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Keywords:

  • metabolic surgery;
  • bariatric surgery;
  • cancer;
  • oncology

Abstract

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

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. Cancer 2011. © 2010 American Cancer Society.

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,1 whereas the overall number of new cancer cases will increase by 300,000 cases per year.2 Both 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 to action.3, 4

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,5 and, therefore, a surgical solution has been developed to provide consistent weight loss in severely obese patients. The operations 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 obese patients.8–10 As a result, these procedures are now considered 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.15 Whereas 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.16 Recently, longitudinal studies on metabolic surgery have revealed that successful weight loss also results in lower cancer rates.7, 17-19 This 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 metabolic surgery.

Epidemiology of Obesity and Cancer

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Although obesity is an ancient disease,21 it was not until 1913 that Frederick L. Hoffman proposed that an “erroneous 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.23 This association, however, was not formally studied in epidemiological studies until 1959 when the American Cancer Society performed a long-term prospective analysis on 750,000 subjects from 26 states.24 Here, the mortality attributable to cancer was higher for individuals 40% above the average weight. To categorize body weight, subsequent studies have applied a classification of obesity based on body mass index (BMI).

The Million Women Study25 in the United Kingdom, which studied more than 1 million female subjects for more than a 5-years with follow-up, revealed a significant association between increased weight and cancer risk, particularly in the postmenopausal group. Several meta-analyses, systematic reviews,26 and 1 collaborative analysis of 900,000adults27 has now confirmed a consistent association 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, gallbladder, colorectal, thyroid, and epidermal (melanoma).

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 recommendations on the opinion of 21 international experts. An association between obesity and cancer was acknowledged, and they recommended “Be as lean as possible within the normal range of body weight.”28 It 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 maintain a normal weight, 900,000 cancer deaths could be prevented.29 The 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.30 Both randomized and prospective studies reveal that the long-term weight loss with intensive lifestyle intervention in diabetic patients with a body mass index of 30 kg/m2 is approximately 2% at 2 years31 and 10 years32 and is even less in patients7 with a body mass index above 35 kg/m2. The significant weight reductions required for the proposed decrease in cancer risk, however, can be consistently achieved in the vast majority of patients who undergo metabolic surgery (Table 1).8, 12

Table 1. Metabolic Surgical Weight Loss Over Time
ProcedureExcess Weight Loss (%)aActual Weight Loss (%)b
 2 Years5 Years7 Years10 Years15 Years
  • 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 = 25 kg/m2.

  • NA indicates not available.

  • a

    Data from systematic review reporting weighted mean results (excluding sleeve gastrectomy.)33

  • b

    Data from prospective study.6, 7

Gastric banding52.755.251.014.013.0
Biliopancreatic diversion with duodenal switch75.173.369.0NANA
Roux-en-Y gastric bypass67.558.255.025.027.0
Sleeve gastrectomy3467.42NANANANA

Metabolic Surgery and the Reduction in Obesity-Related Mortality

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

The adoption of metabolic surgeries has increased over the past half-century so that in 2008, more than 344,000 cases were performed globally.35 They are traditionally subdivided into 3 main groups. Restrictive procedures that decrease stomach size (adjustable gastric banding and sleeve gastrectomy). Pure bypass procedures that “rearrange” gastrointestinal anatomy (duodenojejunal bypass), or combination procedures with elements of both anatomical rearrangement and stomach size restriction (Roux-en-Y gastric bypass—the current gold standard metabolic operation).12 These procedures consist of several physiological steps, the so-called BRAVE10, 11 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. It was initially hypothesized that performing gastric bypass surgery could result in biliary reflux and increased cancer risk.36, 37 The operation was, therefore, modified to include the Roux-en-Y anastomotic technique,38 which has the added advantage of decreasing biliary reflux and preventing subsequent gastric cancer risk.39, 40 The vast majority of procedures are performed laparoscopically41 and demonstrate low postoperative adverse outcomes. A recent multicenter, prospective, observational study42 revealed an overall operative 30-day mortality to be 0.3%.

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/m2 with obesity comorbidities (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 metabolic effects, these procedures31, 43 have been increasingly performed in patients with BMI<35.

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 significantly lower in operated versus unoperated obese patients. Such a decrease, however, does not necessarily achieve a mortality rate comparable to individuals of normal weight,44 although surgery can significantly reduce several obesity-related comorbidities including the resolution of diabetes9 in 78.1% and a decrease17 in diabetes-related death by 92% and coronary-related death by 56%. Several recent studies demonstrate that some of the mortality benefits from surgery are derived from a decreased incidence 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.32 Medical weight loss can reduce diabetes-related mortality in overweight patients by one-third45 and overall mortality in diabetic patients also by one-third,46 whereas 1 observational study of metabolic surgical patients demonstrated a relative risk reduction of overall mortality by 89% when compared with nonsurgical controls.47

Table 2. Comparative Overall Mortality and Cancer Mortality and Incidence Rates Between Obese and Metabolic Surgical Groups
AuthorStudy TypeNo. of Surgery SubjectsMean Follow Up, ySurgical Weight LossOverall MortalityCancer
Surgery Group MortalityNonsurgical Obese MortalityReduction in the Relative Risk of DeathSurgery Group CancerNonsurgical Obese CancerReduction in the Relative Risk of Cancer
  • NIDDM indicates noninsulin-dependent diabetes mellitus; NS, not specified; EWL, excess weight loss (see Table 1.); Retro, retrospective study; Pros, prospective study.

  • a

    Covariate-adjusted figure.

MacDonald48 1997Retro154950% EWL9%28%68%0% Mortality0.6% MortalityNS
Christou47 2004Retro10352.535%0.68%6.17%89%2.03% Incidence8.49% Incidence76% Incidence
Flum49 2004Retro33284.4 medianNS11.8%16.3%27.6%NSNSNS
Adams17 2007Retro99497.1NS2.89%4.41%34.5%0.42% Mortality1.06% Mortality60% Mortality
Adams17 2007Retro79257.1NS2.69%4.05%33.6% (40.0%)a0.39% Mortality0.92% Mortality57.6% Mortality
Sjostrom7 2007Pros201010.9 median13-27%5.0%6.3%20.6%1.4% Mortality2.35% Mortality42.5% Mortality
Peeters50 2007Retro9664.3 median27Kg0.41%10.62%96% (82%)a0.2% MortalityNSNS
Sowemimo51 2007Retro9084.5NS2.9%14.3%79.7% (50%-85%)aNSNSNS
Busetto52 2007Retro8215.637.2% EWL0.97%4.38%77.9% (60%)aNSNSNS
Christou53 2008Retro10352.535%NSNSNS2.03% Medical visits8.49% Medical visits76% Medical visits
Adams18 2009Retro659612.5NSNSNSNS3.85% Incidence; 0.62% Mortality5.05% Incidence; 1.13% Mortality24% Incidence; 46% Mortality
Sjostrom19 2009Pros201010.9 median19.9KgNSNSNS5.8% Incidence8.3% Incidence30% Incidence

Metabolic Surgery and Cancer Reduction

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Metabolic surgery patients have lower cancer rates and lower cancer mortality when compared with obese patients who have not had this surgery (Table 2). Christou et al47, 53 retrospectively 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 corresponded 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 was significantly reduced by 82%.53

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.17 When 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 analyzing cancers according to stage (using Surveillance, Epidemiology, and End Results [SEER]54 staging), 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 detection.18

The SOS (Swedish Obese Subjects) study commenced 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, outnumbered deaths from myocardial infarction or heart failure. Depending on the procedure performed, the surgical patients lost on average 14%-25% of weight and had a 42.5% decrease in cancer mortality.7 This demonstrated a 30% decrease in the incidence of all cancers for metabolic surgical patients, although statistical analysis did not reveal any association in cancer incidence with the amount of weight loss.

These operations have revealed a significant benefit in the reduction of cancer incidence and mortality when stratifying patients by sex (Table 3). McCawley et al retrospectively studied 4977 morbidly obese females, reporting a 38% decrease in the incidence of all cancers defined by the Virginia Cancer Registry.55 This study demonstrated that both obese controls and surgical patients were younger at cancer diagnosis compared with the general population of the Virginia Cancer Registry and that metabolic 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 difference in either mortality or incidence of cancer for men undergoing surgery.18 The 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 corresponds to the decrease in the hormone-sensitive breast53 and endometrial18 cancers after surgery. The beneficial effects of surgery in female and hormone-related tumors may allude to the beneficial association of surgery for sex-steroid–related cancers.

Table 3. Comparative Cancer Incidence and Mortality Rates Between Obese and Metabolic Surgical Groups Stratified by Sex
AuthorStudy TypeFollow Up, ySurgical Weight LossMenWomen
No.Surgery Group CancerNonsurgical Obese CancerReduction in the Relative Risk of CancerNo.Surgery Group CancerNonsurgical Obese CancerReduction in the Relative Risk of Cancer
  • NS indicates not specified.

  • a

    P<.05; incidence specifies the incidence of cancer; mortality specifies mortality from cancer.

Adams18 2009Retro12.5 MeanNS9424.14% Incidence; 1.06% Mortality4.14% Incidence; 1.52% MortalityIncidence; 30% Mortality56543.80% Incidence; 0.55% Mortality5.23% Incidence; 1.05% Mortality27.3% Incidencea; 47.6% Mortalitya
McCawley55 2009Retro16 MaxNSNSNot studiedNot studiedNot studied14823.6% Incidence5.8% Incidence38% Incidencea
Sjostrom19 2009Pros10.9 Median19.9 kg at 10 y5906.4% Incidence6.6% Incidence3% Incidence14475.56% Incidence8.98% Incidence38% Incidencea

A potential bias in these results includes the finding that the bariatric surgery group are sometimes excluded for surgery when they have suffered from active or invasive 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.56 Christou 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.53 Metabolic surgical patients are an ideal group in whom to study the exact effects of weight loss on surgery, although few studies 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 association between weight loss, food intake, and the subsequent development of cancer incidence. The researchers were, however, able to demonstrate that the reduced incidence of cancer in bariatric surgical patients was significantly lower for nondiabetics and for nonsmokers, which may be due to an environment of decreased tumor generation and growth in this subset of patients.

Results from the 2 largest series that studied the association 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.18 Second, the effects of metabolic surgery on decreased cancer mortality is present for all cancers, particularly in obese female patients.18 Third, the extent of weight loss or energy intake was not related to the reduction in cancer incidence.19 The lack of association between weight loss and decreased cancer incidence for surgical patients is unclear and may represent inappropriate regression models.20 The limitations of these studies include their designs, which do not achieve the highest levels of evidence. The majority are comparative retrospective 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 identify cancer-specific outcomes and do not fulfil all criteria 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 surgery may also be more likely to undergo upper-gastrointestinal endoscopy or possibly screening colonoscopy before surgery, and operative candidates may also be more motivated to quit smoking, which could affect outcomes. Other limitations include bias in measuring body mass index, ascertainment bias, secondary treatment biases (such as those for metformin), secondary intervention bias (such as those for hysterectomy), and differential follow-up bias.

Nevertheless, these studies reveal the association between metabolic operations, decreased cancer mortality, decreased cancer incidence, and a cancer-protective effect. This may occur through a through a variety of mechanisms including weight-dependent and weight-independent metabolic pathways.

Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Metabolic surgery offers several protective mechanisms that may lead to decreased cancer incidence, these interrupt several of the pathways associating obesity with tumor generation and growth (Fig. 1).

thumbnail image

Figure 1. Mechanisms of decreased cancer risk by metabolic surgery are depicted. IGF-1 = Insulin-like Growth Factor 1, AMPK = 5′ adenosine monophosphate-activated protein kinase.

Download figure to PowerPoint

Decreased Obesity through Weight loss

The contribution of decreased obesity achieved through surgical weight loss may contribute to a reduction in tumor generation and growth.18-20 When 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.7 In a landmark randomized, unblinded, controlled trial, Dixon et al31 demonstrated 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 diabetes remission.31, 57

The mechanisms for weight loss after metabolic surgery are muiltifactorial11, 12 and include the modulation of gut hormones that lead to alterations in appetite, hunger, dietary feeding behavior, and, more recently, taste modulation in addition to alterations in metabolic rate and resting energy expenditure.11, 58, 59 Although, traditionally, 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 biliopancreatic diversion).11, 60

Surgery does, however, achieve a sustained decrease in caloric intake,61, 62 which has a long-standing association with decreased carcinogenesis in several experimental models that span over a century of research.63, 64 One study has revealed that the Roux-en-Y gastric bypass operation can decrease daily calorie intake by 1479 Kcal/day so that patients only consume 1341 Kcal/day.61 The reduced carcinogenic effect of surgery may, therefore, benefit 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, and cellular proteins including the sirtuins.65

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, 66 These operations may offer some anticancerous effects through increased physical activity as this can decrease mortality and disease progression in tumors including colorectal and breast cancer.67, 68

Anti-inflammatory and Immune effects

There is an established association between inflammation and cancer.69 Obesity 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, 71 Proinflammatory cytokines 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.72 The inflammation of the metabolic syndrome, however, is a subclinical systemic inflammation initiated from adipose tissue. The links between systemic inflammation and cancer risk require further clarification.

Metabolic surgery results in a decrease of both oxidative stress and systemic inflammatory markers including interleukin-6, C-reactive protein (CRP), sialic acid, plasminogen activator inhibitor-1, malondialdehyde, and von Willebrand factor.73-77 Multiple regression analysis reveals that the decrease in postoperative insulin resistance after surgery is independently associated with a decrease in interleukin-6 concentrations.77 At 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.78 This may reveal a role for metabolic surgery in contributing to a cell-mediated cytotoxic immune response against tumor cells79 to achieve surgical anticancerous effects.

Insulin Resistance

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 dyslipidemia, hypertension, and obesity (associated with disordered adipokines, free fatty acids, and inflammation), it is defined as the metabolic syndrome.80 There is now evidence from a few large-scale studies associating metabolic syndrome, insulin resistance with cancer development.

The prospective Risk Factors and Life Expectancy Project (1978-1987) assessing evidence from 9 large epidemiologic studies (N = 62,285) reported an approximately 3-fold increased risk of colorectal cancer mortality for subjects with insulin resistance or associated biochemical abnormalities.81 The 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 = 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).83 In the latter study, the effects on cancer mortality were not associated with body mass index, suggesting a weight-independent mechanism of insulin resistance in cancer mortality.

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 phosphatidylinositol 3-kinase/Akt signaling pathway.85 Furthermore, IGF-1 may stimulate production of adipocyte-derived vascular endothelial growth factor (VEGF), a key factor in tumor angiogenesis.86

Among the most dramatic effects of metabolic surgery are the resolution of insulin resistance, metabolic syndrome, and type II diabetes.10 A 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.9 In metabolic-surgery patients, insulin resistance has typically been measured by the Homeostasis Model Assessment (HOMA-IR) where marked improvements occur within 6 days of surgery.87 This 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.88 Noticeable surgical weight loss, however, can take between 3 months to 1 year to develop.89 Furthermore, 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 with islet hyperplasia) after surgery.10, 90

The mechanisms of diabetes resolution in metabolic-surgery patients consist of the established longer term effects of surgical weight loss,10, 31, 57 as well as 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 inflammation, altered fat and bile metabolism, changes in gut hormone release, metabolic modulation, shifts in gut microbial flora, and intestinal gluconeogenesis.10 The improvement of insulin resistance through these metabolic operations may, therefore, contribute to the anticancerous effects noted in patients who have had these operations.

Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

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 nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The likely mechanisms of carcinogenesis include obesity-related steatosis, lipid peroxidation, and increased oxidative stress.92 These can lead to increased DNA mutations and clonal expansion.93 Metabolic surgery can achieve an improvement or complete resolution of steatosis, steatohepatitis, and fibrosis in the majority of patients.94 These operations demonstrate decreased oxidative stress74, 95 and increase antioxidant levels95 and activity.74

Adipokines

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Leptin is a 16kDa product of the adipose obese (ob) gene, mainly synthesized by fat cells. It acts on the hypothalamus 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 carcinogenesis,96 whereas 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 antidiabetic properties. Low levels of this adipokine are associated with a decreased risk of breast, endometrial, prostate, colorectal, and kidney cancer, whereas exogenous administration can inhibit tumor growth and angiogenesis in animal models.98 Resistin 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 demonstrate raised plasma levels of this adipokine.99, 100

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.101 These procedures have also been shown to produce raised levels of adiponectin for up to a year postoperatively102 and decreased resistin levels at 6 years after surgery.103

Sex steroids

Several cancers are associated with altered sex steroids levels.104, 105 In postmenopausal women, an increased incidence of breast cancer is associated with higher rates of conversion of androgenic precursors to estradiol via adipose aromatase. This results in increased cellular 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 inhibition of endometrial cell apoptosis and increased proliferation. Metabolic surgery efficiently decreases the levels of estradiol and may, therefore, contribute to a decrease in hormone-associated tumors.15, 106 Furthermore, the insulin-resistance state of obesity results in raised insulin levels that subsequently lead to reduced levels of sex-hormone-binding globulin (synthesized in the liver). This protein has a high affinity for binding sex hormones such as estradiol and testosterone.107 Decreased levels of sex steroids as a result of insulin resistance may, therefore, result in increased tumorigenesis, and metabolic surgery may decrease these effects by improving insulin sensitivity and maintaining sex-hormone-binding globulin levels.

Gut Hormones

There is increasing evidence that some gut hormones contribute to cancer growth and development in addition to their release in some neuroendocrine tumors. The appetite-stimulating (orexigenic) hormone ghrelin is 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,108 gastrointestinal tumors109 and prostate cancer.110 There are a wide range of studies on metabolic surgery demonstrating the modulation and decrease of ghrelin levels after surgery,12, 111 which may contribute to decreased tumor growth and carcinogenesis in a subset of patients.

Cellular energetics

Metabolic surgery may also mediate some anticancerous 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 (5′ adenosine 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, 115 and demonstrate increased energetic efficiency through decreased levels of mitochondrial electron transport chain complexes I, II, III and IV and endocannabinoid downregulation that ameliorate mitochondrial electron transport dysfunction.61, 112

Conclusions

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Metabolic operations are increasingly performed worldwide as the obesity epidemic advances. In view of their profound metabolic effects, they are no longer considered as purely weight loss interventions,116 and are increasingly applied to patients of lower body mass indices117 and have been considered as “bionic” therapies.118 These procedures 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-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, adipokines, and the immune system. 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 tumorigenesis and growth.

The future of this field relies on increased research into further clarifying the mechanisms of cancer prevention after these surgeries. This should include the clarification 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 carcinogenesis and metabolic surgery. Identifying the anticancerous 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 metabolism 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 growth.

REFERENCES

  1. Top of page
  2. Abstract
  3. Epidemiology of Obesity and Cancer
  4. Metabolic Surgery and the Reduction in Obesity-Related Mortality
  5. Metabolic Surgery and Cancer Reduction
  6. Mechanisms of Decreased Tumor Generation and Growth After Metabolic Surgery
  7. Reduction of Steatosis, Lipid Peroxidation and Oxidative Stress
  8. Adipokines
  9. Conclusions
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES