Cell Metabolism

Review

Obesity and Cancer: The Oil that Feeds the Flame

Joan Font-Burgada,1 Beicheng Sun,2,* and Michael Karin1,*
1Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD

School of Medicine, La Jolla, CA 92093-0723, USA

2Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, P.R.

China
*Correspondence: sunbc@njmu.edu.cn (B.S.), karinoffice@ucsd.edu (M.K.)
http://dx.doi.org/10.1016/j.cmet.2015.12.015

Although discussion of the obesity epidemic had become a cocktail party cliché, its impact on public health
cannot be dismissed. In the past decade, cancer had joined the list of chronic debilitating diseases whose
risk is substantially increased by hypernutrition. Here we discuss recent advances in understanding how
obesity increases cancer risk and propose a unifying hypothesis according to which the major tumor-pro-
moting mechanism triggered by hypernutrition is the indolent inflammation that takes place at particular
organ sites, including liver, pancreas, and gastrointestinal tract. The mechanisms by which excessive fat
deposition feeds this tumor-promoting inflammatory flame are diverse and tissue specific.

Obesity and Cancer
Cancer is a complex disease with genetic, environmental,
clinical, and lifestyle factors, all of which contribute to tumor
initiation and malignant progression. Tobacco smoke and sun
exposure are two of the most extensively studied lifestyle-
related factors that greatly and directly increase cancer risk,
but the carcinogenic impact of obesity is nearly as profound
and has become more prevalent, as obesity rates in major parts
of the world are beginning to eclipse smoking rates. Epidemio-
logic evidence linking obesity and hypernutrition to elevated can-
cer incidence and greater risk of cancer-related death has accu-
mulated in the past two decades, leading to the realization that
14% and 20% of all cancer deaths in men and women, respec-
tively, are due to overweight and obesity (Calle et al., 2003).
Despite the huge impact, the molecular mechanisms explaining
this association remain poorly understood and their investigation
was only recently initiated.
In nature, food availability is not uniform and a constant caloric
input is rare, other than under laboratory conditions or in highly
affluent societies. All eukaryotes, including plants, store energy
in the form of lipids and complex carbohydrates. Energy storage
is key to physiological homeostasis and essential for maintaining
health and reproductive potential, thereby contributing to the
major driving force of evolution—survival of the species. How-
ever, in recent decades, humans have constantly increased
their caloric intake with a concomitant drop in energy expendi-
ture due to a more sedentary lifestyle. The result of this net
gain in caloric input and access to a constant supply of en-
ergy-rich foods is a metabolic imbalance accompanied by hy-
pertrophy and hyperplasia of adipose tissue and consequent
obesity, associated with fat deposition outside of conventional
lipid storage depots. The pathophysiological impact of obesity
far exceeds its cosmetic effect on body shape.
People are defined as obese when their body mass index
(BMI) exceeds 30 kg/m2 and overweight when it is between 25
and 30 kg/m2 (Rocchini, 2002). BMI, however, is not an accurate
measure of central obesity across all populations, as Asian
Americans and East Asians, for instance, experience central
obesity at a lower BMI than Caucasians (WHO Expert Consulta-
tion, 2004). In 2011–2012, it was estimated that over one-third of
U.S. adults were obese, but certain ethnic groups are at much
higher risk of obesity-related morbidities than the average.
Recently, obesity trends have markedly increased in developing
nations, particularly in children, although traditionally it was
considered as a problem unique to adults in affluent societies
(Ogden et al., 2014). Notably, the incidence of obesity in rapidly
developing countries (Middle East, Oceania, Australasia, and
China) has risen 3-fold or more since 1980 (Ellulu et al., 2014),
and currently the rate of obesity in Mexico is higher than in
most of the US.
In addition to classical metabolic diseases, in particular type 2
diabetes (T2DM) and cardiovascular disease (Ng et al., 2014),
obesity increases cancer risk. A significant association between
obesity and cancer at various sites was detected more than a
decade ago and it was estimated that the overall risk of death
from cancer is 1.5- to 1.6-fold higher in men and women, respec-
tively, with a BMI that exceeds 40 kg/m2 higher (Calle et al.,
2003). At certain sites, such as pancreas and liver in obese
men, the risk of developing deadly cancer is elevated by up to
2.6- and 4.5-fold, respectively, whereas obese women exhibit
a 4.8- and 5.3-fold increase in risk of death due to kidney and in-
testinal cancer, respectively (Calle and Kaaks, 2004; Haslam and
James, 2005). Obesity triggers several systemic and metabolic
alterations that can influence carcinogenesis and tumorigenesis
that will be summarized and discussed in this Review (Figure 1).
Clearly, obesity does not influence cancer risk to the same
extent in different organs, and the tumor-promoting mechanisms
evoked by obesity are not only tissue specific but are also gender
specific. We will mainly focus our discussion on gastrointestinal,
pancreatic, and liver cancers.
Systemic Consequences of Obesity that Promote
Tumorigenesis
Systemic Inflammation
In addition to being hyperplastic and hypertrophic, the obese ad-
ipose tissue exhibits major changes in production of hormones,
adipokines, and cytokines, as well as altered immune infiltration
(Hotamisligil et al., 1993; Weisberg et al., 2003; Xu et al., 2003)

48 Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc.

Cell Metabolism

Review

Figure 1. Systemic Mechanisms of Obesity-Driven Tumor Promotion

Obesity and hypernutrition affect different tissues simultaneously resulting in a systemic increase in NEFA, insulin, glucose, leptin and inflammatory cytokines,
and reduced levels of adiponectin. These imbalances can directly promote cancer cell survival, proliferation, and malignant progression. In the colon, obesity can
promote a shift in the composition of the microbiota that is linked to higher epithelial permeability to microbial components such as LPS, which in turn enhances
local inflammation. In adipose tissue, obesity is linked to adipocyte hyperplasia and hypertrophy followed by infiltration of inflammatory macrophages. The
inflammatory milieu thus generated reprograms the tissue to release NEFA, produce more leptin, and less adiponectin. The liver, exposed to microbial products
from the colon via the portal circulation, also mounts a low-grade inflammatory response. Higher amounts of NEFA from adipose tissue lead to an increased lipid
storage and elevated lipogenesis. The consequence of local inflammation and lipid accumulation is liver insulin resistance and hepatocyte stress and death.
Finally, the pancreas reacts to hepatic insulin resistance and higher glycemia with increased insulin production, which can lead to b-cell stress.

(Figure 1). Although numerous immune cell types are present in
fat depots, macrophages are especially common and their prop-
erties are altered by obesity (Weisberg et al., 2003). Adipose tis-
sue macrophages (ATM) in healthy fat depots are skewed toward
the M2 anti-inflammatory phenotype, but during obesity, pro-in-
flammatory M1 macrophages become more abundant (McNelis
and Olefsky, 2014). Pro-inflammatory ATM produce tumor-pro-
moting cytokines, including TNF, IL-6, and IL-1b, as well as
monocyte chemo-attractants such as MCP-1, CCL-2, and MIF.
Elevated serum IL-6 and TNF are typically found in obese pa-
tients (Weisberg et al., 2003), and the signaling circuitry respon-
sible for their production is orchestrated by the IKK–NF-kB and
JNK–AP-1 pathways (Solinas et al., 2007). The initial activation
of these pathways seems to depend on damage-associated mo-
lecular patterns (DAMPs) secreted by stressed and dying adipo-
cytes and on changes in membrane fluidity caused by uptake
and incorporation of saturated fatty acids (Holzer et al., 2011).
In addition, ATM undergo changes in lysosome-dependent lipid
metabolism that favor lipid accumulation (Xu et al., 2013).
TNF signaling in cancer cells enhances survival and prolifera-
tion through NF-kB and JNK activation (Karin and Lin, 2002). TNF
may also enhance DNA damage, thus increasing mutational load
(Yan et al., 2006). TNF also induces epithelial to mesenchymal
transition (EMT), which provides another route for stimulating
malignancy and metastatic behavior (Kim et al., 2009). IL-6 acti-
vates STAT3, which controls expression of genes that promote
cell proliferation, survival, angiogenesis, invasiveness, metas-
tasis, and stemness (Taniguchi and Karin, 2014). IL-1b exerts
effects similar to those of TNF and all three cytokines, whose
expression is elevated during obesity, have well-established
tumor-promoting activities (Grivennikov et al., 2010). Other
tumor-promoting cytokines whose expression was noted to be
elevated during obesity include IL-8, IL-10, IL-12, IL-17, IL-18,
IL-22, and interferon (IFN)-g. Importantly, protective anti-inflam-
matory Treg cells that are specifically located in abdominal fat
depots are lost in obesity, further exacerbating the pro-inflam-
matory state associated with elevated BMI (Feuerer et al., 2009).
Adipokines
Adipokines are hormones and cytokines that are produced by
adipocytes and exert diverse and important effects on meta-
bolism, angiogenesis, and cell proliferation. Adiponectin, en-
coded by the Ad/Poq gene, is secreted by adipocytes and binds

Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc. 49


to two receptors (AdipoR1 and 2) that differ in their tissue distri-
bution but are frequently expressed by cancer cells. Most exper-
imental data point to adiponectin as an inhibitor of tumorigenesis
due to its ability to activate AMPK and inhibit mTORC1 and other
protumorigenic signaling molecules (Dalamaga et al., 2012).
Congruently, adiponectin expression is inversely associated
with obesity (Antuna-Puente et al., 2008) (Figure 1). Adiponectin
enhances insulin sensitivity by activating AMPK and reducing
inflammation (Yamauchi et al., 2002). Importantly, weight loss in-
creases the amounts of circulating adiponectin in obese individ-
uals (Reinehr et al., 2004). Leptin is an adipokine that was mainly
studied for its appetite-regulating functions exerted in the hypo-
thalamus. Obese individuals produce higher amounts of leptin
due to their larger adipose tissue volume (Considine et al.,
1996) (Figure 1), but this can result in central (hypothalamic) lep-
tin resistance (El-Haschimi et al., 2000). The main pro-tumori-
genic effect of leptin is attributed to its growth factor-like activity
on endothelial cells, resulting in enhanced angiogenesis (Uddin
et al., 2011). Like IL-6, leptin activates STAT3, which provides
another explanation for its pro-tumorigenic activity. Other mole-
cules considered adipokines with possible contribution to can-
cer are chemelin, apellin, PAI-1, FGF-21, omentin, and lipocalin
(Fasshauer and Blüher, 2015).
Insulin Resistance and Hyperglycemia
Obesity is associated with the metabolic syndrome, which in-
cludes insulin resistance (IR), T2DM, atherosclerosis, and high
blood pressure. Conversely, weight loss markedly improves in-
sulin sensitivity and reduces insulin production (Uusitupa et al.,
2003). IR is a physiological condition defined by target cells
that are resistant to insulin action when encountering insulin
within the normal concentration range. IR muscle cells are
compromised in glucose uptake and metabolism, resulting in
hyperglycemia, which exposes other cells, including malignant
cells, to higher than normal glucose concentrations. Obesity trig-
gers IR by diverse mechanisms, but it primarily acts through
elevated non-esterified fatty acids (NEFAs), also called free fatty
acids (FFAs), which arise from adipocytes. Of note, individuals
subjected to an acute increase in NEFA develop IR within hours
(Roden et al., 1996). High saturated NEFA concentrations result
in inhibitory phosphorylation of IRS-1 and -2 and suppression
of insulin signaling (Aguirre et al., 2002; Solinas et al., 2006).
Not all fat depots have the same influence on IR; intra-abdominal
fat has a higher lipolytic activity compared to peripheral fat and
its close proximity to the liver can explain the stronger increase
in liver IR in obese individuals (Nielsen et al., 2004). The systemic
increase in inflammatory cytokines also contributes to IR. TNF
and IL-6 increase adipocyte lipolytic activity (Yang et al., 2008;
Zhang et al., 2002) and thus increase NEFA concentrations
concomitantly with reduced insulin receptor signaling (Figure 1).
By activating JNK, TNF promotes inhibitory phosphorylation of
IRS-1 (Hirosumi et al., 2002) and IRS-2 (Solinas et al., 2006).
Conversely, TNF-deficient mice are protected from obesity-
related IR (Uysal et al., 1997). Administration of exogenous
TNF causes IR and its neutralization reverses IR (Cheung et al.,
1998; Ishikawa et al., 2006; Stanley et al., 2011). IL-6, mainly
secreted by Kupffer cells (resident liver macrophages) and he-
patic stellate cells (HSCs), also induces IR and its effect is
reversed by treatment with IL-6 neutralizing antibodies (Klover
et al., 2005). Furthermore, reduced dietary intake and increased
50 Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc.
Cell Metabolism
Review
physical activity give rise to favorable IL-6 plasma concentra-
tions in obese children and adolescents (Gallistl et al., 2001).
Both IL-6 and TNF elevate the hepatic and circulating concentra-
tions of C-reactive protein (CRP), which is a nonspecific inflam-
matory response marker that is frequently increased in obesity.
Two important tumor-promoting effects are derived from
obesity-induced IR: hyperinsulinemia and hyperglycemia. High
concentrations of insulin, glucose, and NEFA are strong pro-
moters of cell survival, growth, and proliferation and exert similar
effects on tumor progenitors. High glucose concentrations favor
glycolytic cancer cell metabolism characterized by enhanced
glucose consumption (Warburg, 1956). Hyperglycemia also re-
sults in activation of Hif1a, which increases survival of cancer
cells under hypoxic conditions and further enhances expression
of glycolytic enzymes (Catrina et al., 2004). Hyperinsulinemia ex-
erts additional tumor-promoting effects due to the intrinsic
growth stimulatory and antiapoptotic effects of insulin. Interest-
ingly, dietary sugar intake was found to enhance liver tumorigen-
esis in mice independently of excess adiposity (Healy et al.,
2015).
Dysbiosis
Consumption of foods with high fat and low fiber content can
elicit particular changes in the microflora inhabiting the human
digestive tract that lead to decreased microbiome diversity and
dysbiosis (Figure 1). Such alterations were linked to a number
of diseases, including cancer (Schwabe and Jobin, 2013). During
obesity, the composition of the gut microbiota and the properties
of the intestinal epithelium are altered, resulting in decreased
barrier function (Teixeira et al., 2012; Turnbaugh et al., 2006).
Obesity can also cause overrepresentation of bacterial species
that produce pro-carcinogenic metabolites (Louis et al., 2014),
although the clinical significance of such metabolites remains
to be established. Dysbiosis alters metabolic usage and can
aggravate the metabolic imbalance already present in obese in-
dividuals (Tilg and Kaser, 2011). Dysbiosis also alters the gut
epithelial barrier, making it more permeable to microbial prod-
ucts that trespass the mucosa and activate immune cells in the
lamina propria, as well as reach the liver via the portal circulation,
all of which enhance systemic inflammation and contribute to
production of pro-inflammatory cytokines, such as TNF and IL-
6, and to IR (Shi et al., 2006). Recently, it was shown that
commonly used emulsifiers present in processed foods also
alter the intestinal microbiota and elicit a metabolic syndrome
phenotype (Chassaing et al., 2015), demonstrating that dysbio-
sis can have different origins. Uncontrolled antibiotic use can
also lead to dysbiosis and obesity (Cho and Blaser, 2012) and
that may increase cancer risk later in life. Increased barrier
permeability was shown to be a major contributor to colorectal
tumorigenesis (Grivennikov et al., 2012) and can also affect the
liver and pancreas (Tremaroli and Bäckhed, 2012; Yoshimoto
et al., 2013).
Immune Dysregulation
Obesity has been linked to an impaired immune response that
acts as a risk factor for different infections and failure to mount
protective immunity upon vaccination (Sheridan et al., 2012).
Obese individuals have fewer cytotoxic CD8+ T cells and a
reduced number of NK cells with lower cytotoxic activity (Lamas
et al., 2002). Animal studies have corroborated these findings.
Genetically obese mice show thymic atrophy, and fewer T cells
Cell Metabolism
Review
with reduced activation and cytotoxic capacity (Tanaka et al.,
2000). Dendritic and NK cells are also reduced (Macia et al.,
2006). Mice on high-fat diet (HFD) recapitulate these character-
istics with a concomitant increase in macrophages/monocytes
and similar impairment of immune responses to infection and
immunization (Bandaru and Rajkumar, 2013). Possible mecha-
nisms driving these immune alterations could be the above-
mentioned systemic effects. Indeed, higher circulating amounts
of pro-inflammatory cytokines can profoundly alter adaptive
immune responses, although the exact mechanisms remain to
be elucidated. Leptin may also be an important mediator of im-
mune dysregulation since immune cells express its receptor
(Conde et al., 2014). However, Leptin exerts diverse and pleio-
tropic effects depending on the cell type and therefore it is
difficult to discern its exact role. Insulin signaling and glucose
availability also affect immune cell function, as immune cell
activation and the type of the elicited response are strongly influ-
enced by their metabolic profile (Ganeshan and Chawla, 2014).
High insulin or glucose concentrations can alter this profile and
result in a defective immune response. The direct consequence
of impaired adaptive immunity in obese subjects with neoplasia
is enhanced tumor growth due to the absence of effective immu-
nosurveillance that may retard the growth of small early tumors.
Genetic Factors
Numerous genetic factors that affect obesity and therefore may
potentiate obesity-related cancer risk were identified through
genome-wide association studies (GWAS) and more classical
candidate gene approaches (Grarup et al., 2014). Overall,
GWAS had successfully identified more than 100 different loci
associated with increased adiposity, using BMI as a quantitative
measure. One of the most interesting findings was identification
of an FTO locus variant as a T2DM risk factor (Frayling et al.,
2007), a finding replicated by meta-analysis and refined to
include the MC4R locus (Loos et al., 2008). Six additional loci:
TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, and NEGR1
were subsequently identified (Willer et al., 2009) and shown to
also be of relevance for obesity in East Asians together with a
few other loci (Pei et al., 2014; Wen et al., 2012). T2D and obesity
were hypothesized to have an inflammatory basis, and the TNF/
LTA locus has been a long-standing T2D candidate gene (Dan-
dona et al., 2004). However, a recent GWAS found no consistent
association between TNF/LTA locus variation and T2D (Boraska
et al., 2010). Among all obesity risk loci, FTO has the strongest
effect, imposing an allelic 0.39 kg/m2 increase in BMI (Frayling
et al., 2007). T2DM risk is also genetically influenced given the
observation that it goes up by 2- to 3-fold by having a sibling
with T2DM. Currently, about 140 genetic loci have been firmly
established as T2DM risk loci, with the TCF7L2 locus being the
strongest one. Curiously, however, despite the close pathophys-
iological relationship between obesity and T2DM, only a small
number of risk loci are shared between the two conditions. The
common loci are FTO, CDKAL1, GIPR, KCNQ1, LYPLAL1,
TMEM18, ZNF608, MC4R, GRB14, RREB1, and LINGO2, but
so far there is little or no information whether they also increase
cancer risk. Obviously, such studies are needed especially in the
case of liver and uterine cancers, where obesity constitutes a
major risk factor. Recently, IRS1, HMGCS1, ATP8B1, PRMT6,
and CLU were found to be mutated in HCC (Meerzaman et al.,
2014). Since these loci are involved in obesity, T2DM and IR,
these findings suggest a connection between them to increased
HCC risk.
The physiologic hallmarks of T2DM are IR in hepatic and pe-
ripheral tissues and pancreatic b-cell dysfunction (Watanabe,
2010). Interestingly, very few T2DM susceptibility loci were
also mapped as IR loci. So where are the IR loci? Multiple inde-
pendent studies show that the main IR susceptibility loci are
APOC3, PPARG, IRS1, GCKR, and IGF1 (Petersen et al.,
2010b; Watanabe, 2010). In 2011, a GWAS involving 1,040
African Americans was conducted to detect genetic variation
associated with IR from the HyperGEN study. The results high-
lighted several SNPs associated with fasting insulin and homeo-
stasis model assessment of IR (HOMA-IR) near the ATP10A
(rs6576507 and rs8026527) and CACNA1D (rs1401492) loci (Irvin
et al., 2011). In addition, the PPARg P12A GG genotype and
NR5A2 variants were found to be inversely associated with risk
of pancreatic cancer (Tang et al., 2011).
Liver Cancer
Primary liver cancer is the fifth (men) and ninth (women) most
common cancer worldwide but is the second leading cause of
cancer deaths, due to a 5 year survival rate below 10% (Ferlay
et al., 2015). Hepatocellular Carcinoma (HCC) accounts for
85%–90% of primary liver cancers (El-Serag and Rudolph,
2007). At the time being, global HCC burden is mainly driven
by HBV and HCV infections, which account for 80% of cases
(Bosch et al., 2005), but in the near future obesity is likely to
become the leading factor, at least in the U.S. In Southeast
Asia, HCC incidence rates have been declining thanks to HBV
vaccination programs, but in the U.S., HCC incidence has
tripled from 1977–1979 to 2005–2007 and 30%–35% of HCC pa-
tients in the U.S. are virus negative (Davila and El-Serag, 2012).
Non-alcoholic fatty liver disease (NAFLD) and its more aggres-
sive manifestation, non-alcoholic steatohepatitis (NASH), are
emerging as the primary driving force behind this growth. It is
estimated that at least 25% of the U.S. population has NAFLD
(Lazo et al., 2013), with up to 8% of them exhibiting some degree
of NASH (Clark et al., 2003), with around 25% of NASH patients
progressing to cirrhosis, a serious pre-malignant condition
(McCullough, 2004). Alarmingly, current estimates project
1.5%–2% of the U.S. population as having liver cirrhosis due
to NASH, and in a few years this is expected to be the leading
indication for liver transplantation (Holmberg et al., 2013).
Considering that the annual cumulative incidence of HCC in
NASH-cirrhosis is just a bit lower than that of HCV-cirrhosis
(2.6% and 4%, respectively) (Ascha et al., 2010) an upsurge of
new HCC cases is expected in the U.S. in the coming decades.
NAFLD is strongly allied to components of the metabolic syn-
drome and most patients diagnosed with NAFLD have accom-
panying IR (Fabbrini et al., 2010). Due to excessive dietary intake
as well as genetic risk factors or other diseases, accumulation
of lipids in hepatocytes accompanied by de novo lipogenesis
and decreased mitochondrial b oxidation could lead to liver
dysfunction. Mechanistically, high levels of nutrients activate
mTOR, which in turn leads to the processing and release
from the ER of SREBP1, the master regulator of lipogenesis,
through the dissociation of CRTC2 from the COPII subunit
(Han et al., 2015) (Figure 2). Importantly, triglycerides (TG)
Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc. 51
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Figure 2. Mechanisms of Obesity-Induced HCC

Two main pathways converge to drive ER stress in the obese liver. On one hand, microbial products from the intestine reach the liver via the portal vein. Liver-
resident macrophages activate an inflammatory response that includes iNOS expression, which results in S-nitrosylation of IRE1a, thereby compromising the
UPR and consequently leading to ER stress. On the other hand, high amounts of nutrients activate mTORC1 signaling leading to phosphorylation of CRTC2,
freeing SEC31 and allowing the activation of the SEC31/32 complex that processes SREBP1. Processed SREBP1 translocates into the nucleus and activates the
lipogenic program, thereby aggravating the lipid accumulation and inducing severe hepatic steatosis with consequent lipotoxicity, ROS generation, and ER
stress. At the same time, newly synthesized lipids change the composition of the ER membrane and inhibit the sarco/endoplasmic reticulum calcium ATPase
(SERCA) activity producing a decrease of Ca2+ aggravating ER stress. Both pathways synergistically cooperate to drive hepatocyte cell death, while ROS buildup
in liver cells promotes mutagenesis and genomic instability. Importantly, cell death increases tissue inflammation and supports a positive feedback loop that
extends liver damage and compensatory proliferation. When this becomes chronic, it leads to HCC development.

accumulate in hepatocytes and cause hepatic steatosis once
the storage capacity of conventional fat depots has maxed
out. It has been shown that free cholesterol is a potentially impor-
tant player, sensitizing hepatocytes to TNF-induced inflamma-
tion after its accumulation in mitochondria (Marı́ et al., 2006).
Up to a point, NAFLD is a reversible condition, but without proper
treatment it may progress to NASH, which is characterized by
chronic liver inflammation and ongoing tissue damage. Liver
damage results in compensatory proliferation, a major driver of
HCC development (Maeda et al., 2005).
Since HCC almost always evolves in the context of chronic
liver damage, efforts have been concentrated on understanding
what drives chronic liver damage and cirrhosis in NAFLD pa-
tients that progress to NASH and eventually HCC. The ‘‘two-hit
hypothesis’’ suggests that, apart from lipid accumulation due
to hypernutrition and IR, an ill-defined second hit that promotes
oxidative stress, endoplasmic reticulum (ER) stress, inflamma-
tion, and hepatocyte cell death is necessary for progression
from steatosis to NASH (Day and James, 1998). Oxidative and
ER stresses were proposed as the main culprits in driving the
death of steatotic hepatocytes, which is further amplified
through a vicious cycle of chronic liver damage and inflamma-
tion. Liver damage stimulates compensatory proliferation and
the main mitogens involved in this response are IL-6 and TNF,
both of which play important roles in HCC development (He
et al., 2010, 2013; Nakagawa et al., 2014; Naugler et al., 2007).
Lineage-tracing experiments in NASH-induced HCC mouse
models suggest that normal centrilobular hepatocytes are the
cells that give rise to NASH-promoted HCC, rather than so-
called oval cells and newly identified hybrid hepatocytes, which
are the cells that undergo the most extensive damage-induced
proliferation (Font-Burgada et al., 2015). Differentiated hepato-
cytes are the cells that are most likely to accumulate lipids and
suffer the consequences of lipid-influenced oxidative stress
(Figure 2). Importantly, most of the above-mentioned tumor-pro-
moting effects of obesity play a role in HCC development in the
NASH-affected liver (Nakagawa et al., 2014). However, obesity-
induced IR is as pronounced in wild-type mice that develop sim-
ple steatosis as it is in MUP-uPA mice that develop full-blown
NASH, and therefore IR is not a major rate-determining factor

52 Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc.

Cell Metabolism
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in NASH development and its progression to HCC (Nakagawa
et al., 2014). Nevertheless, central obesity and steatohepatitis
also greatly enhance carcinogen-induced HCC, and IL-6 and
TNF play important roles in this process (Park et al., 2010).
Notably, in mice injected with the hepatic carcinogen DEN, die-
tary sugar intake was found to contribute to liver tumor burden
independently of excess adiposity or IR (Healy et al., 2015). In
mice as in humans, the tumor-promoting effect of obesity is
much more pronounced in males than in females. Although he-
patic steatosis and de novo lipogenesis may not be directly
involved in cancer cell growth and malignant progression, they
provide a more cancer-supportive microenvironment by gener-
ating inflammatory signals that exacerbate liver inflammation
and activate resident and newly recruited macrophages that pro-
duce TNF and IL-6. These cytokines promote malignant progres-
sion through activation of NF-kB and STAT3 in initiated hepato-
cytes (Nakagawa et al., 2014). In addition, lipid accumulation can
result in ER stress (Hummasti and Hotamisligil, 2010), a common
feature in many liver diseases, including viral hepatitis (Waris
et al., 2002). ER stress is characterized with an altered composi-
tion of lipids in the ER and inhibition of the sarco/endoplasmic re-
ticulum calcium ATPase (SERCA) (Fu et al., 2011). The resulting
elevated inflammation in turn induces iNOS activity producing
nitrosylation of hepatic IRE1a, which subsequently fails to splice
XBP1, preventing production of ER chaperons (Yang et al., 2015)
(Figure 2). Finally, unresolved ER stress leads to oxidative stress
that promotes necrotic cell death, liver damage, inflammation,
and compensatory proliferation as shown in a novel mouse
model of NASH-induced HCC (Nakagawa et al., 2014). TNF,
which acts as a growth factor for HCC progenitor cells, is likely
to be an important player in human NASH, and the use of anti-
TNF drugs for other morbidities, such as psoriatic arthritis
(PsA), was observed to result in reduced NASH severity, as
long as it was effective in reducing PsA disease activity (Di Minno
et al., 2012). Other immune cells that contribute to NASH devel-
opment and malignant progression are CD8+ T cells, NKT cells,
and cells that produce lymphotoxin (LT), a TNF family member
whose blockade offers another option for interfering with
NASH to HCC progression (Wolf et al., 2014). Unlike TNF, how-
ever, there is little information regarding the involvement of LT in
human obesity and obesity-promoted cancer.
Macroautophagy (hereafter referred to as autophagy) is
an evolutionarily ancient proteolytic process that begins with
formation of an autophagosome that delivers engulfed cellular
constituents to the lysosome, where they are degraded.
Autophagy-related genes (ATGs), which are evolutionarily con-
served, control autophagosome formation and fusion with lyso-
somes. In addition to providing essential building blocks during
periods of starvation, autophagy is also a quality-control mech-
anism that maintains cellular homeostasis and prevents oxida-
tive stress (Yen and Klionsky, 2008). Constitutive autophagy
prevents accumulation of misfolded proteins and damaged or-
ganelles, including ROS-producing non-functional mitochon-
dria and damaged ER membranes (Figure 2). In this sense,
obesity is a condition inextricably linked to defective autophagy
characterized by a marked downregulation of ATG7. Restora-
tion of ATG7 in the liver normalizes ER and insulin sensitivity
(Yang et al., 2010). Thus, by inhibiting autophagy, hypernutrition
can cause oxidative stress, thereby promoting chromosomal
instability (Aghajan et al., 2012). Systemic mosaic deletion of
Atg5 or liver-specific deletion of Atg7 results in liver damage
and the development of benign liver adenomas (Komatsu
et al., 2005; Takamura et al., 2011). Hepatic steatosis leads
to chronic activation of the mTORC1 kinase complex, which
blocks the initiation of autophagy through inhibitory ULK1
phosphorylation (Kim et al., 2011) and unrestrained mTORC1
activation leads to HCC development in mice (Menon et al.,
2012). Hypernutrition also inhibits AMPK, whose activation pro-
motes the initiation of autophagy through stimulatory ULK1
phosphorylation (Kim et al., 2011). One way to prevent exces-
sive inhibition of autophagy during hepatic steatosis involves
induction of sestrins, which are evolutionarily conserved
AMPK activators (Lee et al., 2013). Conversely, persistent he-
patocyte AMPK deficiency due to TAK1 ablation results in auto-
phagy defects and leads to HCC development, even in the
absence of ongoing hepatic steatosis (Inokuchi-Shimizu et al.,
2014; Seki et al., 2009). In fact, the phenotype of Tak1Dhep
mice is very similar to that of Tsc1Dhep mice (Menon et al.,
2012). Because autophagy also leads to degradation of lipid
droplets, its inhibition contributes to hepatic steatosis in HFD-
fed mice (Schneider and Cuervo, 2014). Defective autophagy
also results in accumulation of p62, an autophagy substrate
and chaperon that directs ubiquitinated protein aggregates
and organelles to autophagosomes for subsequent lysosomal
degradation. Deletion of p62 reverses liver injury and inhibits
adenoma development in Atg7Dhep mice (Komatsu et al.,
2007). Notably, p62 is a component of Mallory bodies, inclusion
bodies that are a common pathological feature of different liver
diseases, including alcoholic hepatitis, NASH, and HCC (Zat-
loukal et al., 2002). Accumulation of p62 or insufficient auto-
phagy activates nuclear factor erythroid 2-related factor 2
(NRF2) through titration of Kelch-like ECH-associated protein
1 (Keap1) (Komatsu et al., 2010). Despite its ability to induce
expression of anti-oxidant enzymes, NRF2 activation may
contribute to HCC development (Inami et al., 2011).
Efficient autophagy plays an important role in restraining
inflammation. Apoptosis or necrosis can be observed upon
long-term suppression of autophagy, and autophagy defects
promote inflammation and tumorigenesis (White et al., 2010).
Certain NOD-like receptors (NLRs), a group of pattern recogni-
tion receptors with diverse functions, such as NLRP3, mediate
activation of caspase-1 and secretion of mature IL-1b and IL-
18 by activated myeloid cells (Franchi et al., 2012). Interestingly,
NLRP3 can sense the presence of cholesterol crystals and
various other DAMPs leading to IL-1 and IL-18 release. A poten-
tial link between inflammasome activation and autophagy was
first observed when loss of the autophagy protein Atg16L1
was found to enhance IL-1b and IL-18 production (Saitoh
et al., 2008). Autophagy blockade can result in accumulation of
damaged mitochondria that produce reactive oxygen species
(mtROS) and leak mitochondrial (mt) DNA, both of which stimu-
late NLRP3-dependent caspase-1 activity and result in IL-1b
and IL-18 production (Zhou et al., 2011), further explaining how
long-term inhibition of autophagy can promote inflammation.
By contrast, efficient autophagy can limit NF-kB activation
and TNF receptor-associated factor 6 (TRAF6) signaling, both
of which are involved in inflammation-mediated tumor promo-
tion, by enhancing the degradation of p62/SQSTM1 (Moscat
Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc. 53

and Diaz-Meco, 2012). Autophagy can also prevent secondary
necrosis and DAMP release by clearing apoptotic bodies. Both
ATG5 and damage-regulated autophagy modulator (DRAM)
are required for p53-induced apoptotic death (Crighton et al.,
2006), a tumor-suppressive mechanism. Conversely, Atg5 abla-
tion results in impaired clearance of apoptotic bodies and conse-
quent inflammation (Qu et al., 2007).
Dysbiosis has been detected in liver cirrhosis patients (Bajaj
et al., 2014). As mentioned above, obesity induces changes
in microbiome composition and gut permeability, thereby
increasing endotoxin concentration in the portal circulation,
which connects the gut to the liver. Portal endotoxin stimu-
lates production of inflammatory cytokines by both Kupffer
cells and newly recruited liver macrophages, thereby promot-
ing HCC development (Schwabe and Jobin, 2013) (Figure 2).
The altered gut microbiota of obese mice also produces
higher than normal amounts of deoxycholic acid (DCA), a
secondary bile acid that enhances secretion of cytokines
by senescent hepatic stellate cells (HSCs), a process that
was reported to promote HCC development in carcinogen-
treated mice (Yoshimoto et al., 2013). It should be noted,
however, that HSC senescence is usually associated with res-
olution of inflammation and fibrosis rather than active liver dis-
ease, thus questioning the physiological relevance of these
findings.
Genetic factors are also likely to contribute to obesity-pro-
moted HCC. NAFLD tends to cluster in families and hepatic
steatosis is more common in siblings and parents of children
with NAFLD compared to overweight children without NAFLD
(Schwimmer et al., 2009). NAFLD heritability was estimated to
be 39% after adjusting for age, sex, race, and BMI. So far, a num-
ber of potential genetic determinants were identified by GWAS.
The non-synonymous rs738409 (I148M) SNP in the PNPLA3
gene, which encodes a triacylglycerol lipase that mediates tri-
glyceride hydrolysis in adipocytes, is the first and most important
NAFLD-associated genetic variant (Romeo et al., 2008). These
findings were confirmed by another GWAS (Speliotes et al.,
2011) and are of significance even after adjustment for BMI,
T2DM, alcohol use, and ethnicity. A meta-analysis pooling the
results of 16 studies showed that PNPLA3 rs738409 also had a
strong association with a more aggressive disease, as homozy-
gotes had 3.5-fold greater risk of NASH, 3.3-fold greater risk of
fibrosis, and 28% increase in serum ALT, an indicator of liver
damage (Sookoian and Pirola, 2011). Moreover, the PNPLA3
rs738409 C > G polymorphism is not only associated with
greater risk of progressive steatohepatitis and fibrosis but also
of HCC (Liu et al., 2014). A pilot GWAS of NAFLD, using a rela-
tively small all-female cohort of 236 patients, identified an asso-
ciation between NAFLD activity score and the rs2645424 SNP in
the FDFT1 gene, which encodes an enzyme involved in choles-
terol biosynthesis (Chalasani et al., 2010). Several more SNPs
associated with NAFLD were found in the PNPLA3 (rs738408),
NCAN (rs2228603), PPP1R3B (rs4240624), GCKR (rs780094),
and the LYPLAL1 (rs12137855) loci (Speliotes et al., 2011). The
rs738408 PNPLA3 SNP is in strong linkage disequilibrium with
the rs738409 SNP (Romeo et al., 2008). In addition, a recent
GWAS in adolescents diagnosed with NAFLD identified SNP
associations in two liver-specific genes (GC and LCP1) and
two neuronal-specific genes (LPPR4 and SLC38A8). This study
54 Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc.
Cell Metabolism
Review
also confirmed differential expression of GC and LCP1 in a
NAFLD cohort (Adams et al., 2013).
Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is another highly
aggressive malignancy with a 5 year survival rate of 6%. PDAC
risk is also strongly enhanced by obesity (Calle et al., 2003; Wise-
man, 2008) and PDAC is predicted to become one of the three
top lethal cancers in the U.S. by 2030, together with lung and
liver cancers (Rahib et al., 2014). PDAC development depends
on accumulation of KRAS-activating mutations in pancreatic
acinar cells, which give rise to premalignant PanIN (Pancreatic
Intraepithelial Neoplasia) lesions (Kopp et al., 2012). Curiously,
however, low-grade PanIN harboring oncogenic KRAS alleles
are very common in older individuals (R70 years), but the major-
ity of these individuals never develop PDAC (Hruban et al., 2000;
Lüttges et al., 1999), suggesting that additional genetic events
are needed for malignant progression. In addition to old age
and obesity, PDAC risk factors include chronic pancreatic
inflammation (pancreatitis), alcohol consumption, and tobacco
smoking (Vincent et al., 2011). Chronic inflammation caused by
pancreatitis, obesity, and tumor-associated inflammation could
contribute to PDAC genesis and development (Figure 3). How-
ever, the underlying mechanisms linking obesity and inflamma-
tion to PDAC have not been fully elucidated. Oncogenic KRAS
can activate STAT3 and NF-kB signaling by inducing production
of IL-6, TNF, and IL-11 (Ling et al., 2012). Moreover, activation of
NF-kB by TNF can stimulate Notch signaling, which synergizes
with oncogenic KRAS to further promote PDAC development
(Maniati et al., 2011). Obesity can also promote infiltration of
the pancreas with immunosuppressive cells, including Treg
and so-called myeloid-suppressive cells, that can prevent the
immunosurveillance of early, malignant lesions (Cox and Olive,
2012). Obesity also increases macrophage infiltration into
pancreatic islets (Ehses et al., 2007). Altogether, immune cells
account for roughly 50% of the pancreatic tumor cell mass,
and most of them are immunosuppressive in nature (Feig et al.,
2012). Obesity and inflammation can also promote metastasis,
a common complication of PDAC, by stimulating epithelial-
mesenchymal transition (EMT). Treatment with the immunosup-
pressive agent dexamethasone blocks metastatic dissemination
(Rhim et al., 2012).
Evidence from animal models indicates that dysfunctional
autophagy is associated with pancreatitis and most of the
PDAC risk factors mentioned above are known to interfere with
either initiation or completion of autophagy (Mareninova et al.,
2009) (Figure 3). Defective lysosomal proteolysis results in for-
mation of large cytoplasmic vacuoles, which is a long-noted
but poorly understood pathological feature of pancreatitis (Gu-
kovskaya and Gukovsky, 2012). Autolysosomes account for
most of the vacuoles that accumulate in acinar cells during
pancreatitis. As indicated above, defective autophagy signifi-
cantly extends the half-life of dysfunctional organelles, including
damaged mitochondria that produce mtROS and release
mtDNA. Decreased degradation of long-lived proteins and for-
mation of p62 aggregates also occurs during pancreatitis and
can further exacerbate oxidative stress by triggering ER stress
(Li et al., 2013). As discussed above, ROS accumulation leads
to genomic instability and stimulates tumor initiation. Defective
Cell Metabolism

Review

Figure 3. Mechanisms of Obesity-Promoted PDAC

Defective autophagy in pancreatic acinar cells leads to toxic accumulation of p62 aggregates, inducing ER stress and eventual cell death. Established
inflammation and NRF2 activation cause the metaplasia of surviving acinar cells and converts them to a ductal progenitor phenotype, thereby generating low-
grade PanIN. To convert low-grade PanIN lesions into PDAC, metabolic reprogramming is needed through the action of members of the MITF/TFE family of
transcription factors, which upregulate autophagy, to promote cell survival. Other metabolic changes promote proliferation within PanIN lesions and lead to
PanIN to PDAC progression.

autophagy and insufficient lysosomal proteolysis also cause the
pathologic, intra-acinar accumulation of trypsin, which is another
hallmark of pancreatitis (Gukovskaya and Gukovsky, 2012; Gu-
kovsky and Gukovskaya, 2015). In contrast to high-grade PanIN
in which autophagy is upregulated, lower-grade PanIN exhibit
reduced autophagy rate, and insufficient autophagy can pro-
mote the progression of early PanIN lesions to high-grade PanIN
and PDAC. Exactly how autophagy is upregulated during later
stages of malignant progression is not entirely clear, but a recent
publication suggests that PDAC metabolic reprogramming re-
quires the constitutive activation of MITF, TFE3, and TFEB tran-
scription factors that are otherwise retained in the cytoplasm.
These transcription factors upregulate transcription of genes
related to lysosome biogenesis and autophagy to maintain
essential amino acid pools (Perera et al., 2015) (Figure 3).
Epidemiologic studies have identified T2DM as another
pancreatic cancer risk factor (Lin et al., 2011). The first pancre-
atic cancer GWAS identified a common risk variant, rs505922,
that maps to the first intron of the ABO gene (Amundadottir
et al., 2009). This finding implies that people with blood group
O may have a lower risk than those with groups A or B. A second
GWAS identified additional pancreatic cancer susceptibility loci
at 13q22.1, 1q32.1, and 5p15.33 (Petersen et al., 2010a) and
subsequently five new susceptibility loci were mapped to
21q21.3, 5p13.1, 21q22.3, 22q13.32, and 10q26.11 (Wu et al.,
2012). The exact identity of these risk loci, their mechanism of
action, and whether they are related to obesity or T2DM is un-
known.
Colorectal Cancer
Colorectal cancer (CRC) is the third most common cancer in men
and the second in women (Ferlay et al., 2015). The sequential ge-
netic progression of this malignancy is well established. Colonic
adenomas are considered as precursors to carcinoma and their
prevalence in the general population is strikingly high. As in
PDAC, the adenoma to carcinoma transition is highly influenced
by environmental factors. There are several explanations for the
high incidence of gastrointestinal (GI) cancers. First, the GI
epithelium contains a much larger number of actively dividing
stem and progenitor cells than other epithelial tissues, including
the liver and pancreas, where cell division is mostly evoked in
response to damage. Second, the GI epithelium is in direct con-
tact with the environment, including ingested material that may
contain trace amounts of toxins and carcinogens. Third, the GI
tract, especially the colon, is a host to trillions of commensal mi-
crobes. Although these microbes are normally well-tolerated,

Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc. 55

 Cell Metabolism

Review

Figure 4. Mechanisms of Obesity-Induced CRC

Obesity induces dysbiosis and thinning of the intestinal mucus layer resulting in increased permeability of the intestinal epithelium to microbial products. Resident
immune cells react to these inflammatory cues by secreting a cocktail of inflammatory cytokines that act directly on cancer progenitor cells to stimulate their
survival and proliferation. Obesity-associated microbial dysbiosis can result in elevated concentrations of metabolites that further contribute to tumor promotion.
High levels of circulating IGF-1, insulin and inflammatory cytokines, and reduced levels of adiponectin also contribute to promotion of CRC development.

certain diets, including HFD, can lead to dysbiosis and thereby
trigger an inflammatory response. Fourth, the GI epithelium
serves as a barrier that prevents penetration of luminal microbes
and their disintegration products (endotoxin, nucleic acids, etc.)
into the underlying tissue, where they can evoke a tumor-pro-
moting inflammatory response (Grivennikov et al., 2012). In addi-
tion to HFD, diets that are fiber poor also reduce microbiome
diversity and enhance bowel inflammation (Poullis et al., 2004).
Altogether, such diets play on a common theme in cancer devel-
opment: increased tissue damage and consequent tumor-pro-
moting inflammation (Grivennikov et al., 2010) (Figure 4).
The risk and incidence of CRC go up with increased BMI (Calle
et al., 2003). Meta-analysis revealed a 5% increase in CRC inci-
dence per inch of above-normal waist circumference (Wiseman,
2008). HFD-fed mice showed a marked increase in colonic TNF
expression (Liu et al., 2012). TNF is a potent inducer of IL-6,
whose role in promoting CRC has been widely studied and
recently reviewed (Taniguchi and Karin, 2014). By contrast, adi-
ponectin can inhibit the growth of CRC cells by activating AMPK
(Sugiyama et al., 2009) and, consequently, low adiponectin
levels are associated with increased CRC risk (Gialamas et al.,
2011; Otake et al., 2010). Furthermore, adiponectin ablation en-
hances development of colitis-associated cancer or intestinal
adenomas in Apcmin mice (Mutoh et al., 2011) and HFD feeding
results in similar outcomes (Moon et al., 2013). Mouse studies
have also shown that leptin acts as a growth factor in CRC
(Endo et al., 2011) (Figure 4). Obesity and hyperinsulinemia
also increase expression of IGF-1, another well-established fac-
tor that promotes CRC development and malignant progression
by binding IGFR. Obesity-induced alterations in intestinal barrier
permeability have an additional influence on CRC development.
HFD-fed mice show increased circulating LPS and such endo-
toxemia can promote CRC development (Cani et al., 2007).
Monocolonization of germ-free (GF) mice with different E. coli
strains that produce distinct forms of LPS showed that only
mice exposed to immunogenic LPS exhibited accumulation of
pro-inflammatory macrophages in adipose tissue (Caesar
et al., 2012). These results suggest that obesity-induced barrier
disruption results in mild endotoxemia that synergizes with
pre-existing adipose tissue inflammation to further increase tu-
mor-promoting systemic inflammation. In addition to TNF and
IL-6, IL-22 was shown to play a central role in establishing meta-
bolic imbalances observed in obesity. HFD-fed IL-22R-deficient
mice showed increased propensity to develop metabolic disor-
ders, and administration of IL-22 into genetically obese db/db
mice or mice fed with HFD resulted in a significant amelioration
of IR, hyperglycemia, intestinal barrier disruption, endotoxemia,
and systemic inflammation (Wang et al., 2014). Despite the fact

56 Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc.

Cell Metabolism
Review
that IL-22 can have initial anti-tumorigenic activity, its signaling
can be corrupted by malignant cells to enhance survival and
metastasis (Lim and Savan, 2014), thus obscuring its therapeutic
potential.
Notably, a recent paper had suggested that the pro-tumori-
genic effect on HFD on intestinal cancer is not related to obesity
per se and that tumor promotion is mainly due to dysbiosis. Fecal
transfer from HFD-fed Kras(G12Dint) mice was sufficient to
enhance tumorigenic growth and progression in the absence
of HFD in recipient mice (Schulz et al., 2014) In addition, antibi-
otic treatment blunted the HFD-induced tumor progression.
Prevention, Risk Prediction, and Cancer Treatment
Importantly and despite its profound impact, much of the effect
of obesity on cancer development and mortality can be pre-
vented or even reversed by dietary modification, increased ex-
ercise regimens, or, in more severe cases, bariatric surgery.
Since obesity and hypernutrition mainly act as tumor pro-
moters, even delayed intervention, after early malignancy has
been detected, may be beneficial, if not by itself, then in com-
bination with chemo- or immunotherapy. Early intervention
together with administration of potent insulin-sensitizing drugs
and IGF antagonists may prevent the development of all
obesity-promoted cancers, leading to a 15% decrease in
cancer-related deaths (Calle et al., 2003). However, given the
failure of behavioral modification and bariatric surgery in stem-
ming the impact of the obesity epidemic until now, more so-
phisticated pharmacological and therapeutic approaches are
needed. These may include PPARg modulation, induction of
brown fat via drug treatment or cell transplantation, inhibition
of adipose tissue angiogenesis, or adipokine therapy, although
in most cases the validity and feasibility of such approaches re-
mains to be demonstrated (Rosen and Spiegelman, 2014).
Another plausible, but not yet tested, approach is restoration
of microbiome diversity in those cases where obesity or hyper-
nutrition lead to pronounced dysbiosis. As a matter of fact, it
was recently reported that bariatric surgery elicits sustained
changes in microbiome composition along with weight loss
that are transmissible to recipient germ-free mice upon fecal
transfer (Tremaroli et al., 2015).
As discussed above, common genetic variants impose modest
risk increments on various parameters of the metabolic syn-
drome and associated cancers. So far, GWASs have not resulted
in identification of obvious therapeutic targets and it is not clear
whether addressing a factor that increases relative disease risk
by only a small increment is a worthwhile effort. It is much clearer
that regardless of its initial tissue-specific effects, obesity in-
creases cancer risk and accelerates malignant progression
by causing low-grade chronic inflammation. Thus, anti-inflam-
matory intervention may be the most effective preventative
approach for the majority of obesity-promoted cancers. Indeed,
there is considerable epidemiological evidence that long-term
consumption of Aspirin and other non-steroidal anti-inflamma-
tory drugs (NSAID) results in a considerable decrease in cancer
risk, as first identified in CRC (Flossmann et al., 2007), but now
extended to several other cancers as well (Rothwell et al.,
2011). Importantly, Aspirin and other salicilates were also proven
effective in the treatment of IR and other aspects of the metabolic
syndrome (Goldfine et al., 2013). Thus, an Aspirin a day may be
the most cost-effective way to reduce the enormous cancer-
related burden of overweight and obesity (Calle et al., 2003).
NSAIDs and anti-TNF drugs may also act synergistically with
other treatments. It was reported that PsA patients receiving
anti-TNF drugs presented less hepatostetaosis (Di Minno et al.,
2012). Similar observations were made on the degree of IR in
RA patients on anti-TNF therapy (Burska et al., 2015; Solomon
et al., 2011). The antidiabetic drug metformin has shown prom-
ising effects in reducing cancer-associated risk in diabetic pa-
tients (Evans et al., 2005; Quinn et al., 2013) and some positive ef-
fects in NAFLD (Marchesini et al., 2001), although not in NASH.
Metformin’s anti-cancer effects appear to depend on mTORC1
inhibition, specifically in cancer stem cells (Hirsch et al., 2009).
However, long-term mTORC1 inhibition has adverse effects on
the liver and may increase HCC risk (Umemura et al., 2014).
More potent and specific interventions, however, may be
needed for NASH-driven HCC. First, unlike the low-grade inflam-
mation associated with obesity, NASH is a serious inflammatory
disease that can frequently lead to liver failure well before
appearance of HCC. Mouse studies show that TNF and the
related cytokine LT play important roles not only in the develop-
ment of NASH-related HCC but also in the pathogenesis of
NASH itself (Nakagawa et al., 2014; Wolf et al., 2014). Curiously,
LT also regulates the ability of commensal bacteria to promote
weight gain (Upadhyay et al., 2012). Thus, LT antagonists
together with established anti-TNF drugs may be of particular
therapeutic value in this obesity-induced cancer. The chemical
chaperon TUDCA has shown to reduce inflammation in the adi-
pose tissue in obese mice (Kawasaki et al., 2012) as well as to be
effective in normalizing fatty liver disease in mice and improving
insulin sensitivity in mice and humans (Kars et al., 2010; Ozcan
et al., 2006). Although TUDCA had shown efficacy in mouse
models of NASH (Nakagawa et al., 2014), it has not produced
remarkable effects at normal doses in human NASH. Vitamin
E, however, has shown promise in the treatment of human
NASH. The protective and therapeutic effects of vitamin E may
be related to its antibiotic activity.
Obesity not only increases cancer risk but also increases its
mortality rate (Calle et al., 2003). Little is known about the
intrinsic characteristics of tumors promoted by obesity. For
instance, it is not yet known whether obesity affects the muta-
tional spectrum associated with tumor initiation and progression.
Such knowledge is of particular importance in the case of the
most lethal obesity-promoted cancers reviewed above. For
instance, a specific oncogenic driver induced by obesity may
offer a specific and unique target for drug development, in addi-
tion to the more general approaches discussed above.
Conclusions
d Obesity increases the risk of developing deadly malig-
nancies through a panoply of pathophysiological alter-
ations including systemic inflammation, dysregulation of
adipokines, insulin resistance with hyperinsulinemia and
hyperglycemia, dysbiosis, and immune system alterations.
d Obesity-promoted cancers are amongst the most deadly
and are predicted to become leading killers by 2030 in
the U.S.
Cell Metabolism 23, January 12, 2016 ª2016 Elsevier Inc. 57

d The key to tackling these cancers is to understand the
mechanisms underlying increased risk, thereby identifying
patients who are at highest risk of developing obesity-pro-
moted malignancy. Efforts should be directed to under-
standing the progression of NAFLD to NASH and that of
NASH to HCC and at development of effective early pre-
vention for high-risk individuals.
d The human microbiota was proposed as an important
player in establishment of pathophysiological conditions
associated with obesity and obesity-induced cancer. A
stronger mechanistic understanding of effects attributed
to dysbiosis and human trials of microbiota restoration
are needed to validate the relevance and utility of this
approach.
d Given the fundamental role of inflammation in obesity pro-
moted malignancy, mainly benign anti-inflammatory treat-
ments should be given a priority to be evaluated as general
and inexpensive preventive strategies.
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