP, small heterodimer partner;
STAT, signal transducer and activator of transcription; STAT3, signal transducer and activator of transcription 3; Th1, type 1 T helper
cell; Th2, type 2 T helper cell; TLR4, toll-like receptor 4; TNF-␣, tumour necrosis factor-alpha; UPR, unfolded protein response; VAT,
visceral adipose tissue; VEGF, vascular endothelial growth factor; VLDL, very-low-density lipoproteins; WAT, white adipose tissue.
∗ Corresponding author at: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215

Lodz, Poland.
E-mail address: jakub.fichna@umed.lodz.pl (J. Fichna).

https://doi.org/10.1016/j.orcp.2018.01.005
1871-403X/© 2018 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Tarasiuk A, et al. The mechanisms linking obesity to colon cancer: An overview.
Obes Res Clin Pract (2018), https://doi.org/10.1016/j.orcp.2018.01.005
ORCP-711; No. of Pages 13 ARTICLE IN PRESS
2 A. Tarasiuk et al.

Contents

Introduction .................................................................................................... 00
Insulin, hyperinsulinemia and insulin-like growth factor (IGF-1) ................................................ 00
Visceral and subcutaneous adipose tissue.......................................................................00
Adipose tissue and its role in obesity ........................................................................... 00
Leptin ..................................................................................................... 00
Adiponectin................................................................................................00
Adipose tissue macrophages (ATMs) ........................................................................ 00
Adipose tissue, prolactin and CRC: is there a real connection?..................................................00
Obesity related inflammation —– inflammatory triad ............................................................ 00
TNF-␣......................................................................................................00
IL-1 ........................................................................................................ 00
IL-6 ........................................................................................................ 00
Other mediators of inflammation ............................................................................... 00
NF-␬B ...................................................................................................... 00
ER stress ................................................................................................... 00
Fatty acids, inflammation and colon cancer .................................................................... 00
Nutritional recommendations...................................................................................00
Conclusions.....................................................................................................00
Conflicts of interest .......................................................................................... 00
Author contributions ........................................................................................... 00
Acknowledgements ........................................................................................... 00
References ................................................................................................... 00

Introduction
6), adipokines (leptin, resistin, and adiponectin),
chemokines and many more predispose for carcino-
Currently, obesity is described as a global issue and
genesis, and hence associate with increased risk of
referred to as epidemic; concurrently, colon can-
CRC [9,10]. Indeed unhealthy diet, too little exer-
cer is the second most common cause of death in
cise, contraceptives, alcohol, smoking, and harmful
developed societies [1,2]. Various factors including
environmental factors can lead to increased body
gender, ethnic origin, geographical region and envi-
mass index [11,12]. Consequently, these factors are
ronmental conditions (smoking, alcohol, nutrition
strongly associated with development of CRC. It
and dietary habits, sedentary lifestyle and obe-
has been recently reported that patients who were
sity) are associated with colon cancer risk [3,4].
suffering from obesity are more prone to expe-
Generally, each type of cancer has at least one
rience higher risk of CRC [13]. Moreover, morbid
common characteristic: uncontrollable cell growth,
obesity is not only the main cause of CRC but also
which can be observed by excessive cell prolifera-
it increases mortality and surgical complications
tion. However, cancer cells never differentiate —–
after operative period of colorectal cancer [14].
they continue to divide, cause more damage, and
There is no doubt that better understanding of the
invade new tissues which is a result of pro-survival
links between obesity and cancer may be critical for
properties [5,6]. Colorectal cancer (CRC) develops
the improvement of CRC prevention and treatment
as a result of uncontrolled cell growth within the
strategies.
large intestine, including —– caecum, the ascend-
ing, the transverse, and the descending colon or
rectum, hence symptoms and treatment may dif-
fer substantially. CRC is more common in men than Insulin, hyperinsulinemia and
in women, and rarely occurs before 40 years old; insulin-like growth factor (IGF-1)
the peak incidence falls on the 7th decade of life
[7,8]. The vast majority (90%) of CRCs are carci- Obesity is considered as multifactorial medical
nomas (adenocarcinomas) of the colon. Individuals condition with a complex phenotype. There are
with genetic predispositions are at higher risk of several determinants that are considered as the
earlier CRC development; it can also be triggered main underlying factors of obesity, i.e. genetics
by Crohn’s disease and ulcerative colitis, as well and the so called lifestyle-dependent aspects —–
as smoking. Several factors related to obesity, e.g. physical inactivity and/or longstanding excessive
proinflammatory cytokines (TNF-␣, IL-1, and IL- energy intake [3]. However, not only these fac-

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ORCP-711; No. of Pages 13 ARTICLE IN PRESS
Obesity and colon cancer: an overview
tors should be discussed while considering obesity
—– social factors as well as metabolic and neu-
roendocrine alterations are also of importance.
On the other hand, obesity is characterised as a
chronic, low-grade inflammation which triggers the
increase in blood insulin levels and lowers the level
of free insulin-like growth factor 1 (IGF-1) [15,16].
Obese patients generally present with hyperinsu-
linemia, i.e. an excess of insulin circulating in the
blood relative to the level of glucose, and insulin
resistance. Concurrently, insulin and IGF-1 are the
leading determinants of proliferation and apoptosis
and may thus influence the growth of colon cancer
cells [15,17] and carcinogenesis [18]. Recent find-
ings in animal models have shown that modulation
of insulin and IGF-1 levels, e.g. by excess energy
intake or restriction, genetically induced obesity,
inhibition of insulin secretion and/or pharmaco-
logical inhibition of IGF-1, may significantly affect
colon carcinogenesis [18,19].
The intracellular signal transduction pathways
that relay insulin and IGF-1 and manage/regulate
cell metabolism include mitogen-activated pro-
tein kinases (MAPKs) and phosphatidylinositol-4,5-
bisphosphate 3-kinase (PI3K-Akt) cascade. MAPKs
are involved in directing cellular responses to a
diverse array of stimuli, such as mitogens, osmotic
stress, heat shock and proinflammatory cytokines;
they also regulate cell functions including prolif-
eration, gene expression, differentiation, mitosis,
cell survival, and apoptosis [20,21]. PI3K-Akt sig-
nalling pathway plays a key role in several cellular
processes such as glucose metabolism, apoptosis,
cell proliferation, transcription and cell migration
[15,22]. The relay is delivered by insulin receptor
(IR), a transmembrane protein encoded by a sin-
gle gene INSR, whose alternative splicing during
transcription results in either IR-A or IR-B isoform
[23]. Each isoform translates into two transmem-
brane subunits —– ␣ and ␤. When insulin binds
to ␣-subunits, the ␤-subunits are activated, phos-
phorylating the insulin receptor substrate protein
(IRS1-4) and others. IR-B is expressed at high lev-
els in adipose tissue, liver and muscles; it regulates
glucose metabolism. Interestingly, while IR-A is
expressed at lower levels in healthy cells, it is over-
expressed in cancer cells such as in a variety of
carcinomas or breast cancer cell lines [15].
Visceral and subcutaneous adipose
tissue
Visceral adipose tissue (VAT) is more closely linked
to insulin resistance than subcutaneous adipose tis-
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3
sue (SAT). Excess adipose tissue, especially VAT,
is associated with insulin resistance and impaired
glucose tolerance, which lead to type 2 diabetes;
moreover, it correlates with dyslipidemia, high
blood pressure, activation of prothrombotic and
proinflammatory processes, and thus atherogenic
factors. The complications of obesity are called the
metabolic syndrome, and the frequency of their
detection among adults, but also in the devel-
opmental age, has taken epidemic proportions in
recent years [24].
The differences between VAT and SAT have
been thoroughly investigated [25—27]. In tissues
localised viscerally, higher concentrations of IL-6
and plasminogen activator inhibitor-1 (PAI-1) and
higher expression of glucocorticoid, androgen, AT1
and beta-3 adrenergic receptor are found than in
the subcutaneous tissue. Hormones produced by
visceral fat are secreted into the portal vein sys-
tem, from where they reach the liver directly,
affecting its function [28]. In subcutaneous tis-
sue, the products of which are released into the
general circulation, higher concentrations of lep-
tin and adiponectin are observed than in the tissue
localised in the abdominal cavity [24,25,29]. There-
fore, it is assumed that adipose tissue is not a
homogeneous endocrine organ, but a group of sev-
eral similar, yet differently functioning internal
endocrine organs.
Adipose tissue and its role in obesity
The adipose tissue functions as the main energy
storage in the body (in the form of triglycerides);
it also plays an active role in endocrine signalling.
This loose connective tissue, composed of differ-
ent types of cells (mostly adipocytes), is divided
into white adipose tissue (WAT) and brown adi-
pose tissue (BAT) that have different functions
[3,30,31]. BAT represents only a minor portion and
its role is not well recognised [31,32]. Conversely,
WAT is believed to be an endocrine and secre-
tory organ that is constantly metabolically active.
It comprises various types of cells and produces
cytokines (TNF-␣, IL-1, and IL-6) and adipokines
(leptin, adiponectin, and resistin) [33].
Adipocytes modulate a variety of psychological
responses such as general homeostasis lipid and glu-
cose metabolism, blood pressure, angiogenesis as
well as inflammation [34,35]. In obesity, adipose
tissue hypoxia is considered to be the trigger for
development of insulin resistance; consequently,
the state of chronic inflammation develops. The
inflammatory process is associated with infiltra-
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4 A. Tarasiuk et al.

Figure 1 The mechanisms linking obesity to colon cancer. Excessive body mass index can lead to higher level of
inflammatory cytokines along with elevated level of leptin. Moreover, obesity concurrently declines adiponectin level.
Increased level of inflammatory triad may provoke oncogenic effect in such organs as colon or breast due to chronic
inflammation while in turn low-grade inflammation leads to insulin resistance. Similarly, elevated level of leptin can ati-
vate trancription factors and as a result promote colon carcinogensis. Reduction in adiponectin level induces inhibition
of anti-inflammatory and anti-tumorigenic properties.

tion of macrophages, reduction in adiponectin and
increase in leptin levels, accelerated adipocyte
death, mitochondrial dysfunction and heightened
endoplastic reticulum (ER) stress response —– the ER
activates a signalling network called the unfolded
protein response (UPR) to alleviate this stress and
restore ER homeostasis, promoting cell survival
and adaptation [36] and mitochondrial dysfunction
[31,37,38]. Hence, adipose tissue hypoxia may be
partly responsible for carcinogenesis and develop-
ment of colon cancer in obese subjects [31,39,40].
As a result of the above-mentioned, adipose tissue
is claimed to be a crucial initiator of the inflamma-
tory response in obesity (Fig. 1).
Leptin
Leptin, which is produced by WAT, circulates at lev-
els proportional to the amount of stored body fat; it
helps regulate energy balance by inhibiting hunger.
Obesity is often associated with overproduction of
leptin [19,41]; chronic obesity can result in lep-
tin resistance due to constant stimulation of leptin
receptors (LRs) by a high concentration of their lig-
and.
LR is a transmembrane protein, which is exten-
sively expressed in the body —– including the brain,
muscles, and fat and epithelial cells of the colon
and small intestine [15,42]. The LR belongs to
the family of class I cytokine receptors. There
are several isoforms of this the receptor result-
ing from alternative splicing of the gene coding
for the receptor. The most important are the long
isoform (Ob-Rb, Ob-RL), which contains the extra-
cellular domain, the transmembrane domain and
the intracellular domain made of 303 amino acid
residues, as well as the short form (Ob-Ra, Ob-Rs),
whose intracellular domain is composed of only 34
amino acids [43,44]. In addition, there is also a
soluble form of the leptin receptor (Ob-Re), struc-
turally corresponding to the extracellular domain
of other isoforms [44,45]. Signalling pathways, ini-
tiated by binding of leptin to the receptor, vary
depending on the tissue/organ and type of recep-
tor located there. In the hypothalamus, binding
of leptin to extracellular domain of the long form
of the receptor causes its homodimerisation, fol-
lowed by transphosphorylation of associated Janus
kinase 2 (JAK-2) and phosphorylation of the tyro-
sine residues of the intracellular domain of the
receptor [46]. The phosphorylated Tyr1138 residue is
the binding site of signal transducer and activator
of transcription 3 (STAT3) —– transcription factor,
which after phosphorylation dissociates from the
receptor-JAK-STAT complex, dimerises and moves
to the cell nucleus [44,47]. STAT3 proteins are
synthesised in the same neurons (neurons of the
arcuate of the hypothalamus), in which mRNA syn-
thesis occurs for — among others — neuropeptide Y
and proopiomelanocortin [43]. It seems that leptin
regulates transcription of these neurotransmitters
via STAT3.
In addition, leptin affects the expression of the
c-fos, c-jun and socs-3 genes under the control
of STAT3 transcription factors [43,47]. Of note,
from the in vitro studies it follows that leptin can
activate the majority of known STAT factors [48];
however, it seems that in vivo STAT3 phosphoryla-

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ORCP-711; No. of Pages 13 ARTICLE IN PRESS
Obesity and colon cancer: an overview
tion is of the main importance [43]. Furthermore,
only the long form of the leptin receptor contains
all structural motifs necessary for the stimulation
of the JAK-STAT pathway. SHP-2 (small heterodimer
partner 2) is a tyrosine phosphatase contain-
ing two SH domains, which binds phosphorylated
Tyr985 in the Ob-Rb leptin receptor [47]. Upon
phosphorylation, the protein activates the extra-
cellular signal-regulated ERK in the hypothalamus
[49], which leads to the initiation of the kinase-
dependent transcription of the Egr-1 transcription
factor and the c-fos genes [47,49]. Importantly,
there is also an alternative leptin-dependent way
to activate ERK, which requires phosphatase activ-
ity of SHP-2, but not the phosphorylation of the
Ob-Rb receptor. In this case, SHP-2 phosphatase,
presumably activated via the Ob-Rs receptor, acts
as Grb-2 adapter protein that initiates the Ras-Raf-
M EK-ERK pathway. Taken together, leptin-induced
signalling pathways mediated by STAT-3 and SHP-2
tend to work independently of each other. Finally,
in the hypothalamus, membrane-bound diacylglyc-
erol kinase ␨ (DGK␨) connects with the active form
of Ob-Rb. It is believed that DGK␨ is an interme-
diate link in the system of regulating the mass of
adipose tissue by leptin.
Notably, the LR-related pathway may consti-
tute a link between obesity and colon cancer
since higher leptin level in obese patients increases
the risk of CRC development as shown elsewhere
in the literature [41,42]. Amemori et al. [50],
in the in vitro study, demonstrated that leptin
increases cell growth of several colon cancer cell
lines including HT-29, Caco-2 and T84, while Jaffe
and Schwartz established that leptin promotes
colon cancer cell mobility and invasion [51]. The
same researchers observed that leptin activates Src
kinase and PI3K in the colon cancer cells LS-174-T
and HM-7 [15,51].
Adiponectin
Adiponectin is the main hormone produced by
the adipose tissue and which promotes energy
expenditure and insulin sensitivity. Similarly to lep-
tin, adiponectin may also link obesity and colon
cancer, but their mechanism of action vary. It
has been already proven that In obese individ-
uals, insulin sensitivity and circulating level of
adiponectin are decreased when compared to lean
subjects, however, more recently it has been sug-
gested [52—54]. Fujisawa et al. [55], who examined
whether adiponectin suppresses colorectal carcino-
genesis under the high-fat diet condition, stated
that mice deficient in adiponectin and its receptors
either 1 or 2 had an increased frequency of high-fat
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5
diet-induced colon polyps in comparison with mice
fed a basal diet. Supplementation of adiponectin to
adiponectin-deficient mice suppressed the forma-
tion of polyps, whereas the addition of adiponectin
to immortalised colon epithelial cell culture
blocked leptin-induced cell proliferation [9,55].
Both studies imply that adiponectin has preventive
effects on obesity-related colon cancer. The effect
of adiponectin may be mediated by the inhibition
of mammalian target of rapamycin (mTOR), which
is a member of the phosphatidylinositol 3-kinase-
related kinase family of protein kinases [56].
Adipose tissue macrophages (ATMs)
Proinflammatory cytokines are mainly secreted by
adipose tissue macrophages (ATMs), which are spe-
cialised phagocytes that remove dying or dead cells
or cellular debris. Of note, the presence of dead
adipocytes within the adipose tissue indicates obe-
sity.
Macrophages in adipose tissue have differ-
ent phenotypes and actions. Adipose tissue
macrophages type II (M2) are present in the adi-
pose tissue of lean individuals, whereas in the
obese macrophages type I (M1) predominate [57].
M1 type macrophages are responsible for the
development of inflammation. They are activated
by cytokines produced by type 1 helper T cells
(Th1) that release interferon gamma (IFN-␥). Acti-
vated M1 macrophages produce pro-inflammatory
cytokines, such as tumour necrosis factor-alpha
(TNF-␣) and IL-6, resulting in the activation of
inducible nitric oxide synthase (iNOS) and the elu-
tion of nitric oxide (NO) [45,58]. In addition, M1
macrophages produce pro-inflammatory cytokines
IL-12 and IL-23 with simultaneously reduced syn-
thesis of anti-inflammatory cytokine IL-10 [59]. M2
macrophages are involved in the repair of damaged
tissues and prevent the development of inflamma-
tion. These cells are stimulated by type 2 helper
cells (Th2) that produce cytokines such as IL-4,
IL-10 and IL-13. It was shown that macrophages
with the M2 phenotype secrete significant amounts
of IL-10 with a simultaneous decrease in the syn-
thesis of IL-12 and IL-23 [57,60]. These cells also
express arginase 1, macrophage mannose 1 recep-
tor (macrophage mannose receptor 1, MMR) and
IL-1 receptor antagonist, under the control of per-
oxisome proliferator-activated receptors (PPARs),
the activation of which inhibits inflammation. PPARs
affect the polarisation of macrophages towards
M2 and inhibit the expression of proinflamma-
tory cytokine genes [61,62]. Notably, both types
of macrophages differently influence the develop-
ment of insulin resistance. While M1 cells promote,
ORCP-711; No. of Pages 13 ARTICLE IN PRESS
6 A. Tarasiuk et al.
M2 macrophages act as inhibitors for this process
[57,60,62].
Macrophages surrounding dying or dead
adipocytes form crown-like structures (CLSs)
[63] and produce proinflammatory cytokines,
which can function in a paracrine and potentially
an endocrine fashion to diminish insulin sensitiv-
ity. Moreover, ATMs activation often causes the
release of chemokines, which recruit additional
macrophages infiltrating the adipose tissue in
obese subjects via adipose tissue Th1 lymphocytes
[64,65]. Consequently, macrophages provoke
inflammation, prompting to insulin resistance. This
provocative reaction interceded by adipose tissue
immune cells assumes a leading pathogenic role
in the advancement of obesity-induced insulin
resistance [65].
Adipose tissue, prolactin and CRC: is
there a real connection?
In humans, prolactin (PRL) is produced in the ante-
rior pituitary (frontal pituitary of the pituitary
gland) as well as in other areas, including the
uterus, breast, prostate and skin, and by immune
cells and AT cells. Binding to the cognate recep-
tor (PRLR), PRL activates intracellular signalling via
JAK, ERK and STAT proteins. PRL regulates diverse
activities under normal and abnormal conditions,
including malignancies. Clinical data suggest serum
PRL levels are elevated in CRC patients [66—68].
Neradugomma et al. [68] conducted a study in
which the expression of PRL and PRLR in colon can-
cer tissue and cell line was determined. It has been
observed that greater levels of PRLR expression
were in the cancer cells and cell lines in compari-
son with normal colonic epithelial cells. Incubation
of colon cancer cells with PRL induced JAK2, STAT3
and ERK1/2 phosphorylation and increased expres-
sion of Jagged 1, which is a Notch-1 receptor
ligand. Notch signalling regulates CRC stem cell
population [69]. Moreover, increased accumulation
of the cleaved/active form of Notch-1 receptor
(Notch intracellular domain) and increased expres-
sion of Notch responsive genes HEY1 and HES1, and
stem cell marker genes DCLK1, LGR5, ALDH1 and
CD44 has been noted [68]. Lastly, inhibiting PRL
resulted in inducing JAK2-STAT3 and JAK2-ERK1/2
using AG490 and PD98059, respectively, leading to
complete cancellation of Notch signalling, suggest-
ing a key role for this pathway in regulating CRC
stem cells [70]. Taking all the above-mentioned
findings into account it may be suggested that
cytokine signalling induced by PRL is crucial in col-
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orectal cancers and may provide a novel target for
therapeutic intervention.
Obesity related inflammation —–
inflammatory triad
The tumour microenvironment, or the cancer
microenvironment, is described as the non-
cancerous cells present in the tumour. Like adipose
tissue, tumour microenvironment is composed of
multiple cell types including epithelial cells, fibrob-
lasts, mast cells, and cells of the innate and
adaptive immune system that conduce a pro-
inflammatory and pro-tumorigenic environment;
hence, it comprises the proteins produced by
tumour cells that enhance cell growth and prolif-
eration (Fig. 1) [8,71]. These include cytokines,
which are small soluble proteins that confer instruc-
tions and mediate communication among immune
and non-immune cells, and appear to be major
regulators of adipose tissue metabolism. Therapeu-
tic modulation of the cytokine system offers the
possibility of major changes in the adipose tis-
sue behaviour. There are inflammatory cytokines
that are called ‘‘inflammatory triad’’, i.e. TNF-␣,
interleukin-1 (IL-1) and interleukin-6 (IL-6) [31,72].
TNF-␣
Tumour necrosis factor alpha is a proinflamma-
tory cytokine secreted by the adipocytes. It was
first described as the molecular link between obe-
sity, diabetes, and inflammation [31,65,73]. Recent
studies have shown that TNF-␣ is overexpressed in
the adipose and muscle tissues of obese subjects,
including mice and humans [31,74]. In experimental
animal models, neutralisation of TNF-␣ significantly
improved insulin sensitivity in obese (or fat) Zucker
rats with recessive trait (fa/fa) of the leptin recep-
tor, while the TNF-␣—deficient obese mice were
preserved from obesity-induced insulin resistance
[65,75,76]. It has been observed lately that all
stages of tumourigenesis (tumour cell transforma-
tion, survival, proliferation, invasion, angiogenesis
and metastasis) are associated with the proinflam-
matory role of TNF-␣ [37]. Furthermore, studies
in the animal models have indicated a positive
linkage between TNF-␣ and tumour development
and progression in liver and colon cancer, with its
increased circulating concentrations in different
tumour types [60,77,78]. One of the mechanisms
linking TNF-␣ with cancer induction and further
development is by an increase in reactive oxy-
gen species (ROS) as well as nitrogen species
ORCP-711; No. of Pages 13 ARTICLE IN PRESS
Obesity and colon cancer: an overview
(RNOS) levels in cancer microenvironment, which
may cause irreversible damage to DNA or generate
genomic instability that provokes colon carcinogen-
esis [9,79,80].
IL-1
IL-1 is a regulatory cytokine expressed in both nor-
mal tissues as well as in tumour cells. IL-1 can lead
to the activation of transcription factors [81] such
as:
• nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-␬B) which controls tran-
scription of DNA, cytokine production and cell
viability;
• activator protein 1 (AP-1), a transcription factor
which regulates gene expression in response to
array of stimuli, such as cytokines, growth fac-
tors, stress, and bacterial and viral infections
[82].
Through these transcription factors, IL-1 pro-
motes the expression of some genes that regulate
cell viability and proliferation, and tumour angio-
genesis. For example, in obesity-induced inflam-
mation, IL-1 over-regulates one of the critical
molecules that is believed to control the cel-
lular response to hypoxia —– hypoxia-inducible
factor 1-alpha protein (HIF-1␣), which is a tran-
scription factor that supports expression of a
great range of genes associated with angio-
genesis, inflammation or/and energy metabolism
[83]. Overregulating undergoes through a classi-
cal NF-␬B/COX-2 inflammatory signalling pathway
culminating in an increased expression of the angio-
genic vascular endothelial growth factor (VEGF),
which is essential for tumour development and
metastasis [84].
IL-6
IL-6 is another proinflammatory cytokine secreted
by WAT and its levels are also increased in obese
subjects [10,85]. IL-6 is a critical factor that modu-
lates inflammation-induced carcinogenesis as well
as the expression of genes involved in tumour
growth and progression via the JAK/STAT signalling
pathway [40,58,86]. Recently, it was showed that
increased circulating level of IL-6 correlates with
cancer aggressiveness and poor diagnosis [87—91].
Inflammatory triad, due to individual properties
of each component, is able to inhibit the expres-
sion of lipoprotein lipase in the capillaries. The
deficiency of the enzyme on the wall of the cap-
illaries in the adipose tissue blocks the release
of triglycerides from circulating very-low-density
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Obes Res Clin Pract (2018), https://doi.org/10.1016/j.orcp.2018.01.005
7
lipoproteins (VLDL) in the blood, and prevent fatty
acids from entering the adipocytes; as a result,
the levels of triglycerides and cholesterol in the
blood increase [92,93]. Moreover, inflammatory
triad inhibits the activity of the insulin receptors in
adipocytes, what leads to development of insulin
resistance [94,95].
Other mediators of inflammation
NF-␬B
It may be assumed that there is a significant cor-
relation between inflammation and carcinogenesis
with NF-␬B. NF-␬B induces cellular transformation,
mediates cellular proliferation, and prevents elim-
ination of pre-neoplastic and fully malignant cells
by up-regulating the anti-apoptosis proteins. Con-
stitutive activation of NF-␬B in inflammatory bowel
disease (IBD) increases the risk of colon cancer
throughout diverse target genes that are involved in
cell proliferation, angiogenesis, and/or metastasis.
The inhibition of NF-␬B may be a crucial therapeutic
target when considering treatment and prevention
in case of the colon cancer. However, still too little
is known about the specific roles of different NF-
␬B subunits in various stages of carcinogenesis and
the inhibitors of specific subunits of NF-␬B family
[87,96,97].
ER stress
Disturbances in the normal functions of the ER
inevitably lead to an evolutionarily conserved cell
stress response, what initially compensate the
ensuing damage but can ultimately trigger cell
death if ER dysfunction is prolonged. While con-
sidering obesity and the impact it has on the ER
it may be noticed that excessive nutrient intake
in conjunction with cell expansion simply results in
constant ER stress. It denotes a so called ‘‘unfolded
protein response’’, which is associated with an
increased production of ROS and there from inflam-
matory response. Cytokines which are produced
due to ER overactivation are believed to be linked
to colon carcinogenesis [87,98,99].
Fatty acids, inflammation and colon
cancer
Björkbacka et al. [100] demonstrated that abnor-
mally elevated levels of lipids and/or lipoproteins
in the blood (hyperlipidemia) intermediate the
ORCP-711; No. of Pages 13 ARTICLE IN PRESS
8 A. Tarasiuk et al.
inflammatory response throughout the activation
of the innate immunity signalling pathways via
toll-like receptor 4 (TLR4) binding [97], which
may result in inflammation-related colon cancer.
Fatty acids are strictly associated with obesity
and insulin resistance. Saturated fatty acids acti-
vate transmembrane protein TLR4 on fat cells
and macrophages, which recognises pathogen-
associated molecular patterns (PAMPs) that are
expressed on infectious agents (e.g. bacteria,
viruses, fungi), and hence fat cells mediate the
production of cytokines necessary for the devel-
opment of effective immunity [101]. It has been
showed that the capacity of fatty acids to induce
inflammatory signalling in adipose cells or tissue
and macrophages is blunted in the absence of TLR4.
Unsaturated fatty acids are weakly proinflamma-
tory or neutral [87,101—103].
The G protein-coupled receptor 120 (GPR120)
is an omega-3 fatty acid receptor which mediates
potent anti-inflammatory and insulin-sensitising
effects [104]. GPR120, expressed in ATM and in
adipocytes is a very important signalling molecule
for many aspects of cellular function. It was deter-
mined that docosahexaenoic acid (DHA), which
activates GPR120, may weaken the proinflamma-
tory effect of TNF-␣ and lipopolysaccharide (LPS)
on macrophages. In vivo studies showed that acti-
vation of GPR120 by omega-3 fatty acids, due
to repressing macrophage-induced tissue inflam-
mation, promotes strong insulin sensitisation and
other antidiabetic effects [101,102,105]. In paral-
lel, long-chain polyunsaturated omega-3 fatty acids
(LC-PUFAs) may activate nuclear receptor proteins
that function as transcription factors regulating
the expression of genes, specifically peroxisome
proliferator-activated receptor-␥ (PPAR␥), which
plays a significant role in the prevention of high-
fat diet-induced adipose tissue inflammation and
remodelling [103,106,107]. Another study revealed
that reducing monocyte chemoattractant protein
1 (MCP-1) and NO production by the ethanolamide
metabolite of DHA (docohexaenoylethanolamine —–
DHEA) modulates inflammation [108]. To sum up,
oils containing unsaturated fatty acids, like fish
oil supplements can alleviate metabolic disease by
modulating inflammatory signalling pathways [65],
what has already been proven in selected popula-
tions. For example, a positive effect of unsaturated
omega-3 fatty acids, mainly LC-PUFAs, such as
eicosapentaenoic acid (EPA) and DHA, were found
among the Inuit living in Greenland and are known
as anti-inflammatory factors [102,109]. The Inuit
diet is principally based on sea-fish, which are rich
in the above-mentioned fatty acids. It is believed
that Inuit diet reduces the risk of cardiovascu-
Please cite this article in press as: Tarasiuk A, et al. The mechanisms linking obesity to colon cancer: An overview.
Obes Res Clin Pract (2018), https://doi.org/10.1016/j.orcp.2018.01.005
lar diseases, asthma, diabetes mellitus type 1 and
multiple sclerosis is observed in this population.
In addition, lower incidence of various types of
cancer, IBD, rheumatoid arthritis and psoriasis are
associated with the consumption of omega-3 fatty
acids [110—112]. On the contrary, higher risk of
colon tumourigenesis is observed while ingesting
omega-6 fatty acids (mainly linoleic and arachi-
donic acids) [111].
The mechanism of the protective role of fatty
acids is still not completely understood and requires
further research. Currently, there are several
hypotheses trying to explain this phenomenon
[112]:
1. Tumour cells secrete substantial amounts of
locally acting hormone —– prostaglandin E2
(PGE2). Increasing concentration of PGE2 leads
to reduction of immune activity (suppression),
which promotes tumour cell proliferation. It has
been shown that supplementation of omega-3
fatty acids reduces the concentration of PGE2
in the serum [113].
2. Consumption of omega-3 LC-PUFAs leads to
the improvement of the physical properties
of cell membranes. Above all, these fatty
acids increase membrane permeability, which
is important in chemotherapy-as a result, anti-
cancer drugs cross the cancer cell membrane
barrier distinctly faster than without LC-PUFAs.
3. In vitro studies revealed that the addition
of polyunsaturated fatty acids (PUFAs) to the
tumour cell line leads to cytolysis of these
cells. Due to excessive accumulation of toxic
metabolites of fatty acids (mainly their oxi-
dation products) in tumour cells. However, no
cytolysis was observed to normal cells after the
addition of PUFAs.
Yehuda-Shnaidman & Schwartz have recently
indicated that several molecular mechanisms of
induction of colon cancer by fatty acids may involve
a nuclear transcription factor that binds DNA as a
homodimer —– hepatocyte nuclear factor 4-alpha
(HNF-4␣) [114]. This protein controls the expression
of several genes including hepatocyte nuclear fac-
tor 1 alpha (HNF-1) —– a transcription factor which
regulates the expression profiles of several hepatic
genes that are expressed in the liver. HNF-4␣ plays a
crucial role in development of the liver, kidney, and
intestines. It also fills in as the main aim for fatty
acid nutrients and xenobiotic amphipathic carboxy-
lates and consequently represents the subsequent
impact of dietary fatty acids on colon carcinogene-
sis [87,115]. Yehuda-Shnaidman & Schwartz studied
the effect of HNF-4␣ antagonists and HNF-4␣ siRNA
on colon cancer growth and proliferation in cul-
ORCP-711; No. of Pages 13 ARTICLE IN PRESS
Obesity and colon cancer: an overview
tured colon cancer cells (HT-29 and Caco-2) and in
xenotransplanted nude mice in vivo. Through the
analysis of DNA content (increased cell population
in Sub-G1) and raised apoptotic death they dis-
covered that HNF-4␣ antagonists and siRNA inhibit
proliferation and growth of HT-29 and Caco-2 [87].
It has also been suggested that there may be a
molecular justification for the colon cancer occur-
rence among diabetic subjects and its supposed
improvement by diet enriched with omega-3 PUFAs,
what was reported for the first time by Algamas-
Dimantov et al. [116]. They observed that increased
epithelial cell proliferation and differentiation are
considered as leading rationale for the intestinal
ontogenic programme of obesity-related diabetes.
Plausibly the aforementioned programme and the
transformation sequence of colorectal cancer are
both identified by increased epithelial cell prolif-
eration and dedifferentiation, or integration. The
possible linkage between the intestinal ontogenic
programme of diabetes and the increase in intesti-
nal HNF-4␣ activity may imply that overactivity of
HNF-4␣ enhances CRC. Furthermore, the seeming
correlation between the intestinal ontogenic pro-
gramme of fat-1 transgenic mice rich in n-3 PUFAs
and a decrease in intestinal HNF-4␣ activity may
indicate that suppression of HNF-4␣ transcription
activity mitigates CRC [10,117]. Interestingly, these
mice are capable of producing n-3 fatty acids from
the n-6 type, leading to abundant n-3 fatty acids
with reduced levels of n-6 fatty acids in their organs
and tissues, without the need of a dietary n-3
supply [118]. Altogether, these data reveal that sup-
pression of intestinal HNF-4␣ activity by n-3 PUFA
may enhance diabetes related to obesity and hence
intestinal ontogenesis and at the same time sug-
gest a successful approach to forestall occurrence
of colon cancer [10].
Finally, in vivo studies revealed that obesity
remarkably increases gastrointestinal tumourigen-
esis in adenomatous polyposis coli Apc-mutant mice
[119]. Mutoh et al. examined overexpression of
LDL and lipid accumulation in intenstinal polyps in
multiple intestinal neoplasia mice, which carry a
truncation mutation at codon 850 of the Apc gene
and can develop up to 100 polyps in the small
intestine in addition to colon tumours [120]. It was
established that these mice display low expres-
sion of lipoprotein lipase, a high concentration of
serum triglycerides, large numbers of intestinal
polyps and a high number of large lipid droplets in
the polyps. Consequently, lipid accumulation in the
intestinal polyps may play a crucial role in intesti-
nal polyp formation in Apc-deficient mice. These
findings indicate that obesity associated with type
2 diabetes promotes gastrointestinal tumourigene-
Please cite this article in press as: Tarasiuk A, et al. The mechanisms linking obesity to colon cancer: An overview.
Obes Res Clin Pract (2018), https://doi.org/10.1016/j.orcp.2018.01.005
9
sis in Apc-deficient mice and provides evidence of a
mechanistic link between obesity and colon cancer.
Nutritional recommendations
A diet that protects against colon cancer should not
provide too excessive amounts of energy. It must
also include the share of fats (up to 30%). The diet
should be balanced —– in addition to the products of
animal origin, it should also contain plant ingredi-
ents. This limits the amount of saturated fatty acids
and cholesterol in the food intake. It is also neces-
sary to limit the share of highly processed foods,
including smoked and chemically preserved foods.
In this way, the exposure of the body to many muta-
genic and potentially mutagenic substances that
may become inducers of the development of can-
cerous tissues within the colon is reduced.
Vegetable foods contain many natural ingredi-
ents to protect the body against colorectal cancer.
These include fibre (dietary fibre) and antioxidants.
The dietary fibre consists of plant polysaccharides
and lignins resistant to digestive enzymes of the
human digestive tract. Fibre speeds the colonic
peristalsis, preventing constipation. Consequently,
people with a good dietary fibre content are able to
reduce the chance of contact of the large intestinal
mucosa with carcinogens in the faeces. In the pre-
vention of colorectal cancer, it is advisable to take
at least 30 g of dietary fibre daily.
Vegetables and fruits are also beneficial because
of their high antioxidant content. These include
vitamins (A, C and E), minerals (especially sele-
nium) and many plant compounds (e.g. polyphe-
nols). They protect the cells from damaging free
radicals, which trigger mutations leading to the
development of cancerous tissue.
It has been shown that calcium ions counteract
an excessive proliferation of large intestinal epithe-
lial cells and delay the onset of CRC. Therefore,
about 800—1000 mg of calcium should be included
in daily diet.
It is important to eat fresh and high quality prod-
ucts. The risk of colon cancer increases with the
presence of rancid fats, as well as mouldy prod-
ucts, which most often contain significant amounts
of carcinogenic mycotoxins [121].
Conclusions
There is growing evidence for a strong connection
between obesity and the risk of developing colon
cancer. Undoubtedly, the impact which obesity may
have on colon caricinogeneis is well known and
ORCP-711; No. of Pages 13 ARTICLE IN PRESS
10
recognised. However, further understanding of the
underlying factors is needed as it may be critical
for the improvement of the treatment strategies.
Nonetheless, it is important to notice that not all
patients with inflammation-related obesity are suf-
fering from colon caner.
Recommendations for colon cancer prevention
and prophylaxis rely on three stages. Stage one,
primary prevention, is prevention of disease devel-
opment by eliminating or reducing external risk
factors. The second stage, or secondary prevention,
involves early detection of cancer. The disease is
diagnosed at a stage where it has not yet produced
symptoms and is largely curable. The third type of
prevention concerns people with clinical disease.
Tertiary prevention measures aim to reduce the risk
of death and to prevent serious, lasting effects of
the disease in the form of various degrees of invalid-
ity. In view of the link between obesity and cancer,
the dietary ammendments to these recommenda-
tions may be proposed.
Conflicts of interest
None.
Author contributions
Aleksandra Tarasiuk, Paula Mosińska, and Jakub
Fichna provided the overall concept and frame-
work of the manuscript; Aleksandra Tarasiuk
researched and identified appropriate articles, and
wrote the manuscript; Aleksandra Tarasiuk, Paula
Mosińska, and Jakub Fichna revised the manuscript.
All authors approved the final version of the
manuscript.
Acknowledgements
Supported by grant from the Medical Univer-
sity of Lodz (#503/1-156-04/503-11-001 to JF and
#502-03/1-156-04/502-14-343 to PM) and National
Science Centre (2016/21/N/NZ5/01932 to PM).
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