GASTROINTESTINAL CANCER AND OBESITY

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Obesity and gastrointestinal cancer:
the interrelationship of adipose and
tumour microenvironments
Jacintha O’Sullivan1,2, Joanne Lysaght1,2, Claire L. Donohoe1 and John V. Reynolds1*
Abstract | Increasing recognition of an association between obesity and many cancer types exists,
but how the myriad of local and systemic effects of obesity affect key cellular and non-​cellular
processes within the tumour microenvironment (TME) relevant to carcinogenesis, tumour
progression and response to therapies remains poorly understood. The TME is a complex cellular
environment in which the tumour exists along with blood vessels, immune cells, fibroblasts, bone
marrow-​derived inflammatory cells, signalling molecules and the extracellular matrix. Obesity ,
in particular visceral obesity , might fuel the dysregulation of key pathways relevant to both the
adipose microenvironment and the TME, which interact to promote carcinogenesis in at-​risk
epithelium. The tumour-​promoting effects of obesity can occur at the local level as well as
systemically via circulating inflammatory , growth factor and metabolic mediators associated with
adipose tissue inflammation, as well as paracrine and autocrine effects. This Review explores key
pathways linking visceral obesity and gastrointestinal cancer, including inflammation, hypoxia,
altered stromal and immune cell function, energy metabolism and angiogenesis.

1
Trinity Translational Medicine
Institute, Trinity College
Dublin and St. James’s
Hospital, Dublin, Ireland.
2
These authors contributed
equally: Jacintha O’Sullivan,
Joanne Lysaght.
*e-​mail: reynoljv@tcd.ie
https://doi.org/10.1038/
s41575-018-0069-7
Large-​scale epidemiological studies have demonstrated
a consistent and compelling association between the risk
of cancer development and obesity (defined by BMI) for
several cancers1 (summarized in Table 1). An umbrella
review of the literature comprising 204 meta-​analyses
of large studies with limited heterogeneity or evidence of
bias was published in 2017 (ref.2). For gastrointestinal
cancer, the analysis revealed a strong and potentially
causal association between obesity and oesophageal
adenocarcinoma, colon cancer in men, biliary tract can-
cer and pancreatic cancer. The evidence is also highly
suggestive of an association between liver cancer and
adenocarcinoma of the gastric cardia (the oesophago-
gastric junction)2. In 2016, the International Agency
for Research on Cancer (IARC) reported relative risks
(RRs) of 1.5 to 1.8 for the highest BMI (up to ≥40 kg/m2)
compared with a normal BMI (18.0–24.9 kg/m2) for
these tumour sites1. Oesophageal adenocarcinoma was
notable for a progressive increase in RR for each 5 kg/m2
increase in BMI (RR 4.8 for a BMI ≥40 kg/m2), suggest-
ing a dose–response effect for this tumour type. The
IARC report concluded that the absence of excess body
fat reduces the risk of most cancers1.
These epidemiological reports are in the context of
an increase in the global prevalence of obesity between
1975 and 2014 from 3.2% to 10.8% in men and from
6.4% to 14.9% in women; currently, 640 million adults
and 110 million children worldwide are obese3. In the
United States, the obesity prevalence in men and women
is 35% and 40%, respectively, and approximately 5% of
men and 10% of women have a BMI >40 kg/m2 (ref.4).
Obesity is estimated to contribute to approximately 9%
of all cancers5 and between 5% and 20% of all cancer-​
related deaths6. Furthermore, the prevalence of obesity
in the United States in the 2–19-year age group was
estimated to be 17% in 2014, with a BMI ≥40 kg/m2
in 5.8%; additionally, the prevalence of overweight in
those <10 years of age is up to 40% in some European
countries, presenting a concerning vista for the future7–9.
Globally, excess body weight is third behind smoking
and infection as an attributable risk factor for cancer, and
second to smoking in Western populations10.
In addition to promoting carcinogenesis, obesity
might also affect the tumour biology of established can-
cers. For instance, poorer survival is reported in patients
with colon cancer and pancreatic cancer who are over-
weight or obese at the time of diagnosis11,12. The risk
of dying is increased in both patients with overweight
(HR 1.26, 95% CI 0.94–1.69, P = 0.04) and with obe-
sity (HR 1.86, 95% CI 1.35–2.56, P < 0.001) with pan-
creatic cancer12 and in men with obesity treated with
adjuvant chemotherapy for colon cancer (HR 1.16, 95%
CI 1.01–1.33, P = 0.0297)11. Although this finding might
be partially due to later diagnosis and reduced uptake of

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Key points
• Epidemiological evidence implicates obesity as a risk factor for the development of
cancers at multiple sites in the gastrointestinal tract, including the oesophagus, liver,
colon, gastric cardia and pancreas.
• Immune, metabolic and inflammation-​associated properties of excess adiposity are
increasingly understood, but how they influence the tumour microenvironment
(TME), which comprises tumour cells, blood vessels, immune cells, fibroblasts and the
extracellular matrix, remains unclear.
• Adipocyte stem cells are increased in adipose tissue of individuals with obesity;
in mouse models, these cells migrate to tumour sites and differentiate into cell types
that might affect the TME.
• Interstitial fibrosis within the TME can influence cytokine signalling, epithelial cell
morphology and stem cell differentiation. Adipocyte stem cells might be a source of
cancer-​associated fibroblasts, and obesity might play a part in fibrosis-​associated
mechanosignalling within tumours.
• Metabolic reprogramming in the TME is associated with obesity, hypoxia and
angiogenesis. These processes are tightly interconnected and represent a potential
target affecting not only tumours but also immune or inflammatory cells within Adipose tissue is largely located in two main depots:
the TME.
• Bariatric or metabolic surgery is associated with an improvement in the metabolic
profile of patients with obesity and a marked decrease in the incidence of cancer
development.
screening or diagnostic tests in populations with obe-
sity13,14, it is also linked to a reduction in the efficacy of
conventional therapies, including chemotherapy, radio-
therapy and agents that target angiogenesis6,7,12,15–17. This
negative association with outcomes, treatment effects
and prognosis is acknowledged by a position statement
in 2014 from the American Society of Clinical Oncology
(ASCO), which committed to tackling the problem of
obesity and cancer through increasing education and
awareness, the provision of tools and resources for
providers to address obesity with their patients, and
the development of robust research models, as well as
increasing support for public health policies to prevent
and treat obesity18.
A clear need therefore exists for scientific knowl-
edge that aligns compelling epidemiological associ-
ations between obesity and gastrointestinal cancer
with a better understanding of the altered biological
processes that occur in the context of obesity within
adipose tissue, the microenvironment of preneoplastic
and tumour tissues, and immunoregulatory organs, in
particular the liver. However, research in this area is
in its infancy. One focal point for research should be the
tumour microenvironment (TME), the cellular environ-
ment in which a tumour exists. The TME includes blood
vessels, immune cells, fibroblasts, bone-​marrow-derived
inflammatory cells, signalling molecules and the extra-
cellular matrix (ECM) (Fig. 1). The key processes linking
obesity and cancer that are commonly dysregulated in
both adiposity and in the TME include inflammation,
hypoxia, energy metabolism, angiogenesis and epithe-
lial to mesenchymal transition (EMT)19–23. The effect of
obesity on the TME can occur both at the local level
and systemically via circulating inflammatory, growth
factor and metabolic mediators associated with adipose
tissue inflammation.
Although the broad scientific principles that link
obesity and cancer apply across many tumour sites,
most reviews to date have largely focused on hormone-​
sensitive cancers, in particular breast and prostate
cancer24, or on specific adipokines and growth factors,
including leptin, adiponectin, insulin and insulin-​like
growth factor 1 (IGF1) (refs25,26). In this Review, we
discuss the relationships between obesity and gastro­
intestinal cancers (oesophagus, stomach, pancreas, liver
and colorectal), with a particular focus on key cellular
components, such as immune cells and adipose-​derived
stem cells (ASCs), and common themes in both the TME
and the obese adipose microenvironment, including
inflammation, hypoxia, angiogenesis and altered energy
metabolism. In addition, the prospect of therapeutically
targeting obesity to reduce cancer risk or to improve
patient outcomes is considered.
Obesity-​associated inflammation
subcutaneous and visceral. The main function of adi-
pose tissue is in energy homeostasis, but it also acts as
an endocrine organ, releasing hormones, growth factors
and adipokines, the cell signalling proteins produced
by adipose tissue27. Excess caloric intake leads to alter-
ations in insulin sensitivity and cellular stress within
adipocytes owing to surplus lipid accumulation, with
consequent release of inflammatory cytokines and
adipokines from adipocytes and infiltrating immune
cells28. Visceral adipose tissue (VAT), which includes
central depots including the omentum, mesenteric,
epiploic, gonadal, epicardial and retroperitoneal fat
pads, is thought to be a key source of obesity-​derived
inflammation and altered metabolism in comparison
with subcutaneous adipose tissue29. The largest and
best studied VAT depot is the omentum, the so-​called
fatty apron that connects the stomach and colon and
lies anterior to the intestines29. Increased waist circum-
ference is a proxy measure of VAT and is a predictor of
elevated health risk in individuals who are overweight
(BMI 25.0–29.9 kg/m2) or obese (BMI ≥30 kg/m2)30.
Individuals with increased VAT deposits are more
likely to have hypertension, type 2 diabetes mellitus
(T2DM) and dyslipidaemia, features that characterize
the metabolic syndrome and are also associated with
a risk of cardiovascular disease30,31. Although the epi­
demiological evidence for the association between waist
circumference and cancer incidence is limited by the
absence of prospective cohort studies, there is an asso-
ciation between increased abdominal obesity, measured
by waist circumference, and the incidence of colorectal
cancer32, as well as obesity-​related cancers combined33.
An important aspect unique to VAT is its anatomical
link to the liver via portal vein drainage, and the VAT–
liver axis is thought to account for the greater influence
that VAT has on insulin resistance and inflammation
compared with subcutaneous adipose tissue34. The
so-​called portal hypothesis describes how the liver is
directly exposed to increasing amounts of free fatty
acids and pro-​inflammatory factors released from VAT
directly into the portal vein of individuals with obesity,
ultimately increasing the risk of liver inflammation and
nonalcoholic fatty liver disease (NAFLD), as well as
promoting insulin resistance35.
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Table 1 | relative risk of gastrointestinal cancer at high BMI low-​grade chronic inflammation in neighbouring and
distal organs (Fig. 2).
site relative risk of 95% CI strength of
the highest BMI evidencea
category versus Obesity and the hallmarks of cancer
normal BMI The modern molecular understanding of cancer was
proposed in 2000 by Douglas Hanahan and Robert
Oesophageal 4.8 3.0–7.7 Strong
adenocarcinoma Weinberg46, with six original hallmarks that included
sustained angiogenesis, invasion and metastasis, growth
Colon 1.3 1.3–1.4 Strong in men,
suggestive in women and replication, self-​sufficiency, resistance to anti-​
growth signals and the evasion of apoptosis46. An update
Gallbladder 1.3 1.2–1.4 Strong
published in 2011 added the emerging hallmarks and
Pancreas 1.5 1.2–1.8 Strong enabling characteristics of genomic instability, tumour-​
Liver 1.8 1.6–2.1 Not reported promoting inflammation, reprogramming of energy
Gastric cardia 1.8 1.3–2.5 Suggestive
metabolism and the evasion of immune destruction47.
It is now accepted that it is not only the functional
Rectum 1.3 1.3–1.4 Suggestive capabili­ties of cancer cells that define a cancer but also the
Breast: postmenopausal 1.1 1.1–1.2 Strong influence of its microenvironment, and in this context,
Corpus uteri 7.1 6.3–8.1 Strong inflammation provides a key added dimension; a so-​
called seventh hallmark48. Inflammation, first mooted
Ovary 1.1 1.1–1.2 Suggestive
as a factor relevant to carcinogenesis in 1863 by
Renal cell carcinoma 1.8 1.7–1.9 Strong Rudolf Virchow, is now widely accepted as predispos-
Meningioma 1.5 1.3–1.8 Not reported ing to cancer, whether mediated by extrinsic or intrinsic
Multiple myeloma 1.5 1.2–2.0 Strong influences48. It can lead to tissue damage and genetic
instability and can disrupt homeostasis within the
Thyroid 1.1 1.0–1.1 Suggestive
immune system and tissue microenvironments.
Data from a meta-​analysis reported by the International Agency for Research on Cancer
(IARC) working group1. aThe strength of evidence is reported from an umbrella meta-​analysis2
The simplest scientific explanation for the asso-
with quality determined as strong when P < 10−6 from a meta-​analysis random effects model ciation of obesity with an increased risk of cancer of
(>1,000 cancer cases) and suggestive if P < 10−3 in a random effects model (>1,000 cancer any type is that the microenvironment of precancer
cases). Cancer sites such as the oesophagus, colon, gallbladder, pancreas, breast, corpus uteri
and renal cell carcinoma are often referred to as obesity-​related cancers, distinguishing them or cancer is altered and enabled by obesity-​associated
from tumours at other sites that have not been found to be associated with obesity. inflammation, particularly when obesity is associated
with dysmetabolism and characterized by the metabolic
Within VAT, adipocytes comprise ~90% of the adi- syndrome, insulin resistance or T2DM49. Inflammation
pose tissue volume, but adipose tissue is also rich in linked to obesity might be fuelled by systemic adi-
other cells from the stromal–vascular fraction, includ- pokines, pro-​inflammatory cytokines or endocrine and
ing innate and adaptive immune cells, endothelial cells, metabolic influences, as well as pleiotropic influences
peri­cytes, fibroblasts and stem and progenitor cells36–39. within the TME, such as the modulation of stemness
VAT has more pleiotropic properties influencing car- and the promotion of EMT19. Although 10–50% of
cinogenesis than subcutaneous fat, including differ- individuals with obesity might remain free of metabolic
ent gene expression profiles of adipocyte stem cells40. abnormalities and be ‘metabolically healthy’ (refs50–52),
Within adipose tissue, the increased number and altered these individuals often have chronic systemic inflam-
activation phenotype of immune cells, including mac- mation with elevated circulating levels of inflammatory
rophages41, are an important source of activated inflam- cytokines, such as TNF, IFNγ and C-​reactive protein53,54,
matory pathways in individuals with obesity29, with clear which might have key enabling roles in driving carcino-
links between inflammation and dysregulated metabolic genesis from initiation to progression and invasion
pathways, such as TNF production correlating with or metastasis19,55.
insulin resistance42.
In addition, the serum levels of the adipokine leptin, Antitumour immunity in obesity
which is derived from adipocytes, increase with obe- The link between inflammation and obesity within the
sity and play a central part in controlling appetite and TME should be viewed in the context of disruption of
energy expenditure43,44. Leptin has extensive immuno- the cancer-​immunity cycle, as proposed by Chen and
modulatory roles through the stimulation of inflamma- Mellman56,57, which describes the basic antitumour
tory cytokines including IL-6, TNF, IL-8 and IL-12 from immune response. This cycle begins with maturing
macrophages, dendritic cells, and natural killer (NK) dendritic cells presenting processed tumour antigens on
cells, as well as through fuelling T helper 1 (TH1)-type major histocompatibility complex I (MHC I) or MHC II
T cell responses from the adaptive immune system43. molecules to naive T cells in sentinel lymph nodes, lead-
Leptin is also involved in many pro-​cancer processes, ing to the activation and clonal expansion of effector
including the promotion of cell proliferation, metastasis, T cells56. The activated effector T cells then migrate
anti-​apoptosis and angiogenesis, via pathways synergis- to the tumour in response to chemokine signals and
tic with vascular endothelial growth factor (VEGF)45. infiltrate the tumour. Upon encountering their cognate
Thus, elevated levels of inflammatory cytokines and antigen, cytotoxic CD8+ T cells will kill their targets,
adipokines enter the circulation from VAT in obe- resulting in the release of additional tumour antigens
sity, leading to both local inflammation and systemic for dendritic cells to process, and the cycle begins

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Tumour microenvironment
Neutrophil or
granulocyte
Carcinoma cell
Adipocyte
Blood vessel
Macrophage
Fibroblast,
myofibroblast
or MSC
ECM
T cell
ASC
Tumour microenvironment in obese state
Fig. 1 | the tumour microenvironment in obesity. The tumour microenvironment within
an obese state is characterized by increased numbers of adipocyte-​derived stem cells
(ASCs). There are also increased numbers of fibroblasts and increased extracellular matrix
(ECM) deposition along with an increase in numbers and activation of different immune
cell populations. ASCs can differentiate into fibroblasts, and this process might be
promoted by factors secreted by tumour cells, such as transforming growth factor-​β or
platelet-​derived growth factor. Obesity stimulates interstitial fibrosis with alterations in
ECM mechanics noted in the tumours of obese mice. ASC-​derived pro-​angiogenic factors
might also affect tumour vascularity. Tumour vascularity is increased in obese mice versus
lean controls, particularly in niches rich in ASCs, in which the proliferative index of cells
adjacent to vessels and adipocytes is increased. MSC, mesenchymal stem cell.
again56. However, in reality, this cycle might be circum-
vented as tumours develop multiple evasion strategies
and can avoid immunosurveillance owing to physio-
logical characteristics of the TME, including hypoxia,
acidosis and nutrient deprivation58,59, which all counter
effective antitumour immunity60. The key to unlock-
ing the link between obesity and cancer might be an
improved understanding of how obesity affects immune
cell function within the TME and the pre-​malignant
epithelium to both impair antitumour responses and
promote inflammatory processes that can affect all the
hallmarks of cancer. In this context, studies in colorec-
tal cancer and prostate cancer have demonstrated that
at the local TME level, tumour cell–adipocyte inter­
actions within an adipocyte-​rich microenvironment
can lead to tumours becoming dependent on adipocyte-​
derived excess nutrients, growth factors and inflamma-
tory cytokines, potentially offering novel avenues for
therapeutic targeting61,62.
Obesity-​induced alterations in visceral adipose tis-
sue immune cell profiles. Although local interactions
between immune cells, adipocytes and tumour cells
occur within the TME, systemic alterations first occur
at an organ level in adipose depots, in particular VAT,
as obesity develops. The normal homeostatic profiles
of innate and adaptive immune cell populations within
VAT and the liver are substantially altered with increas-
ing levels of obesity, either through induced expansion
in situ or active recruitment from blood, bone marrow
and neighbouring tissues63. In VAT, factors including
lipogenesis, lipotoxicity, polyunsaturated fatty acid
composition and adipose tissue fibrosis are implicated
in obesity-​associated inflammation through alterations in
immune cell subset composition and the production
of cytokines and growth factors, including IL-6, leptin,
VEGF and IGF1 (refs64–67). In lean individuals, VAT
is characterized by low numbers of activated neutro-
phils, mast cells, γδ T cells and a prevalence of M2-type
macrophages, NK cells, invariant NK T (iNKT) cells,
regulatory T cells (Treg cells) and CD4+ TH2 cells, with
IL-4, IL-10 and adiponectin exerting important homeo­
static anti-​i nflammatory functions12,68–72 (Fig.  3). In
humans, excessive caloric intake associated with obe-
sity can result in a several-​fold increase in adipose tis-
sue volume, and as a result, the immune cell profile is
substantially altered with a decrease in CD4+ TH2 cells,
M2-type macrophages and FOXP3+ Treg cells and a con-
comitant increase in M1 macrophages, CD8+ T cells,
NK cells, B cells, mast cells and OX40+ Treg cells68,70,73,74
(Fig. 3). This profile is largely pro-​inflammatory, with a
dominance of TH1 cells, with consequent IFNγ prod­
uction being of considerable importance as a potential
driver of macrophage polarization to the classically acti-
vated inflammatory M1 phenotype. Other character-
istics of the obesity-​associated profile include elevated
IL-6, TNF, IL-1β and leptin and reduced production
of adiponectin. Overall, the predominant TH2-like
anti-​inflammatory immune cell phenotype in healthy,
lean individuals is lost with obesity, and the ensuing
pro-​inflammatory state leads to a dysregulation of
immune homeostasis.
Obesity-​induced alterations in liver immune cell
profiles. In obesity, the liver receives increased lev-
els of secreted inflammatory adipokines, particularly
from VAT via the portal vein, as well as associated
growth factors, hormones, cytokines, chemokines and
free fatty acids35. In healthy, lean individuals, the liver
maintains immunological tolerance by producing anti-​
inflammatory factors, predominantly IL-10, with selec-
tive expansion of hepatic Treg cells75 (Fig. 3). Resident
hepatic lymphocytes are diverse and, similar to their
innate counterparts, reflect their unique functional
phenotype, including NK cells, NKT cells, mucosal-​
associated invariant T (MAIT) cells, γδ T cells, CD4+ and
CD8+ T cells and B cell populations76–79. Excess visceral
obesity is associated with NAFLD, which can progress
with hepatic inflammation and immune cell activation
to nonalcoholic steatohepatitis (NASH), which is a major
risk factor for liver fibrosis and hepatocellular carci-
noma (HCC)80. Increased triglyceride content within
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hepatocytes, fibrosis, increased levels of free fatty acids
and hepatocyte cell death are all thought to result in
enhanced local inflammation and immune cell activation
in the liver of individuals with obesity81,82. As a result, this
normally tolerogenic organ contains increased numbers
of Kupffer cells83, neutrophils84, dendritic cells85, TH17
CD4+ T cells86, CD8+ T cells87 and NKT cells88.
In studies of the VAT and liver from patients with
oesophageal adenocarcinoma undergoing surgery, parallel
alterations in immune and inflammatory pathways were
identified, including activation of T cells expressing IFNγ
and TNF, as well as activation of TH17 cells70,82,89,90. Such
studies suggest that VAT and the liver are closely linked
in a local and systemic milieu of altered immune, inflam-
matory and metabolic processes that might synergize and,
when combined, provide a compelling mechanistic link to
altered metabolism and the immune and inflammatory
changes associated with the evident risk of carcinogenesis.
Obesity-​induced alterations in circulating immune
cell profiles. In the circulation, the factors associated
with a systemic inflammatory state in obesity include
leptin, IL-6, IFNγ, TNF, growth factors, visfatin, resistin,
ghrelin, C-​reactive protein and a range of chemokines

Oesophageal adenocarcinoma Gastric cancer

• Increased IL-4, IL-10, IL-1β • Increased leptin, ghrelin,
• NF-κB activation Liver CD4+ TH17 cells, MDSCs
• STAT3 activation
Stomach
Hepatocellular carcinoma
• Increased IGF1, IL-8, IL-6 Colorectal cancer
• Activated RAS–MAPK • Increased IL-1, IL-6,
signalling TNF, IL-8, IL-17A, IL-22
• Dysregulated PI3K and/or • Increased COX2 and
AKT–mTOR signalling VEGF expression
Colon • Increased MAIT cells
and neutrophils

Visceral adipose tissue secretes bioactive Tumour-adjacent adipose tissue functions

compounds into systemic circulation in a paracrine manner
Macrophage recruitment
T cell
Adipocyte infiltration

Tumour
microenvironment

Systemic Tumour
circulation vascular supply
Increased visceral adiposity Pro-tumorigenic environment
• ↓ Adiponectin • ↑ IL-10 • ↑ CCL2 • ↑ Inflammation
• ↑ Leptin • ↑ IFNγ • ↑ Free • ↑ Insulin resistance
• ↓ IL-4 • ↑ TNF IGF1 • ↑ Angiogenesis
• ↑ IL-6 • ↑ Insulin

Fig. 2 | obesity induces a local inflammatory state within the omentum that can drive carcinogenesis at multiple
sites. A local inflammatory state is induced by obesity in the omentum, leading to the secretion of inflammatory cytokines,
chemokines and growth factors into the circulation that then lead to systemic inflammation. This systemic inflammation
affects neighbouring organs, including the liver, through the accumulation of fat and the passive drainage of inflammatory
mediators and potential active migration of immune cells via the portal system, further exacerbating systemic
inflammation through the release of acute phase proteins and inflammatory mediators. Chronic systemic inflammation
also affects organs of the gastrointestinal tract at distal sites including the stomach, colon and oesophagus, through the
activation of resident immune cells and triggering of inflammatory signalling pathways that drive local carcinogenesis.
AKT, protein kinase B; CCL2, CC-​chemokine ligand 2; COX2, cyclooxygenase 2; IGF1, insulin-​like growth factor 1; MAIT,
mucosal-​associated invariant T; MAPK , mitogen-​activated protein kinase; MDSC, myeloid-​derived suppressor cell; mTOR ,
mechanistic target of rapamycin; NF-​κB, nuclear factor-​κB; PI3K , phosphoinositide 3-kinase; STAT3, signal transducer and
activator of transcription 3; TH17 , T helper 17; VEGF, vascular endothelial growth factor.

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including CC-​chemokine ligand 2 (CCL2) and CCL5
(refs91,92) (Fig. 3). Obesity itself, in the absence of can-
cer, induces changes in the frequencies of circulating
innate and adaptive immune cells, including a decrease
in activated CD8+ cytotoxic T lymphocytes, Treg cells and
Vδ2 T cells68 and an increase in M1-type macrophages,
CD4+ T cells, B cells and NK cells93. However, changes in
circulating immune cells appear dependent on the extent
of obesity and the cellular subset examined.
In the cancer context, a better understanding of the
effect of obesity on systemic immunity is important, par-
ticularly owing to an increasing interest in the prognostic
and therapeutic implications of the immune cell infil-
trate in solid tumours. For example, the Immunoscore,
which measures the densities of CD3+ and cytotoxic
CD8+ T cells in the tumour core and in the invasive mar-
gin94,95, has clearly demonstrated the applied potential of
introducing immune cell parameters into cancer clas-
sification and as a prognostic tool in colorectal cancer.
Whether obesity, with its potential effect on the TME,
influences the T cell phenotype within tumours and
response to therapies remains unclear60,65,96,97.
In summary, the appropriate activation of immune
cells is required to prevent, control and remove malig-
nant cells. Conversely, inappropriate activation of the
immune system can lead to sustained inflammation,
Circulation in obesity
• Increase in IL-6, IFNγ, TNF, CRP,
visfatin, grehlin, resistin,
CCL2 and CCL5
• Decrease in activated CD8+ T cells
• Increase in M1 macrophages,
CD4+ T cells, B cells and NK cells
Lean liver
• Normal resident Treg cells,
CD56hi NK cells,
iNKT cells, CD161+Vα7.2+ Lean omentum
MAIT cells, Vδ1 and • Enrichment of CD4+
Vδ3 T cells, CD4+ T cells, TH2 cells, iNKT cells,
CD8+ T cells and B cells regulatory Treg cells and
M2 macrophages
Obese liver
• Increase in CD14+ Obese omentum
Kupffer cells, • Hypoxia, cellular stress
MOP+ neutrophils, and rupturing hypertrophic
TNF+ dendritic cells, adipocytes
TH17 CD4+ T cells, • Enrichment of CD4+ TH1
CD8+ T cells and and CD8+ T cells, NK cells,
CD3+CD56+Vα24+ B cells, M1 macrophages
iNKT cells and neutrophils
Fig. 3 | Immune cell composition in lean versus obese omentum, liver and blood.
Lean adipose tissue of the omentum is characterized by an enrichment of anti-​
inflammatory innate and adaptive immune cells, including CD4+ T helper 2 (TH2) cells,
invariant natural killer T (iNKT) cells, regulatory T cells (Treg cells) and M2 macrophages,
which maintain local homeostasis.  In the obese omentum, this homeostasis is disrupted
owing to hypoxia, cellular stress and rupturing hypertrophic adipocytes that release free
lipids. As a result, there is an accumulation of pro-​inflammatory immune cells, including
CD4+ TH1 and CD8+ T cells, natural killer (NK) cells, B cells, M1 macrophages and
neutrophils. Accompanying this infiltration of inflammatory cells is the increased release
of pro-​inflammatory cytokines, adipocytokines and chemokines into the blood and
directly into the liver via the portal system, which adds to local and systemic
inflammation and changes in the immune cell populations normally resident in healthy
lean liver and blood. CCL , CC-​chemokine ligand; CRP, C-​reactive protein; MAIT,
mucosal-associated invariant T.
which promotes carcinogenesis through increased
mutational rates, angiogenesis and dysregulation in the
normal immune cell infiltrate within tissues. Obesity
directly leads to alterations in the immune cell pheno-
type and inflammatory profile within various organs,
which can affect the ability of the immune system to
control cancer growth. Although substantial progress
has been made in identifying specific cellular changes
induced as a result of obesity within adipose tissue, much
research is needed to identify the changes in immune
cells and their functions within the TME as a direct result
of visceral obesity or tumour-​adjacent adipose depos-
its. Developing immune-​based therapies for patients
with obesity-​associated cancer presents a unique chal-
lenge for cancer immunologists: to successfully dampen
pathological adipose tissue-​derived inflammation while
simultaneously not interfering with ongoing antitumour
immune responses at distal sites.
Adipose-​derived stem cells in the TME
Although the majority of research to date has focused on
the systemic effects of excess adiposity, adipocytes per se
are active players in the TME. Adipocytes in tumours are
in close contact with cancer cells, with a bidirectional
crosstalk being a putative contributor to carcinogen-
esis98,99 (Fig. 4). In the appropriate context, adipocytes
within the TME, as in VAT and other depots, are a
potential source of both growth factors and signalling
molecules, including pro-​inflammatory adipokines and
cytokines, pro-​angiogenic factors and components of the
ECM100–102. Within both fat depots and the TME stroma,
adipocyte progenitors known as ASCs represent approx-
imately 15–30% of cells in the stromal–vascular fraction
of adipose tissue and can be mobilized in response to
chemokines such as CC-​chemokine receptor 2 (CCR2)
and CXC-​chemokine receptor 4 (CXCR4) ligands from
the TME103–106. The TME within an obese state is charac­
terized by increased numbers of ASCs, which might fuel
carcinogenesis and tumour progression107. ASCs are
phenotypically similar to bone-​marrow-derived mesen-
chymal stem cells (MSCs), although their proteasome
and immunomodulatory ability might differ108. ASCs,
immunologically privileged by lacking MHC II expres-
sion and lacking a response to co-​stimulatory molecules,
might also exert an immunomodulatory role at the inter-
face between tumours and immune cells in the TME, in
particular through decreased NK cell, cytokine and B cell
responses109. ASCs from patients with obesity compared
with normal weight individuals differ functionally; for
example, obesity enhances the ability of ASCs to differen-
tiate into adipocytes with consequent reduction in tissue
repair capabilities and an upregulation of inflammatory
genes110,111. In mouse models of diet-​induced obesity,
ASCs derived from the visceral tissue of humans resulted
in increased growth of tumour cells implanted in the peri­
toneum112. In other mouse models, ASCs migrate via the
systemic circulation into tumour sites and can undergo
differentiation into endothelial cells, pericytes and peri­
tumoural adipocytes, putatively important for neovas-
cularization and maintenance of the tumour niche113.
ASC-​derived pro-​angiogenic factors, including hepato-
cyte growth factor and VEGF114,115, might also influence
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TME the ECM, as in cancer, might be permissive of uncon-

trolled tumour cell proliferation or evasion from apopto-
sis. In tumours associated with genetically induced and
Adipokines
Cytokines
diet-​induced obesity, ASCs differentiate into myofibro-
Adipocyte Angiogenic factors blasts, which leads to a stiffer ECM with increased depo-
sition of fibronectin and type I collagen20. Consequently,
increased rigidity results in a reciprocal signalling loop
between the ECM and cancer cells, enhancing invasive-
Differentiation CXCR4 ness126, and this process might occur via mechanotrans-
Chemokines Adipose tissue duction, whereby mechanical stimuli are converted
into chemical signals, promoting cancer progression
CCR2
ASC and invasion20.
A dense and stiff ECM results in changes in cytokine
signalling, epithelial cell morphology with a loss of polar-
Bone marrow ity and stem cell differentiation125,127,128. Receptors such as
periostin seem to be required for tissue to be enriched
Bone with cancer stem cells129, creating a tumorigenic niche
that is thought to be important for the development
Fig. 4 | Interplay between adipocytes, stem cells and the tumour microenvironment. of metastatic disease. CAFs are pro-​inflammatory; for
Chemokines produced in the tumour microenvironment (TME), such as CXC-​chemokine example, CAFs from a mouse model of squamous skin
ligand 1 (CXCL1), CXCL8, CXC-​chemokine receptor 4 (CXCR4) and CC-​chemokine carcinoma have a pro-​inflammatory genetic signature,
receptor 2 (CCR2), result in the recruitment of adipose-​derived stem cells (ASCs) from mediated via nuclear factor-​κB (NF-​κB)130. In gastric
adipose tissue, as well as potentially from the bone marrow107. ASCs act both as a source cancer, an inflammatory IL-6–STAT3 (signal transducer
of adipocytes (upon differentiation) and as a source of adipokines, cytokines and and activator of transcription 3) signalling cascade and
angiogenic factors, which in turn might influence the TME. Adipocytes also act in a associated MSCs result in the activation of neutro-
paracrine manner to secrete factors that favour tumour progression by promoting phils, and crosstalk between MSCs and neutrophils
mechanisms such as angiogenesis, tumour fibrosis, altered extracellular matrix
favours transformation of MSCs into CAFs131. Thus,
mechanics and mechanosignalling103,246,247.
the stroma is a key player in creating the environmen-
tal conditions that support the survival of tumour cells,
tumour vascularity, which is increased in obese mice with obesity promoting an environment conducive to
compared with lean controls, particularly in niches rich tumour development.
in ASCs, where the proliferative index of cells adjacent
to vessels and adipocytes is augmented116. Epithelial to mesenchymal transition. Another impor-
tant link between ASCs, the adipose microenvironment
Fibroblasts and the extracellular matrix in the TME. and the TME is the promotion of EMT in the TME,
Within the TME, ASCs promote fibrosis and provide which results in an invasive tumour phenotype that
a source of cancer-​associated fibroblasts (CAFs)117,118 might also be relatively chemoresistant132–134. EMT is the
(Fig. 5). CAFs are the dominant cell type in the stroma process by which epithelial cells acquire mesenchymal-​
surrounding tumour cells119. CAFs are characterized like properties — an increased ability to migrate, evade
by the expression of α-​smooth muscle actin (α-​SMA), apoptosis and produce ECM components — and is
neural/glial antigen 2 (NG2), tenascin C and platelet-​ hypothesized to be a key method by which tumour cells
derived growth factor receptor α (PDGFRα), and they acquire the ability to metastasize135. At the time of EMT,
might be associated with a more aggressive tumour bio­ there is a loss of apical–basal polarity and cell–cell junc-
logy and poorer survival119–121. For example, in a study tions in epithelial cells, with cytoskeletal reorganization
of 183 patients with oesophageal adenocarcinoma who and associated changes in signalling and gene expres-
underwent surgery, 93% of tumours contained CAFs, sion132. The process of EMT generally progresses through
and their density correlated with poor survival (HR 7.1, conserved pathways with minor variations according to
95% CI 1.7–29.4, P = 0.0016)122. The ECM or intra-​ tissue type136. Triggering factors for EMT are complex,
tumour stroma content is also relevant. For instance, in and although transcription factors drive EMT, several
stage II and III colon cancer, it is an independent predic- master regulators are involved in the process, includ-
tor of overall survival, with overall and disease-​free sur- ing epigenetic changes and microRNAs137. Other fac-
vival times being substantially lower in patients whose tors within the TME promoting EMT include hypoxia,
tumours have a high stromal content, defined as >50%123. acidosis, leptin and low glucose 138. Inflammatory
In mice, obesity stimulates interstitial fibrosis medi- cytokines fuel EMT in several different cancer cell lines,
ated by fibroblasts, with alterations in the ECM mechan- including HCC139. For example, in a mouse model of
ics. For example, a fibrotic phenotype has been reported HCV-​associated HCC, diet-​induced obesity increased
in pancreatic neoplasia in a mouse model124 as well as in inflammatory signalling via STAT3, and this finding was
a study of patients with oesophageal cancer122. The ECM associated with larger tumours with a cancer-​stem-cell-​
undergoes continuous remodelling, and the dynamics of like phenotype140. Oesophageal adenocarcinoma cell
the process are thought to be crucial to the normal func- lines co-​cultured with fat taken from patients with obe-
tion of tissue by providing an organizational platform for sity resulted in the upregulation of EMT programmes141
cellular migration and cell growth125. Disorganization of and expression of matrix metalloproteinases (MMPs)142.

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Differentiation
ASC MSC
CAF
• Growth factors
(TGFβ, HGF, IGF)
• Angiogenesis factors
(VEGF, PDGF, HGF)
• Inflammatory factors
(IL-6, IL-1, ATP)
ECM deposition • Hypoxia
and remodelling (HIF1α, LDH)
Altered immune Tumour cell
environment
↑ Proliferation ↑ Motility Angiogenesis
Fig. 5 | the role of cancer-​associated fibroblasts in the tumour microenvironment.
Cancer-​associated fibroblasts (CAFs) are stromal cells of the tumour microenvironment
(TME) that are derived from mesenchymal stem cells (MSCs) and also potentially from
adipose-​derived stem cells (ASCs)106,108. CAFs might be influenced by ASCs via
bidirectional crosstalk , whereby ASCs migrate to the TME under the influence of factors
produced by CAFs, and ASCs cause the activation of resident quiescent fibroblasts into
CAFs. The pro-​tumorigenic effects of ASCs (secretion of growth factors, angiogenic
factors, inflammatory factors and hypoxia factors) might be mediated via CAFs rather
than directly by ASCs. CAFs secrete and remodel extracellular matrix (ECM), but they
also secrete numerous factors, such as growth factors and pro-​angiogenic factors,
which facilitate increased motility and proliferation of tumour cells as well as increased
tumour angiogenesis109,248,249. CAFs contribute to an inflammatory and metabolically
dysregulated TME through the production of hypoxia-​inducible factor 1α (HIF1α) and
lactate dehydrogenase (LDH), as well as inflammatory cytokines that lead to effects on
the local immune cell infiltrate and on tumour cells. CAFs, perhaps with infiltrating
immune cells, might also play a role in the development of tumour fibrosis, a factor
thought to favour the persistence of cancerous epithelial cells through the production of
growth factors or ECM components. Mouse models of obesity demonstrate increased
fibrosis within the TME and altered ECM mechanics that, in turn, influence local tumour
cells20,112. HGF, hepatocyte growth factor ; IGF, insulin-​like growth factor ; PDGF, platelet-​
derived growth factor; TGFβ, transforming growth factor-​β; VEGF, vascular endothelial
growth factor.
ASCs (or MSCs) from the stroma of adipose tissue
can induce EMT-​like changes in cancer cell lines143,144
including colon cancer145 and pancreatic cancer146. The
adipokine leptin has also been found to mediate
the in vitro induction of EMT markers by ASCs from
donors with obesity in breast cancer models 147,148.
Nonetheless, the link between an EMT–inflammation
axis and cancer progression in the context of obesity
remains unclear and inconsistent149. Furthermore, some
studies demonstrate that the majority of cells within
metastases are not derived from those that undergo
EMT but rather are derived from circulating epithelial
cells133,134, which might enter the circulation through
collective epithelial cell migration150,151 or tumour frag-
mentation152 and survive even without association with
other cells of the TME and in the absence of mesenchy-
mal markers. In this context, whether EMT is a common
source of metastasis or merely a marker of metastatic
potential requires future study, as does the influence of
obesity on the EMT–inflammation phenotype.
From a therapeutic viewpoint, treatment of obesity-​
induced pancreatic tumours in mice using an angioten-
sin 1 inhibitor, losartan, reduced mechanical stress on
the tumour cells and decreased tumour growth124. In a
study comparing ASCs from lean adults and those with
obesity, ASCs from the cohort with obesity expressed
higher levels of CAF markers, suggesting that obesity
resulted in more rapid conversion of ASCs to CAFs
within the TME99. Although conceptually appealing, the
role of ASCs and CAFs is dynamic and remains incom-
pletely understood, and it might be context-​dependent,
as shown by studies with HCC153,154, colon cancer155
and pancreatic cancer156 cell lines, in which MSCs were
found to both promote and inhibit cancer growth157.
Moreover, the specific link between VAT, the TME and
altered tumour biology is unclear. In addition, it should
be acknowledged that the majority of studies to date
on ASCs and cancer have been in non-​gastrointestinal
tumour sites103.
Processes linking obesity and the TME
Inflammation. Although inflammation in the TME can
be influenced by systemic factors derived from VAT and
fatty liver, as already discussed, tumour-​adjacent adi-
pose tissue might also act as an energy source, supply­
ing non-​esterified fatty acids and growth factors not
only for tumour cells but also for immune and stromal
cells within the TME158,159. The majority of studies on
peritumoural fat have been in breast cancer, but many
tumour types, including gastric cancer and colon cancer,
develop in close contact with adipose tissue, suggesting
that dysregulated peritumoural adipocytes affect the
TME through the release of local inflammatory medi­
ators158. For example, Trevellin et al. highlighted a poten-
tial role for peritumoural adipose tissue in promoting
lymph node metastasis in oesophageal adenocarcinoma,
with human adipocyte-​derived leptin influencing the
expression of the EMT regulatory genes α-​SMA and
E-cadherin and promoting metastasis in the oesophageal
adenocarcinoma cell line OE33 (ref.160).
The robust epidemiological data linking obesity and
carcinogenesis suggest that obesity is permissive to can-
cer development in pre-​malignant disease, which has
led to studies in experimental models and in patients
with gastrointestinal pre-​malignant conditions, such
as Barrett oesophagus, Helicobacter pylori-​associated
gastritis, NAFLD or NASH, and pancreatic intraepi-
thelial neoplasia. Rebours et al., for instance, evaluated
obesity and pancreatic intraepithelial neoplasia and
reported significant correlations of the lesions with
VAT (P = 0.02), pancreatic fatty infiltration (extralobular
(P = 0.01) and intralobular (P < 0.0001)) and intralobular
fibrosis (P = 0.003)161.
Additionally, hepatic steatosis is thought to sensi-
tize the liver parenchyma in humans for progression to
NASH and HCC as a result of multiple subsequent hits,
including dysregulated adipokine production, lipotoxic-
ity, insulin resistance, oxidative stress, generation of reac-
tive oxygen species (ROS), defective mitochondrial ATP
activity and hypoxia162,163. Oxidative stress in the liver
results in increased IL-8 expression and the chemoat-
traction of neutrophils, which can further exacerbate
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inflammation164,165. Hyperinsulinaemia and enhanced
bioavailability of IGF1 associated with obesity lead to
the downstream activation of insulin receptor substrate 1
(IRS1), which activates a range of signalling path-
ways including p53, mitogen-​activated protein kinase
(MAPK) and phosphoinositide 3-kinase–protein
kinase B (PI3K–AKT) that might induce proliferation
and anti-​apoptotic pathways relevant to both liver can-
cer and carcinogenesis at other sites166,167. Leptin is both
pro-​inflammatory and a mitogen, with anti-​apoptotic
and pro-​angiogenic properties within the TME through
Janus kinase (JAK)/STAT-​dependent mechanisms168. In
the liver, leptin is also reported to have a role in driving
key features of NASH, including fibrosis, local inflam-
mation and angiogenesis169,170, and it also results in HCC
cell cycle progression, inhibition of endoplasmic reticu-
lum stress-​associated apoptotic pathways and the induc-
tion of autophagy, resulting in decreased apoptosis171.
STAT3 activation driven by IL-6 and leptin enhances
HCC development through the promotion of tumour
cell proliferation and inhibition of apoptosis172. In mouse
models of HCC, including Mdr2 or Tsc1 knockouts, key
inflammatory mechanisms including NF-​κB activation,
endoplasmic reticulum stress and ROS accumulation
have been reported as drivers of carcinogenesis55,173,174.
Barrett oesophagus and oesophageal adenocarci-
noma are strongly associated with acid, bile reflux and
obesity, and pro-​inflammatory changes in immune cell
phenotypes are increased in VAT, liver and oesophageal
tissue from patients with these diseases70,82,89,90. In Barrett
oesophagus, the pathological precursor to oesophageal
adenocarcinoma, visceral obesity is an independent pre-
dictor of progression from the adaptive epithelium of
intestinal metaplasia to high-​grade dysplasia or adeno­
carcinoma (P < 0.0001)175. A murine model using a
human IL-1β transgene that mirrors human oesophagitis,
metaplasia, dysplasia and adenocarcinoma progression
was developed by Quante and colleagues176. This model
is dependent on IL-1β expression in the oesophagus and
on systemic IL-6. In this context, both IL-1β and IL-6 are
elevated in the adipose tissue and blood of individuals
with obesity, suggesting a possible link in the progression
of Barrett oesophagus to cancer177–179. In addition, IL-6
and leptin both drive STAT3 activation, the constitutive
activation of which plays a key role in carcinogenesis of
numerous cancers, including oesophageal adenocarci-
noma, by inducing tumour cell proliferation, survival and
invasion, promoting inflammation via NF-​κB activation
and suppressing antitumour immunity180,181.
The inflammation-​to-cancer model for gastric cancer
occurs via H. pylori infection and chronic gastritis182. In
a murine model of H. pylori-​driven gastric adenocarci-
noma using Helicobacter felis, obesity induced by a high-​
fat diet resulted in significantly increased inflammation,
metaplasia and dysplasia in infected mice through
increased recruitment of myeloid-​derived suppressor
cells (MDSCs) and TH17 cells in the stomach183. In addi-
tion, increased macrophages were observed in adipose
tissue of obese mice with Helicobacter infection but not
in Helicobacter-​infected lean mice183.
In colorectal cancer, a prominent role for IL-6 is
well documented, and higher levels of IL-6 are detected
Nature Reviews | Gastroenterology & Hepatology
in the serum of patients than in healthy individuals
(9.3 ± 2.1 pg/ml versus 4.4 ± 0.8 pg/ml). Moreover, IL-6
levels correlate with tumour grade and are associated
with a poorer overall survival184,185. IL-1β can induce the
production of other inflammatory, chemoattractant and
pro-​angiogenic factors such as IL-6, TNF, IL-8, cyclooxy­
genase 2 (COX2) and VEGF, which are all reported to
have a role in colorectal cancer pathogenesis186. These
factors are abundant within human obese VAT and are
released into the circulation where they can potentially
influence tissue homeostasis within the lower gastrointes-
tinal tract. In addition, conditioned media from the obese
adipose tissue of patients with oesophageal, gastric and
colorectal cancer significantly (P < 0.05) enhance the pro-
liferation of colorectal and oesophageal adenocarcinoma
cells in vitro compared with conditioned media from
lean adipose tissue of patients with or without cancer,
with VEGF and IL-6 among many factors implicated187.
Figure 2 summarizes the connection between obesity and
the induction of the inflammatory state within visceral fat
and its influence on different gastrointestinal cancer sites.
Hypoxia. Hypoxia in VAT and in the TME is a key con-
tributor to the local and systemic inflammation charac-
teristic of obesity and constitutes a potential link between
the adipose microenvironment and the TME179,188,189.
Adipose tissue depots become hypoxic in obesity as adi-
pocytes grow and exceed the diffusion capacity of oxygen,
and this effect can initiate and promote an inflammatory
process involving macrophage recruitment, enhanced
adipokine secretion, increased glucose utilization, insulin
resistance and lactate production190–193.
In the TME, hypoxia induces a metabolic switch
from oxidative metabolism to anaerobic glycolysis (dis-
cussed further in the next section)194. A key process is
the activation of hypoxia-​inducible factor 1α (HIF1α)
in response to hypoxia. HIF1α promotes angiogenesis,
neovascular­ization and sustained inflammation193,195–197.
HIF1α expression in tumours is also associated with a
poor prognosis and a reduced response to standard ther-
apies. For instance, in human HCC, co-​overexpression of
programmed cell death 1 ligand 1 (PD-​L1) and HIF1α
in tumour tissue was associated with an increased risk
of recurrence or metastasis and death, suggesting a
benefit from HIF1α inhibitors in conjunction with
PD-​L1 blockade198–200.
Hypoxia also increases expression of the obesity-​
related pro-​inflammatory cytokine IL-32 in VAT in
patients with colon cancer and obesity201. IL-32 expres-
sion has been correlated with metastatic potential and
the regulation of cancer-​stem-cell-​like properties, and it
is a potent inducer of prostaglandin E2 in colorectal can-
cer201,202. In the TME of hypoxic colorectal cancer tumours,
HIF1α increases the transcription of the cell-​surface glu-
cose transporter GLUT1, inducing key glycolytic enzymes
such as lactate dehydrogenase, and inhibits acetyl-​CoA
formation and oxidative phosphorylation197,203.
Hypoxia and angiogenesis are closely linked, and
HIF1α induces angiogenic growth factors including
leptin, VEGF, MMP2 and MMP9204. Specifically, in
gastric carcinomas, MMP2, MMP9 and VEGF largely
contribute to the angiogenic profile of the tumour and
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disease progression205. The process of angiogenesis plays
an instrumental role in adipose tissue homeostasis; for
instance, adipose tissue produces angiogenic factors
including VEGF206,207, and inhibition of adipocyte differ-
entiation reduces angiogenesis208–210. Studies performed in
diet-​induced obese mice or in ob/ob mice that cannot pro-
duce leptin showed that inhibition of VEGF substantially
reduces weight gain211,212, which highlights the impor-
tance of angiogenesis regulation in the adipose micro­
environment. In this regard, VEGFR1–PGF (placental
growth factor) signalling appears to be involved in the
link between obesity and angiogenesis, both in the TME
and adipose tissue microenvironment, suggesting cognate
influences213. Leptin, similarly to VEGF, is also induced by
hypoxia or HIF1α and promotes angiogenesis214,215. Leptin
activity is mediated through the leptin receptor (ObR),
and expression of both can be stimulated by hypoxia, with
increased leptin levels and ObR and HIF1α expression
observed in human colorectal cancer, highlighting that
overexpression of the leptin pathway is tightly connected
with the abundance of HIF1 (refs216,217). In oesophageal
adenocarcinoma, obesity has also been associated with
an upregulation of the ObR receptor within the tumour
tissue, as well as with advanced tumour stage218.
The development of hypoxia within both expanded
obese adipose tissue and the TME results in similar pro-​
inflammatory responses, which can fuel and sustain the
carcinogenic process. A lack of oxygen forces all cells,
including adipocytes, tumour cells and immune cells, to
adapt their metabolic process to survive. Consequently,
this interrelationship should be a key focus of research
on obesity-​related carcinogenesis.
Metabolism. Cellular metabolism, in particular the
balance between oxidative phosphorylation and glyco­
lysis, is also a common theme that links the adipose
microenvironment and the TME and is relevant to not
only tumour and pre-​malignant cells but also immune
cells. Glycolysis is stimulated by hypoxic conditions,
and common mutations in many cancers, such as in the
p53-encoding gene TP53, support glycolytic pathways
by promoting GLUT1 translocation to the plasma mem-
brane219. The Warburg effect is a metabolic phenotype in
cancer cells referring to a metabolic shift in ATP gener­
ation from oxidative phosphorylation to glycolysis, even
under aerobic conditions220. This effect is observed in
routine oncological clinical practice with 18fluorodeoxy­
glucose (FDG) PET in combination with CT, which is
utilized to optimally stage many cancer types221. Within
the TME, energy production from stromal cells can
reverse the Warburg effect, a process known as metabolic
symbiosis, in which lactate from a hypoxic glycolytic
tumour can be a metabolite for oxidative phosphoryl-
ation and ATP generation222. The survival-​promoting
effects of fat cells, through pathways that are currently
unknown but possibly via metabolic symbiosis, might
play a role in cancer progression223.
The gene TP53, which is commonly mutated in chro-
mosomally unstable tumours including gastrointestinal
cancers, represents an interesting link with metabolism
and hypoxia, responding to challenging conditions in
the tissue microenvironment224. It is proposed that p53
can promote oxidative phosphorylation and dampen
glycolysis in cells; disruption of this balance is asso-
ciated with mutations in p53 and oncogenic transfor-
mation224. In human Barrett oesophagus, for instance,
indirect measurements of hypoxia by HIF1α in the
tissue microenvironment correlate with p53 status and
energy metabolism, specifically oxidative phosphoryl-
ation, and are associated with visceral obesity225. These
studies suggest that HIF-1α is a useful biomarker to help
profile metabolic activity in tumours and has potentially
important therapeutic implications.
A further intriguing dimension in the TME is the
parallel metabolic changes, particularly aerobic glycoly-
sis, in both tumour cells and activated immune cells such
as M1 macrophages and pro-​inflammatory T cells226,227.
The metabolic switch in tumour and immune cells
in the TME rapidly provides ATP and intermediates
for the biosynthesis of nucleotides, lipids and proteins
as well as certain tricarboxylic acid intermediates that
can activate HIF1α228. Consequently, there is a parallel
metabolic shift not only in tumour cells but also in the
surrounding stromal compartment of the TME, which
includes immune cells, T cells and macrophage infiltrate.
In human Barrett oesophagus, increasing adiposity was
positively associated with glycolysis and negatively
associated with oxidative phosphorylation within the
metaplastic oesophageal tissue225. In addition, condi-
tioned media from VAT from patients with obesity and
oesophageal adenocarcinoma significantly (P < 0.05)
altered mitochondrial biology and energy metabolism
profiles in oesophageal cancer cell lines, and metabo-
lomic profiling revealed elevated lactate production as
a consequence of increased glyco­lysis229. Expression
of a glycolytic marker, pyruvate kinase M2 (PKM2),
which catalyses the final rate-​limiting step of glycoly-
sis and stimulates HIF1α, was also positively associated
with obesity229. This finding might be of therapeutic
relevance, as PKM2 also plays a role in regulating mac-
rophages, T cells and dendritic cells in the TME and is
required for the expression of the immune checkpoint
PD-​L1 in immune cells and in CT26 murine colon
tumours, highlighting its potential value as a marker
associated with tumour metabolism that is relevant to
obesity-​associated cancer230.
With the enormous interest in understanding the
immune microenvironment of tumours, both for prog-
nostication and targeting with immunotherapeutic
agents, the potential to target metabolism within the TME
is an attractive therapeutic concept for all cancers, with
perhaps greater potential gain in the context of obesity, in
which altered metabolic processes relevant to T2DM and
cardiovascular disease might already exist. For example,
the insulin-​sensitizing drug metformin, which targets
mechanistic target of rapamycin complex 1 (mTORC1)
signalling via AMP-​activated protein kinase (AMPK)-
dependent and AMPK-​independent pathways, might
reduce tumour cell growth and impair mitochondrial
function and energy metabolism, with the greatest effects
observed in the setting of obesity231. Further understand-
ing of the interactions between metabolites in the obese
TME and their oncogenic nature will provide insight
into the development of novel antimetabolic therapies
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Adipose tissue
Obese state T cell infiltration
Inflamed
adipose tissue M1 macrophage

Lean state

M2 macrophage
Blood vessel Peritumoral adipose tissue
• ↑ Leptin • ↑ Angiogenic factors
• ↓ Adiponectin • ↑ Metabolic mediators
• ↑ Inflammatory mediators • ↑ Resistin

Mitochondria

Altered tumour metabolism Tumour hypoxia Active tumour angiogenesis

• Shift to glycolytic metabolism: Warburg • ↑ HIF1α • ↑ VEGF • VEGF • ANG1
• ↑ PKM2 • ↑ Metabolic genes • ↑ Leptin • VEGFR1 • ANG2
• ↑ Mitochondrial mass • ↑ IL-32 • VEGFR2 • ↑ CD31: blood vessel numbers

Altered tumour metabolism, hypoxia and dysregulated tumour angiogenesis

Altered tumour microenvironment drives disease progression and alters treatment responses in tumours

Fig. 6 | links between obese adipose tissue and cellular process in the tumour microenvironment. The obese state
leads to inflamed adipose tissue that stimulates the secretion of many inflammatory , metabolic and angiogenic mediators
from adipocytes and immune cells, in addition to modulating leptin and adiponectin levels. These mediators can, in turn,
stimulate the upregulation and dysregulation of a number of key cellular processes in the tumour micro­environment,
including altered energy metabolism, hypoxia and dysregulated angiogenesis, which all promote a tumour microenvironment
favourable for driving disease progression and influencing treatment response. ANG, angiopoietin; HIF1α, hypoxia-​
inducible factor 1α; PKM2, pyruvate kinase M2; VEGF, vascular endothelial growth factor ; VEGFR , vascular endothelial
growth factor receptor.

that target the obese TME. Figure 6 illustrates how the
obesity state can influence the different cellular processes
in the TME, specifically hypoxia, energy metabolism and
angiogenesis, three processes that are interlinked.
Targeting obesity to prevent cancer
If the obesity and cancer paradigm is founded on con-
vincing epidemiological data, and the science discussed
herein is increasingly consistent in linking the adipose
and tumour microenvironments, an obvious question is
whether a reverse paradigm exists: does treatment of obe-
sity or key associated metabolic and endocrine pathways
reduce cancer risk? Clinical prospective studies or rand-
omized clinical trials to address this question, requiring
many thousands of patients and years of follow-​up, might
not be feasible, and most indirect evidence is provided
from long-​term follow-​up of patients who have had sur-
gery for morbid obesity, so-​called bariatric surgery, or
metabolic surgery when performed for obesity compli-
cated by T2DM. Diet and lifestyle changes usually result
in the loss of 4% of body weight; however, bariatric sur-
gery generally leads to between 15% and 30% weight loss,
maintained usually for at least 3 years and associated with
a high rate of resolution of dysmetabolism, particularly
T2DM232–237. Intriguingly, for cancer, although no rand-
omized data exist, there is considerable indirect evidence
from observational studies that weight loss in the popu-
lation with obesity reduces cancer risk. In a prospective
observational study from Sweden, the Swedish Obese
Subjects (SOS) study, which included 2,010 patients with
obesity who underwent bariatric surgery, and a well-​
defined matched comparison group of 2,037 individuals
with obesity who received standard care with no specific
intervention, there were fewer overall cancer diagnoses
in the group who underwent surgery (HR 0.67, 95%
CI 0.53–0.85, P = 0.0009). The effect was primarily
observed in women, but the study was too small to inves-
tigate site-​specific changes or to assess the effects on men,
who comprised 29% of the cohort238. In another study
from Utah, in the United States, wherein men represented

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14% of the study population, individuals with obesity
who received bariatric surgery were compared with con-
trols with obesity who were recruited from the state driver
licence database239. A risk reduction was observed for all
cancers (HR 0.76, 95% CI 0.65–0.89, P = 0.0006), as well
as obesity-​related cancers (HR 0.62, 95% CI 0.49–0.78,
P <0.0001) and cancers in women only (HR 0.73, 95%
CI 0.62–0.87, P = 0.0004). In another large retro­spective
case–control study using an integrated health insurance
database, matched patients undergoing bariatric sur-
gery (n = 22,198) and matched controls not undergo-
ing surgery (n = 66,427) were followed for a median of
3.5 years240. The incidence of obesity-​related cancers1
(Table 1) was reduced in the bariatric surgery cohort (HR
0.59, 95% CI, 0.51–0.69, P < 0.001), and the reduction in
incidence was greater than for cancers of other sites not
associated with obesity. Similar to other studies, differ-
ences were noted only in female patients, who repre-
sented 80% of the overall cohort, reflecting the increased
prevalence of bariatric surgery in females. For gastro-
intestinal cancer, surgery was associated with reduced
colon cancer (HR 0.59, 95% CI 0.36–0.97, P = 0.04) and
pancreatic cancer (HR 0.46, 95% CI 0.22–0.97, P = 0.04),
whereas there were no cases of oesophageal adenocarci-
noma in the surgical group compared with 16 cases in the
non-​operative control group (P = 0.02)240.
Although some methodological limitations might
apply, including unmeasured differences with control
groups and perhaps a greater health focus on cancer
diagnosis and prevention, including diet, exercise and
screening, the consistency across studies, with the haz-
ard risks remaining proportional over time, suggests
causality and supports the hypothesis of a reduction in
cancer incidence with a reduction in body mass. It is
unclear how long the lead time for a potential decrease
in obesity-​related cancers would be, and this effect might
also reflect a bias in these retrospective studies. It is also
unknown whether the reduction of smaller amounts of
weight than is usual for bariatric surgery affects can-
cer incidence or whether the duration of excess weight
before weight loss affects cancer risk. Large prospec-
tive studies with high-​quality longitudinal data will be
required to answer these questions.
Box 1 | Unanswered questions in obesity and cancer research
• What is the explanation for the profound gender differences in some obesity-​
associated cancers, in particular oesophageal adenocarcinoma, which predominates
in males?
• What is the effect of obesity and its aligned tumour microenvironment in response to
cancer therapies, including chemotherapy, radiation therapy, targeted therapy and
immune-​based therapies?
• Does immunotherapy in the context of obesity have a differential response compared
with in a non-​obese context?
• Does immunotherapy in the context of obesity exacerbate pro-​inflammatory
processes at key sites such as the visceral adipose tissue and liver?
• Do approaches affecting metabolic pathways in cancer and immune cells, through public health policies to reduce the prevalence
such as metformin, have differential effects in patients with obesity compared with
non-obese patients?
• Does bariatric or metabolic surgery decrease the risk of cancer in patients with
obesity and high-​risk pre-​malignant conditions, such as fatty liver disease or liver
fibrosis and dysplastic Barrett oesophagus?
Most scientific research exploring the association
of cancer and obesity originates from mouse models
or indirectly in humans where inflammatory mark-
ers are studied. One systematic review in 2017 of the
effect of lifestyle interventions on adipose tissue gene
expression profiles demonstrated that interventions,
such as reduced dietary intake and/or increased phys-
ical activity that lead to weight loss, resulted in altered
gene expression of adipokines and inflammatory
markers241, suggesting that weight loss reduces the
activity of key inflammation and tumour-​associated
transcription factors. In humans, weight loss is asso-
ciated with decreased levels of C-​reactive protein, IL-6
and TNF and reduced activity of tumour-​promoting
transcription factors, including NF-​κB, STAT3 and AP1
(refs55,242–244). Dietary modification might also have an
effect; for example, in obese diabetic mice, adipose
tissue inflammation induced by a high-​fat diet can be
prevented by a diet containing n-3 polyunsaturated
fatty acids, possibly via reducing the production of
pro-​inflammatory arachidonic acid metabolites, with
downstream effects on NF-​κB activation and related
pathways245. These and other studies suggest that weight
loss is an effective strategy to reverse energy imbalance
and white adipose tissue inflammation, with second-
ary consequences in the precancer microenvironment
or the TME that might reduce cancer risk or improve
cancer outcomes.
Conclusions
The epidemiological association between obesity and
many cancers is now firmly established, and there is
increasing acceptance that bariatric or metabolic sur-
gery in individuals with morbid obesity might affect
cancer risk. Notwithstanding this clear and compelling
link, as well as an understanding of how obesity, par-
ticularly visceral obesity, might affect all the hallmarks
of cancer, research is still in its infancy, and to date, no
obesity-​specific marker of risk or specific target has been
identified. Major unanswered questions are summarized
in Box 1. It is clear, however, that the factors distinguish-
ing adipocytes and the adipose microenvironment in
individuals with obesity, particularly patients who are
metabolically unhealthy, compared with non-​obese
individuals are linked with pro-​inflammatory and pro-​
tumorigenic events that have a potential effect in the
microenvironment of preneoplastic and neoplastic dis-
ease, affecting all established and emerging hallmarks
of cancer. Parallel processes in obesity and the TME,
including hypoxia, altered immune function and adi-
pokine and cytokine production, ASCs, CAFs, hypoxia,
metabolism and angiogenesis, represent key areas for
future research to unravel the biological mechanisms
specific to obesity-​associated pathways in carcinogenesis
and to identify potential targets for prevention and ther-
apy. At this time, however, primary cancer prevention
of obesity and secondary prevention through appropri-
ate management of severe obesity, particularly if associ-
ated with systemic inflammation and dysmetabolism,
are compelling approaches towards a reduction in the
incidence and mortality from many cancers that have
www.nature.com/nrgastro
 G A S T R O I N T E S T I N A L C A N C E R A N D OR BE v
E ISEIw
TYS

increased commensurate with the obesity epidemic.
For the research community, accurately characterizing
the obese state based on the site of adipocyte depots
(such as visceral compared with subcutaneous) as well
as the associated metabolic health and biomarkers
of an adipose tissue inflammatory profile, including,
for instance, CRP, IL-6 and insulin resistance, might
help to identify patients at increased risk of cancer
development and progression. Moreover, in studies of
targeted and immune therapies for obesity-​associated
cancers, subgroup analysis of the TME in patients with
obesity compared with non-​obese individuals should be
an important component of translational research and
clinical trials.
Published online xx xx xxxx

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Author contributions
J.O., J.L., C.L.D. and J.V.R. researched data for the article. All
authors contributed equally to the discussion of content, writ-
ing of the article and the reviewing and/or editing of the
manuscript before submission.
Competing interests
The authors declare no competing interests.
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