Metabolic surgery and cancer: protective effects of bariatric procedures.
ABSTRACT The worldwide epidemic of obesity and the global incidence of cancer are both increasing. There is now epidemiological evidence to support a correlation between obesity, weight gain, and some cancers. Metabolic or bariatric surgery can provide sustained weight loss and reduced obesity-related mortality. These procedures can also improve the metabolic profile to decrease cardiovascular risk and resolve diabetes in morbidly obese patients. The operations offer several physiological steps, the so-called BRAVE effects: 1) bile flow alteration, 2) reduction of gastric size, 3) anatomical gut rearrangement and altered flow of nutrients, 4) vagal manipulation and 5) enteric gut hormone modulation. Metabolic operations are also associated with a significant reduction of cancer incidence and mortality. The cancer-protective role of metabolic surgery is strongest for female obesity-related tumors; however, the underlying mechanisms may involve both weight-dependent and weight-independent effects. These include the improvement of insulin resistance with attenuation of the metabolic syndrome as well as decreased oxidative stress and inflammation in addition to the beneficial modulation of sex steroids, gut hormones, cellular energetics, immune system, and adipokines. Elucidating the precise metabolic mechanisms of cancer prevention by metabolic surgery can increase our understanding of how obesity, diabetes, and metabolic syndrome are associated with cancer. It may also offer novel treatment strategies in the management of tumor generation and growth.
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ABSTRACT: Social deprivation is associated with a greater morbidity and shorter life expectancy. This study evaluates differences in weight loss following bariatric surgery and deprivation, based on UK deprivation measures in a London bariatric centre. All patients undergoing bariatric surgery between 2002 and 2012 were retrospectively identified. Demographic details, type of surgery and percentage excess weight loss data were collected. UK Index of Multiple Deprivation (IMD, 2010) and IMD domain of the Health Deprivation and Disability (HDD) scores were used to assess deprivation (where 1 is the most deprived in rank order and 32,482 is the least deprived). Two-way between-subjects analysis of variance (ANOVA) was performed to examine the effect of IMD score, deprivation, procedure type and gender on percentage excess weight loss. Data were included from 983 patients (178 male, 805 female) involving 3,663 patient episodes. Treatments comprised laparoscopic gastric bands (n = 533), gastric bypass (n = 362) and gastric balloons (n = 88). The average percentage excess weight loss across all procedures was 38 % over a follow-up period (3 months-9 years). There was no correlation between weight loss and IMD/HDD rank scores. Gastric bypass was significantly more effective at achieving weight loss than the other two procedures at 3-, 6- and 9-month and 1-year follow-up. Social deprivation does not influence weight loss after bariatric surgery, suggesting that all socioeconomic groups may equally benefit from surgical intervention. Social deprivation should not therefore negatively influence the decision for surgical intervention in these patients.Obesity Surgery 05/2014; · 3.74 Impact Factor
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ABSTRACT: Obesity is a risk factor for many cancers and obese cancer patients have a poorer prognosis. This study aimed to evaluate the prevalence of obesity and attempts to lose weight among cancer survivors. The effects of cancer treatment and time since cancer treatment were also evaluated.Sultan Qaboos University medical journal 08/2014; 14(3):e330-6.
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ABSTRACT: Obesity constitutes one of the most important metabolic diseases being associated to insulin resistance development and increased cardiovascular risk. Association between obesity and cancer has also been well established for several tumor types, such as breast cancer in post-menopausal women, colorectal, and prostate cancer. Cancer is the first death cause in developed countries and the second one in developing countries, with high incidence rates around the world. Furthermore, it has been estimated that 15-20% of all cancer deaths may be attributable to obesity. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment. In this sense, obesity may lead to cancer development through dysfunctional adipose tissue and altered signaling pathways. In this review, three main pathways relating obesity and cancer development are examined: (i) inflammatory changes leading to macrophage polarization and altered adipokine profile; (ii) insulin resistance development; and (iii) adipose tissue hypoxia. Since obesity and cancer present a high prevalence, the association between these conditions is of great public health significance and studies showing mechanisms by which obesity lead to cancer development and progression are needed to improve prevention and management of these diseases.Frontiers in Endocrinology 01/2014; 5:65.
Metabolic Surgery and Cancer
Protective Effects of Bariatric Procedures
Hutan Ashrafian, MRCS; Kamran Ahmed, MRCS; Simon P. Rowland, BSc(Hons); Vanash M. Patel, MRCS;
Nigel J. Gooderham, PhD; Elaine Holmes, PhD; Ara Darzi, KBE, FMedSci; and Thanos Athanasiou, MD, PhD, FETCS
The worldwide epidemic of obesity and the global incidence of cancer are both increasing. There is now epidemiolog-
ical evidence to support a correlation between obesity, weight gain, and some cancers. Metabolic or bariatric surgery
can provide sustained weight loss and reduced obesity-related mortality. These procedures can also improve the
metabolic profile to decrease cardiovascular risk and resolve diabetes in morbidly obese patients. The operations
offer several physiological steps, the so-called BRAVE effects: 1) bile flow alteration, 2) reduction of gastric size, 3)
anatomical gut rearrangement and altered flow of nutrients, 4) vagal manipulation and 5) enteric gut hormone
modulation. Metabolic operations are also associated with a significant reduction of cancer incidence and mortality.
The cancer-protective role of metabolic surgery is strongest for female obesity-related tumors; however, the underly-
ing mechanisms may involve both weight-dependent and weight-independent effects. These include the improve-
ment of insulin resistance with attenuation of the metabolic syndrome as well as decreased oxidative stress and
inflammation in addition to the beneficial modulation of sex steroids, gut hormones, cellular energetics, immune sys-
tem, and adipokines. Elucidating the precise metabolic mechanisms of cancer prevention by metabolic surgery can
increase our understanding of how obesity, diabetes, and metabolic syndrome are associated with cancer. It
may also offer novel treatment strategies in the management of tumor generation and growth. Cancer 2011;117:1788–
C 2010 American Cancer Society.
KEYWORDS: metabolic surgery, bariatric surgery, cancer, oncology.
The worldwide epidemic of obesity and the global incidence of cancer are both increasing. According to the World
Health Organization (WHO), obesity is rising by 30 million cases per year,1whereas the overall number of new cancer
cases will increase by 300,000 cases per year.2Both obesity and cancer contribute to increased worldwide mortality and
healthcare costs. They are now both recognized as global healthcare concerns and have been the subject of worldwide calls
Several treatment strategies have been developed to decrease obesity; these include prevention, lifestyle, behavioral
modification, and pharmacotherapy. The weight-loss effects of these strategies have only been marginally successful,5and,
therefore, a surgical solution has been developed to provide consistent weight loss in severely obese patients. The opera-
tions initially titled ‘‘bariatric procedures’’ have demonstrated long-term weight loss at more than 15 years after surgery6,7;
however in addition, they achieve pronounced metabolic effects including diabetes resolution in the majority of morbidly
obesepatients.8–10Asaresult,these proceduresarenowconsidered as‘‘metabolic’’operations.10-14
The epidemiological association between obesity rates and cancer rates has come under increased scrutiny as there is
now evidence to establish obesity as a significant risk factor for the development of cancer.15Whereas weight gain
can result in higher cancer rates, the converse finding of losing weight and lower cancer rates did not traditionally exist, as
there were no successful weight-loss modalities.16Recently, longitudinal studies on metabolic surgery have revealed
that successful weight loss also results in lower cancer rates.7,17-19This has contributed to fulfilling the Bradford Hill
criteria for assessing a causal association between obesity and cancer20; however, it also provides mechanistic insights into
obesity-cancer pathogenesis. In this review, we describe the effects and potential mechanisms of cancer prevention by
DOI: 10.1002/cncr.25738, Received: July 11, 2010; Revised: September 8, 2010; Accepted: September 27, 2010, Published online November 29, 2010 in Wiley
Online Library (wileyonlinelibrary.com)
Corresponding author: Hutan Ashrafian, MRCS, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM-Building, Praed Street, London
W2 1NY, United Kingdom; Fax: (011) 44(0)207886 6309; firstname.lastname@example.org
Department of Surgery and Cancer, Imperial College London, London, England
May 1, 2011
Epidemiology of Obesity and Cancer
Although obesity is an ancient disease,21it was not until
1913 that Frederick L. Hoffman proposed that an ‘‘erro-
neous diet’’ was a contributory factor in the etiology of
cancer development22; and in 1940, Albert Tannenbaum
established that body weight was significantly associated
with cancer incidence in a rodent animal model.23This
association, however, was not formally studied in epide-
miological studies until 1959 when the American Cancer
Society performed a long-term prospective analysis on
750,000 subjects from 26 states.24Here, the mortality at-
tributable to cancer was higher for individuals 40% above
the average weight. To categorize body weight, subse-
quent studies have applied a classification of obesity based
The Million Women Study25in the United King-
dom, which studied more than 1 million female subjects
for more than a 5-years with follow-up, revealed a signifi-
cant association between increased weight and cancer risk,
particularly in the postmenopausal group. Several meta-
analyses, systematic reviews,26and 1 collaborative analysis
ation between body mass index, mortality, and several
male and female cancers. These include breast, renal,
immune (leukemia, lymphoma, myeloma), ovarian,
esophagus, pancreas, prostate, cervix, hepatobiliary, gall-
The World Cancer Research Fund reviewed the
international literature to study the associations between
food, nutrition, physical activity, weight gain, and obesity
with the risk of developing 17 cancers. They performed
systematic reviews at 9 centers and made recommenda-
tions on the opinion of 21 international experts. An asso-
ciation between obesity and cancer was acknowledged,
and they recommended ‘‘Be as lean as possible within the
normal range of body weight.’’28It has been estimated
that for the United States, obesity may account for 14%
of all deaths from cancer, and 20% of those in women.
Furthermore, if both US men and women were to main-
tain a normal weight, 900,000cancer deaths could be pre-
vented.29The role, therefore, for intentional weight loss
to decrease cancer rates has gained increased favor,
although this has proven difficult to achieve with diet and
lifestyle therapies.30Both randomized and prospective
studiesrevealthat thelong-term weightlosswithintensive
lifestyle intervention in diabetic patients with a body mass
index of 30 kg/m2is approximately 2% at 2 years31and
10 years32and is even less in patients7with a body mass
index above 35 kg/m2. The significant weight reductions
required for the proposed decrease in cancer risk, how-
ever, can be consistently achieved in the vast majority of
Metabolic Surgery and the Reduction in
The adoption of metabolic surgeries has increased over
the past half-century so that in 2008, more than 344,000
cases were performed globally.35They are traditionally
subdivided into 3 main groups. Restrictive procedures
that decrease stomach size (adjustable gastric banding and
sleeve gastrectomy). Pure bypass procedures that ‘‘rear-
range’’ gastrointestinal anatomy (duodenojejunal bypass),
or combination procedures with elements of both anato-
mical rearrangement and stomach size restriction (Roux-
en-Y gastric bypass—the current gold standard metabolic
operation).12These procedures consist of several physio-
logicalsteps,the so-calledBRAVE10,11effects:1) bileflow
Table 1. Metabolic Surgical Weight Loss Over Time
2 Years 5 Years7 Years10 Years15 Years
Biliopancreatic diversion with
Roux-en-Y gastric bypass
Actual Weight Loss has only recently been calculated in surgical weight-loss studies. Older studies consider Excess
Weight Loss (EWL) to be (weight before ? weight after [kg]/excess body weight before) where excess body weight is
(total body weight minus; ideal body weight). Ideal body weight refers to the weight when BMI ¼ 25 kg/m2.
NA indicates not available.
aData from systematic review reporting weighted mean results (excluding sleeve gastrectomy.)33
bData from prospective study.6,7
Metabolic Surgery and Cancer/Ashrafian et al
May 1, 2011
alteration, 2) reduction of gastric size, 3) anatomical gut
rearrangement and altered flow of nutrients, 4) vagal
manipulation, and 5) enteric gut hormone modulation. It
was initially hypothesized that performing gastric bypass
surgery could result in biliary reflux and increased cancer
risk.36,37The operation was, therefore, modified toinclude
the Roux-en-Y anastomotic technique,38which has the
addedadvantageofdecreasing biliaryreflux and preventing
subsequent gastric cancer risk.39,40The vast majority of
procedures are performed laparoscopically41and demon-
strate low postoperative adverse outcomes. A recent multi-
center, prospective, observational study42revealed an
Metabolic gastrointestinal operations can produce
sustained long-term weight loss, resolution of diabetes, and
modification of the metabolic syndrome (Table 1).6-9,17
Traditionally, they have been applied only to patients
with body mass indices >35kg/m2with obesity comor-
bidities (currently accepted by the National Institutes of
Health (NIH) in the United States and the National
Institute for Health and Clinical Excellence (NICE)
in the United Kingdom. In view of their favorable meta-
bolic effects, these procedures31,43have been increasingly
Metabolic surgery demonstrates a clear overall all-
cause mortality benefit when compared with nonsurgical
obese matched controls (Table 2). Although reported
studies vary as to the magnitude of reduction in relative
risk of mortality, the long-term decrease in death rates
achieved by bariatric surgery has been shown to be signifi-
cantly lower in operated versus unoperated obese patients.
Such a decrease, however, does not necessarily achieve a
mortality rate comparable to individuals of normal
weight,44although surgery can significantly reduce several
obesity-related comorbidities including the resolution of
diabetes9in 78.1% and a decrease17in diabetes-related
deathby92%andcoronary-related deathby 56%.Several
recent studies demonstrate that some of the mortality
benefits from surgery are derived from a decreased inci-
dence of cancer. Although intentional weight loss through
lifestyle, diet, and pharmacotherapy can all achieve
improvements in glucose homeostasis and diabetes, these
effects are difficult to maintain in the long-term.32Medi-
cal weight loss can reduce diabetes-related mortality in
overweight patients by one-third45and overall mortality
in diabetic patients also by one-third,46whereas 1 obser-
a relative risk reduction of overall mortality by 89% when
Table 2. Comparative Overall Mortality and Cancer Mortality and Incidence Rates Between Obese and Metabolic Surgical Groups
Risk of Death
in the Relative
Risk of Cancer
2.03% Medical visits
8.49% Medical visits
76% Medical visits
NIDDM indicates noninsulin-dependent diabetes mellitus; NS, not specified; EWL, excess weight loss (see Table 1.); Retro, retrospective study; Pros, prospective study.
May 1, 2011
Metabolic Surgery and Cancer Reduction
Metabolic surgery patients have lower cancer rates and
lower cancer mortality when compared with obese
et al47,53retrospectively studied 6781 morbidly obese
patients matched for age and sex from a single-payer
healthcare system database from 1986-2002. Patients
who had undergone bariatric surgery had a 76% decrease
in physician and hospital visits for cancer, which corre-
sponded to a 76% decrease in overall cancer incidence.
Patients had a mean weight loss of 35% or 62.1% excess
weight loss. Specifically the relative risk of breast cancer
Adams et al studied patients undergoing gastric
bypass between 1984-2002 and compared them to
severely obese individuals determined from Utah drivers
license applications that were linked to the Utah Cancer
Registry (UCR). They reported a 60% decrease in overall
long-term cancer mortality for these patients at a mean
follow-up of 7.1 years.17When the follow-up was
increased to a mean of 12.5 years, the cancer mortality
was 46% lower in the group who had had gastric bypass
surgery, which was associated with a 24% decrease in
overall-cancer incidence. There was no difference seen in
cancer incidence for tumors not related to obesity, and
there was a 38% reduction in obesity-related cancers.18
Uterine cancer incidence was significantly decreased in
patients who had had gastric bypass surgery (although
there was no data to consider the potential bias of whether
these women had undergone hysterectomies). When ana-
lyzing cancers according to stage (using Surveillance, Epi-
demiology, and End Results [SEER]54staging), regional
cancers were significantly lower in the group who had
bariatric surgery with a trend toward significance for the
distant cancers. There was no significant difference in the
incidence of in situ, local, or unstaged tumors. There was
also no difference in the mean time to cancer diagnosis or
case-fatality rates. As a result, the authors concluded that
the improved mortality rates in the gastric bypass surgery
group were likely to result from a decreased incidence of
cancer and unlikely to have resulted from earlier
The SOS (Swedish Obese Subjects) study com-
menced in 1987 and is ongoing. It is a prospective
controlled study of more than 4000 matched individuals
approximately divided into 2 equally sized arms:
surgically treated patients and a conventional obesity
treatment group. In this study with a mean follow-up of
10.9 years, cancer was the most common cause of death
from noncardiovascular causes and, furthermore, out-
numbered deaths from myocardial infarctionor heart fail-
ure. Depending on the procedure performed, the surgical
patients lost on average 14%-25% of weight and had a
42.5% decrease in cancer mortality.7This demonstrated a
30% decrease in the incidence of all cancers for metabolic
surgical patients, although statistical analysis did not
These operations have revealed a significant benefit
in the reduction of cancer incidence and mortality when
stratifying patients by sex (Table 3). McCawleyet al retro-
spectivelystudied 4977 morbidlyobese females,reporting
a 38% decrease in the incidence of all cancers defined by
the Virginia Cancer Registry.55This study demonstrated
that both obese controls and surgical patients were
younger at cancer diagnosis compared with the general
populationof the Virginia Cancer Registry and that meta-
bolic surgical patients had the diagnosis of the majority
cancers at a younger age than obese controls. Adams et al
noted that although there was a significant decrease in
both incidence and mortality for morbidly obese females
compared with controls, there was no significant differ-
ence in either mortality or incidence of cancer for men
undergoing surgery.18The prospective SOS Study also
demonstrated a significant benefit for decreased cancer
incidence in women undergoing surgery that was not
demonstrated for obese men. The decreased incidence of
cancer in postbariatric surgery patients is significantly
associated with women after the menopause, which corre-
sponds to the decrease in the hormone-sensitive breast53
and endometrial18cancers after surgery. The beneficial
effects of surgery in female and hormone-related tumors
may allude to the beneficial association of surgery for sex-
A potential bias in these results includes the finding
that the bariatric surgery group are sometimes excluded
cancer in the past 5 years, and this cohort may have lower
cancer rates preoperatively when compared with obese
controls who have not had bariatric surgery.56Christou et
al accounted for this by excluding control subjects who
had visited a physician and/or a hospital within 6 months
for cancer and within 6 months of the study.53Metabolic
surgical patients are an ideal group in whom to study the
exact effects of weight loss on surgery, although few stud-
ies account for weight loss in their analysis of decreased
cancer incidence and mortality. The SOS study is an
exception, although, surprisingly, it failed to show an
Metabolic Surgery and Cancer/Ashrafian et al
May 1, 2011
association between weight loss, food intake, and the sub-
sequent development of cancer incidence. The researchers
were, however, able to demonstrate that the reduced inci-
dence of cancer in bariatric surgical patients was signifi-
cantly lower for nondiabetics and for nonsmokers, which
maybe dueto anenvironment ofdecreasedtumorgenera-
tion andgrowth inthissubsetof patients.
ation between cancer and metabolic surgery reveal 3 points.
First, the protective effect of surgery is associated with a
decrease in the incidence of obesity-related cancers.18Sec-
ond, the effects of metabolic surgery on decreased cancer
mortality is present for all cancers, particularly in obese
female patients.18Third, the extent of weight loss or energy
The lack of association between weight loss and decreased
resent inappropriate regression models.20The limitations of
these studies include their designs, which do not achieve the
highest levels of evidence. The majority are comparative ret-
rospective studies, other than the SOS study, which stands
out as being prospective and controlled. As a result, these
studies were not intentionally designed to prospectively
for the causal association between metabolic surgery and its
effects on cancer resolution, progression, or prevention.
Much of the data used may be influenced by the bias that
many obese patients with cancers might have been declined
bariatric surgery or might not have been included in the
data-collection process. Patients undergoing bariatric sur-
gery may also be more likely to undergo upper-gastrointesti-
nal endoscopy or possibly screening colonoscopy before
surgery, and operative candidates may also be more moti-
vated to quit smoking, which could affect outcomes. Other
limitations include bias in measuring body mass index,
for metformin), secondary intervention bias (such as those
Nevertheless, these studies reveal the association
between metabolic operations, decreased cancer mortal-
ity, decreased cancer incidence, and a cancer-protective
effect. This may occur through a through a variety of
mechanisms including weight-dependent and weight-in-
Mechanisms of Decreased Tumor Generation
and Growth After Metabolic Surgery
Metabolic surgery offers several protective mechanisms
that may lead to decreased cancer incidence, these
Table 3. Comparative Cancer Incidence and Mortality Rates Between Obese and Metabolic Surgical Groups Stratified by Sex
in the Relative
Risk of Cancer
Reduction in theRelative Risk
at 10 y
NS indicates not specified.
aP<.05; incidence specifies the incidence of cancer; mortality specifies mortality from cancer.
May 1, 2011
interrupt several of the pathways associating obesity with
Decreased Obesity through Weight loss
The contribution of decreased obesity achieved
in tumor generation and growth.18-20When comparing
medical therapy to surgery in obese subjects with a body
mass index larger then 35kg/m2, the authors of the
prospective weight-controlled SOS study revealed that
15-year surgical weight loss was as high as 27% for gastric
bypass patients compared with minimal weight loss in the
medically treated group.7In a landmark randomized,
unblinded, controlled trial, Dixon et al31demonstrated
that at 2 years, laparoscopic adjustable gastric-banding
surgery achieved 20.7% weight loss compared with 1.7%
in a medical intervention group of recently diagnosed
diabetic patients (<2 years)with a body mass index of
30-40Kg/m2. Here, the surgical patients had a 5 times
higher remission rate for diabetes compared with medical
controls, and weight loss was the principal predictor of
The mechanisms for weight loss after metabolic
surgery are muiltifactorial11,12and include the modula-
tion of gut hormones that lead to alterations in appetite,
modulation in addition to alterations in metabolic rate
and resting energy expenditure.11,58,59Although, tradi-
tionally, surgery was considered to achieve weight loss
through the malabsorption of food and restriction of
stomach size, there is some discrepancy supporting the
effects of stomach-pouch size or calorific malabsorption
other than for a minority of procedures (such as the bilio-
Surgery does, however, achieve a sustained decrease
in caloric intake,61,62which has a long-standing associa-
tion with decreased carcinogenesis in several experimental
models that span over a century of research.63,64One
study has revealed that the Roux-en-Y gastric bypass oper-
ation can decrease daily calorie intake by 1479 Kcal/day
Figure 1. Mechanisms of decreased cancer risk by metabolic surgery are depicted. IGF-1 ¼ Insulin-like Growth Factor 1, AMPK ¼
50adenosine monophosphate-activated protein kinase.
Metabolic Surgery and Cancer/Ashrafian et al
May 1, 2011
so that patients only consume 1341 Kcal/day.61The
fit from the reduced carcinogenesis mechanisms of dietary
caloric restriction, which include altered growth, metabolic
mediators including insulin and insulin-like growth factor
1, steroid and adipose hormones, inflammatory mediators,
Furthermore, metabolic surgery patients can find
increased physical activity more feasible after surgery where
the degree of postoperative weight loss is associated with
increased levels of exercise.31,66These operations may offer
ity as this can decrease mortality and disease progression in
Anti-inflammatory and Immune effects
There is an established association between inflam-
mation and cancer.69Obesity is associated with a chronic
inflammation derived from white adipose tissue (WAT)
that leads to the release of proinflammatory cytokines.
These include tumor necrosis factor alpha (TNF-alpha),
C-reactive protein (CRP) and several interleukins (IL)
such as IL-1beta and IL-6.70,71Proinflammatory cyto-
kines act on tissues and cells at the microenvironment
level, which results in cancer development through direct
and indirect effects on innate and adaptive immune cells,
disordered tissue homeostasis, and increased oxidative
stress.72The inflammation of the metabolic syndrome,
however, is a subclinical systemic inflammation initiated
from adipose tissue. The links between systemic inflam-
mationand cancerriskrequire furtherclarification.
Metabolic surgery results in a decrease of both oxi-
dative stress and systemic inflammatory markers includ-
ing interleukin-6, C-reactive protein (CRP), sialic acid,
plasminogen activator inhibitor-1, malondialdehyde, and
von Willebrand factor.73-77Multiple regression analysis
reveals that the decrease in postoperative insulin resistance
after surgeryis independentlyassociatedwithadecreasein
interleukin-6 concentrations.77At 6 months after surgery,
there is also an increase in the production of interferon-
gamma, IL-12, and IL-18 that is associated with a rise in
natural killer (NK) cell activity.78This may reveal a role
for metabolic surgery in contributing to a cell-mediated
cytotoxic immune response against tumor cells79to
The significant increase in the prevalence of obesity
is associated with the concomitant rise in the incidence of
insulin resistance and type II diabetes mellitus. When
insulin resistance is accompanied by atherogenic dyslipi-
demia, hypertension, and obesity (associated with disor-
dered adipokines, free fatty acids, and inflammation), it is
defined as the metabolic syndrome.80There is now evi-
dence from a few large-scale studies associating metabolic
The prospective Risk Factors and Life Expectancy
Project (1978-1987) assessing evidence from 9 large epi-
demiologic studies (N ¼ 62,285) reported an approxi-
mately 3-fold increased risk of colorectal cancer mortality
cal abnormalities.81The Chicago Heart Association
Detection Project in Industry (which also considered
cancer outcomes) reported a 50% increased risk of colon
cancer mortality among subjects with insulin resistance.82
A 10-year prospective Korean study (N ¼ 1,298,385)
reported an approximate 30% increase in the risk of death
from all cancers in subjects fasting serum glucose (use a as
proxy for insulin resistance).83In the latter study, the
effects on cancer mortality were not associated with body
mass index, suggesting a weight-independent mechanism
Increased insulin resistance raises systemic insulin
levels, which can subsequently potentiate anabolic effects
to mediate cell proliferation and cancer progession.15,84
These effects occur via insulin-like growth factor 1 (IGF-
1) production that can activate IGF-1 and insulin
receptors on normal and cancer cells via the phosphatidyl-
inositol 3-kinase/Akt signaling pathway.85Furthermore,
IGF-1 may stimulate production of adipocyte-derived
vascular endothelialgrowth factor (VEGF),a key factor in
Among the most dramatic effects of metabolic
surgery are the resolution of insulin resistance, metabolic
syndrome, and type II diabetes.10A recent systematic
review and meta-analysis assessed the effects of metabolic
surgery on diabetes. The review, which comprised 621
studies with 888 treatment arms and 135,246 patients,
reported that 78.1% of diabetic patients had complete
resolution, and diabetes was improved or resolved in
86.6% of patients.9In metabolic-surgery patients, insulin
resistance has typically been measuredby the Homeostasis
Model Assessment (HOMA-IR) where marked improve-
ments occur within 6 days of surgery.87This results in
30% of diabetic patients being discharged from hospital
on average 2.8 days after surgery with no antidiabetic
medication and normal plasma glucose levels.88Noticea-
ble surgical weight loss, however, can take between 3
May 1, 2011
months to 1 year to develop.89Furthermore, in a small
minority of patients, the Roux-en-Y gastric bypass
procedure not only resolves diabetes but can overshoot to
result in a hyperinsulinemic hypoglycemia that may result
from nesidioblastosis (pancreatic beta-cell hypertrophy
The mechanisms of diabetes resolution in meta-
bolic-surgery patients consist of the established longer
termeffects of surgicalweightloss,10,31,57as wellas several
proposed weight-loss–independent mechanisms that
improve insulin resistance after surgery. These include the
rearrangement of gastrointestinal anatomy (foregut,
midgut, and hindgut hypotheses), decreased inflam-
mation, altered fat and bile metabolism, changes in gut
hormone release, metabolic modulation, shifts in gut
microbial flora, and intestinal gluconeogenesis.10The
improvement of insulin resistance through these meta-
bolic operations may, therefore, contribute to the anti-
cancerous effects noted in patients who have had these
Reduction of Steatosis, Lipid Peroxidation
and Oxidative Stress
Epidemiological studies have shown that both obesity and
diabetes are risk factors for hepatocellular carcinoma.91
These conditions are associated with nonalcoholic fatty
liver disease (NAFLD) which can progress to nonalco-
holic steatohepatitis (NASH), cirrhosis, and hepatocellu-
lar carcinoma. The likely mechanisms of carcinogenesis
include obesity-related steatosis, lipid peroxidation, and
increased oxidative stress.92These can lead to increased
DNA mutations and clonal expansion.93Metabolic
surgery can achieve an improvement or complete resolu-
tion of steatosis, steatohepatitis, and fibrosis in the major-
ity of patients.94These operations demonstrate decreased
oxidative stress74,95and increase antioxidant levels95and
Leptin is a 16kDa product of the adipose obese (ob) gene,
mainly synthesized by fat cells. It acts on the hypothala-
mus to increase energy expenditure and decrease food
intake, although in obese individuals leptin levels are
chronically high. Leptin can stimulate the proliferation of
cancer cells and may contribute to cellular carcinogene-
sis,96whereas a decrease in leptin levels (in the context of
an enriched environment for rodents) is associated with
reduced tumor growth and increased cancer remission.97
Adiponectin is exclusively synthesized from adipose
tissue and demonstrates both anti-inflammatory and anti-
ated with a decreased risk of breast, endometrial, prostate,
colorectal, and kidney cancer, whereas exogenous
administration can inhibit tumor growth and angiogene-
sis in animal models.98Resistin is a 12.5 kDa adipokine
secreted from human macrophages that decreases adipose
and muscle glucose uptake. There is early evidence that
some patients with colorectal and breast cancer demon-
Metabolic operations can beneficially modulate the
release of adipokines involved in tumorigenesis. These
procedures have been associated with a significant
decrease in leptin levels, which have been shown to persist
for up to 2 years after surgery.101These procedures have
also been shown to produce raised levels of adiponectin
for up to a year postoperatively102and decreased resistin
levelsat6 yearsafter surgery.103
Several cancers are associated with altered sex ste-
In postmenopausal women, an
increased incidence of breast cancer is associated with
higher rates of conversion of androgenic precursors to es-
tradiolviaadiposearomatase.This resultsinincreased cel-
lular ligand-dependent transcription by the estrogen
receptor leading to increased cell proliferation and
decreased apoptosis. Increased estradiol levels are also
associated with a raised risk of endometrial cancer via in-
hibition of endometrial cell apoptosis and increased pro-
liferation. Metabolic surgery efficiently decreases the
levels of estradiol and may, therefore, contribute to a
decrease in hormone-associated tumors.15,106Further-
more, the insulin-resistance state of obesity results in
raised insulin levels that subsequently lead to reduced lev-
els of sex-hormone-binding globulin (synthesized in the
liver). This protein has a high affinity for binding sex hor-
mones such as estradiol and testosterone.107Decreased
levels of sex steroids as a result of insulin resistance may,
surgery may decrease these effects by improving insulin
sensitivity and maintaining sex-hormone-binding globu-
There is increasing evidence that some gut hor-
mones contribute to cancer growth and development in
addition to their release in some neuroendocrine tumors.
The appetite-stimulating (orexigenic) hormone ghrelin is
Metabolic Surgery and Cancer/Ashrafian et al
May 1, 2011
primarily released from the stomach and may promote
carcinogenesis and tumor growth through its actions via
its receptor that acts as a growth hormone secretagogue. It
has subsequently been proposed to have a possible role in
the development of neuroendocrine tumors,108gastroin-
testinal tumors109and prostate cancer.110There are a
wide range of studies on metabolic surgery demonstrating
the modulation and decrease of ghrelin levels after sur-
gery,12,111which may contribute to decreased tumor
growth andcarcinogenesis inasubset ofpatients.
Metabolic surgery may also mediate some antican-
cerous effects through altered cellular energetics.61,112
Obesity is a disorder that demonstrates irregular cellular
energetics and signaling pathways. Disruptive cellular
energetics through the cellular AMPK (50adenosine
monophosphate-activated protein kinase) master switch
may ultimately lead to cancer through clonal expansion,
proliferation, and spread via the ‘‘Janus’’ energy effect.113
Metabolic operations can improve energy homeostasis at
the cellular level114,115and demonstrate increased ener-
getic efficiency through decreased levels of mitochondrial
electron transport chain complexes I, II, III and IV and
endocannabinoid downregulation that ameliorate mito-
Metabolic operations are increasingly performed world-
wide as the obesity epidemic advances. In view of their
profound metabolic effects, they are no longer considered
as purely weightloss interventions,116and are increasingly
been considered as ‘‘bionic’’ therapies.118These proce-
dures demonstrate a significant reduction of mortality
and incidence of cancer. The cancer protective role of
metabolic surgery is strongest for female obesity-related
tumors, although the anticancerous activity of surgery
may comprise both weight-dependent and weight-inde-
resistance with attenuation of the metabolic syndrome as
well as decreased oxidative stress and inflammation in
addition to the beneficial modulation of sex-steroids,
gut hormones, cellular energetics, adipokines, and the
immune system. Elucidating the precise metabolic mech-
anisms of cancer prevention by metabolic surgery can
increase our understanding of how obesity, diabetes, and
metabolic syndrome are associated with tumorigenesis
The future of this field relies on increased research
into further clarifying the mechanisms of cancer preven-
tion afterthesesurgeries.This shouldincludetheclarifica-
tion of the role of surgical weight loss on cancer outcomes
and the quantification of currently understood metabolic
effects on subsequent cancer prevention. This will require
further randomized control trials and the application of
validated in vitro and in vivo (animal) models of carcino-
genesis and metabolic surgery. Identifying the anticancer-
ous mechanisms of metabolic surgery include the study of
genomic, genotoxic, transcriptomic, and metabolomic
profiles by using a systems biology approach in addition
to other novel technologies that consider cellular metabo-
lism and energy efficiency. This may ultimately result in
the refinement of metabolic operations to maximize their
anticancerous effects. It may also offer novel treatment
strategies in the management of tumor generation and
CONFLICT OF INTEREST DISCLOSURES
The Wellcome Trust and the NIHR Biomedical Research
Centre Funding Scheme supported this study.
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