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Keywords:

  • obesity;
  • cancer;
  • hormones;
  • growth factors;
  • inflammation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Obesity-related hormones, growth factors, and their signaling pathways
  5. Lessons from calorie restriction research
  6. Obesity and chronic inflammation
  7. Conclusion
  8. Conflicts of interest
  9. References

The prevalence of obesity, an established risk factor for many cancers, has risen steadily for the past several decades in the United States and in many parts of the world. This review synthesizes the evidence on key biological mechanisms underlying the obesity–cancer link, with particular emphasis on the impact of energy balance modulation, such as diet-induced obesity and calorie restriction, on growth factor signaling pathways and inflammatory processes. Particular attention is placed on the proinflammatory environment associated with the obese state, specifically highlighting the involvement of obesity-associated hormones/growth factors in crosstalk between macrophages, adipocytes, and epithelial cells in many cancers. Understanding the contribution of obesity to growth factor signaling and chronic inflammation provides mechanistic targets for disrupting the obesity–cancer link.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Obesity-related hormones, growth factors, and their signaling pathways
  5. Lessons from calorie restriction research
  6. Obesity and chronic inflammation
  7. Conclusion
  8. Conflicts of interest
  9. References

The prevalence of obesity, defined as having a body mass index (BMI) > 30 kg/m2, has increased dramatically in the last three decades in the United States1 and in many parts of the world.2 As waistlines have expanded, so have the rates of several chronic diseases. Obesity is associated with an increased production of metabolic hormones coupled with a chronic low-grade state of inflammation that is linked to various disease states, such as type II diabetes, cardiovascular disease, and certain types of cancer.3 In prospective studies such as the Nurses’ Health Study,4 the Health Professionals Follow-up Study,5 and the Framingham Health Study,6 individuals who gained weight over a 10- to 15-year period had a significantly increased risk of developing type II diabetes and coronary heart disease. The relationship between obesity and cancer was poorly understood until Calle et al.3 conducted a large prospective study examining the role of obesity or excess adiposity in increasing the risk of dying from most types of cancer. Possible mechanisms underlying the link between obesity and cancer will be discussed below, with an emphasis on hormones, growth factor signaling, and inflammation.

Obesity-related hormones, growth factors, and their signaling pathways

  1. Top of page
  2. Abstract
  3. Introduction
  4. Obesity-related hormones, growth factors, and their signaling pathways
  5. Lessons from calorie restriction research
  6. Obesity and chronic inflammation
  7. Conclusion
  8. Conflicts of interest
  9. References

Leptin

Leptin is a peptide hormone produced by adipocytes that is positively correlated with adipose stores and nutritional status.7 Under normal conditions, leptin functions as an energy sensor and signals the brain to reduce appetite. In the obese state, however, there is an overproduction of leptin by the adipose tissue, and the brain no longer responds to the signal. The release of leptin is stimulated by insulin, glucocorticoids, tumor necrosis factor-alpha (TNF-α), and estrogens.7 Leptin has direct effects on peripheral tissues, as well as indirect effects on hypothalamic pathways.7 Leptin also modulates other biological processes including immune function, cytokine production, angiogenesis, and carcinogenesis.8–10 The leptin receptor has similar homology to class I cytokines that signal through the janus kinase and signal transducer activator of transcription (JAK/STAT) pathway that is often dysregulated in cancer.11,12

The findings from epidemiological studies have been inconsistent in regard to the association between leptin and cancer.13–17In vitro studies have shown that leptin has a proliferative effect on human esophageal, breast, and prostate cancers; however, leptin decreased growth of pancreatic cancer cell lines.18 Additionally, Jaffe et al.19 demonstrated that leptin promoted cell motility and invasiveness in human colon cancer cell lines.

Adiponectin

Adiponectin is a hormone mainly secreted from adipocytes in visceral adipose tissue. Unlike leptin, levels of adiponectin are negatively correlated with adiposity. Adiponectin functions to counter the metabolic profile associated with obesity by modulating glucose metabolism, increasing fatty acid oxidation and insulin sensitivity, and decreasing production of inflammatory cytokines associated with obesity.20 Following secretion from the adipocyte, adiponectin undergoes posttranslational modifications to generate globular, low and high molecular weight isoforms that bind to one of two adiponectin receptors, adipo1 and adipo2.21 While both receptors are ubiquitously expressed, adipo1 is found mostly in skeletal muscle and adipo2 is found mostly in the liver.

In addition to its role in metabolism, adiponectin may exert anticancer effects. An inverse relationship between systemic adiponectin concentrations and cancer risk has been observed in colon, prostate, gastric, endometrial, and renal cancers in multiple case-controlled studies.22–25 The potential mechanisms through which adiponectin exerts it anticancer effects include increasing insulin sensitivity, decreasing insulin/insulin-like growth factor (IGF)-1 and mTOR signaling via activation of 5′AMP-activated protein kinase (AMPK), and reducing proinflammatory cytokine expression via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).26

Insulin

Insulin is a peptide hormone produced by the beta cells of the pancreas and released in response to elevated blood glucose. BMI correlates with serum insulin levels, and obesity is linked to the development of insulin resistance, hyperglycemia, hyperinsulinemia, and type II diabetes.27–29 In the obese state, blood glucose levels increase and trigger the pancreas to increase insulin production, resulting in hyperinsulinemia and insulin resistance. The development of insulin resistance is associated with aberrant glucose metabolism, chronic inflammation, and production of other metabolic hormones, such as adiponectin and IGF-1.30–32 Additionally, hyperinsulinemia and type II diabetes increase the risk for colorectal, kidney, breast, endometrial, and pancreatic cancers, independent of obesity.33–38 Insulin promotes cancer development through binding of the insulin receptor and initiating signal transduction in extracellular signal–regulated kinase (ERK) and phosphtidylinositol-3 kinase (PI3K) pathways.39 In contrast to the glucose metabolism effects that occur at physiologic levels of insulin, the mitogenic effect of insulin occurs mainly at supraphysiological levels, and proliferative effects of insulin are believed to take place indirectly through increasing levels of bioavailable IGF-1.39

IGF-1

IGF-1 is a hormone and growth factor produced primarily by the liver following stimulation by signals received from the central nervous system. It plays an important role in regulating growth and development of many tissues, particularly in prenatal growth.40 Similar to insulin, levels of IGF-1 correspond to energy status and are often elevated in obese individuals.41,42 IGF-1 in circulation is typically bound to IGF-binding proteins (IGFBPs), which function to regulate free IGF-1 levels, controlling the availability of IGF-1 to bind to its receptor.41 Insulin can influence IGF-1 synthesis and reduce IGFBPs, thereby increasing the amount of bioavailable IGF-1 that interacts with the IGF-1 receptor (IGF-1R). Binding of IGF-1 to its receptor activates downstream signaling pathways such as ERK and PI3K, modulating transcription factors that control gene expression related to cancer development.

The role of IGF-1 as a risk factor for cancer has been established in many cancer types.11,43–46 Experimentally, transactivation of the IGF-1 receptor and leptin receptor was demonstrated in human breast cancer cells.47 The synergistic effects of IGF-1 and leptin receptor activation on breast cancer cell proliferation suggest that obesity is likely promoting cancer development through multiple metabolic hormones and pathways.47 Additionally, tumor volume and multiplicity were decreased in IGF-1–deficient mouse models of colon48 and pancreatic cancer (Lashinger et al., personal communication) compared to wild-type mice.

Lessons from calorie restriction research

  1. Top of page
  2. Abstract
  3. Introduction
  4. Obesity-related hormones, growth factors, and their signaling pathways
  5. Lessons from calorie restriction research
  6. Obesity and chronic inflammation
  7. Conclusion
  8. Conflicts of interest
  9. References

Calorie restriction (CR), a dietary regimen involving a reduction in total energy (typically 20–40%), is an effective way to increase life span of mammals and inhibit carcinogenesis.49 Among many activities, CR has been shown to modulate the hormones discussed above, as well as to increase antioxidant defense mechanisms, increase DNA repair processes, and decrease expression and production of inflammatory cytokines.50 Energy balance modulation, ranging from CR to diet-induced obesity regimens, impacts circulating levels of IGF-1, insulin, adiponectin, and leptin, all of which function as a network of messengers to regulate metabolism and inflammation and are intimately involved with several aspects of tumor development, as discussed above. Given how difficult it is for many people to adopt a low-calorie diet for an extended period, the identification of drugs or natural products that could either complement or even reproduce the anticancer effects of CR without drastic changes in diet and lifestyle is a goal for many investigators and pharmaceutical companies. Thus far, promising data have emerged for mTOR inhibitors, such as rapamycin and metformin, or sirtuin modulators, such as resveratrol, as CR mimetics.49

Obesity and chronic inflammation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Obesity-related hormones, growth factors, and their signaling pathways
  5. Lessons from calorie restriction research
  6. Obesity and chronic inflammation
  7. Conclusion
  8. Conflicts of interest
  9. References

Adipocytes, macrophages, and inflammatory cytokines

Obesity is associated with a chronic low-grade state of inflammation that is attributed to increased fatty acids, inflammatory cytokine production, and an influx of immune cells, such as macrophages, that also produce inflammatory mediators. Adipocytes can transdifferentiate into macrophages in vivo, highlighting the role of adipose tissue as an immune organ in addition to an energy storage depot.51 Adipocytes can enlarge past the point of effective oxygen diffusion, which results in hypoxia, inflammation, and increased macrophage infiltration. Enlarged adipocytes produce more inflammatory cytokines and exhibit greater insulin resistance than smaller adipocytes. Furthermore, adipocytes have a limited amount of storage capacity, and when exceeded and in the context of excess lipids, there are increases in circulating free fatty acids that deposit in other tissues and result in diabetes, hypertension, and fatty liver disease.52 Adipose tissue can be classified as subcutaneous and visceral adipose tissue, the latter being more predictive of obesity-related comorbities and mortality.53 Visceral adipose tissue also exhibits increased insulin resistance, lipolysis, and inflammatory cytokine expression relative to subcutaneous adipose tissue. Visceral adipose tissue is in close proximity to the portal vein; this proximity allows drainage of excess free fatty acids and inflammatory mediators directly to the liver, which in turn creates additional inflammation and affecting metabolism.52

In addition to adipokine hormones such as leptin and adiponectin, adipose tissue produces inflammatory cytokines such as TNF-α, interleukin (IL)-6, IL-1β, and monocyte chemoattractant protein (MCP)-1. In acute inflammatory conditions, these mediators are present for short periods of time, typically in response to bacterial or viral stimuli. It is through a negative feedback loop initiated by the production of antiinflammatory cytokines that proinflammatory cytokine levels return back to normal. Obesity is associated with a chronic state of inflammation because a major source of inflammatory mediators is the expanding adipose tissue. Furthermore, as a result of the inflammatory environment present in adipose tissue, macrophages are recruited to the site and in turn produce additional proinflammatory mediators. Adipose-derived macrophages are more prevalent in obese individuals and correlate with BMI. Subbaramaiah et al. showed that fatty acids released from adipocytes are able to stimulate release of TNF-α, IL-1β, and the inflammatory inducible enzyme, cyclooxygenase (COX)-2, from a human monocyte–derived cell line, further demonstrating the underlying complexity of diverse cell types and their crosstalk present in adipose tissue.54

In addition to its role in inflammation, TNF-α contributes to insulin resistance through downregulation of insulin receptors and glucose transporters. Recently, IL-6 has been shown to contribute to systemic insulin resistance.55 In addition, plasma IL-6 levels are higher in the portal vein than in peripheral artery blood in obese individuals, suggesting that inflammatory cytokines are elevated in visceral fat compared to subcutaneous fat.56 Fenton et al.57 demonstrated that IL-6 induced proliferation of preneoplastic colon epithelial cells, leptin increased cell proliferation via an IL-6–dependent mechanism, and leptin increased IL-6 secretion from preneoplastic colon cells in a time- and dose-dependent manner. These findings suggest a link between adipose-derived hormones and inflammatory cytokines in cancer development.

Inflammatory signaling regulated by NF-κB

NF-κB is a transcription factor that is activated in response to bacterial and viral stimuli, growth factors, and inflammatory molecules, such as TNF-α, IL-6, and IL-1β. In addition, NF-κB is responsible for inducing gene expression associated with cell proliferation, apoptosis, inflammation, metastasis, and angiogenesis. The NF-κB complex is made up of five subunits (Rel A/p65, c-Rel, Rel-B, p105/p50, and p100/p52) that have the ability to form multiple homo- and/or heterodimers depending on the stimulus. NF-κB typically remains sequestered in the cytoplasm, but upon activation by upstream activators IκB kinase α and β (IKK-α and IKK-β), the inhibitor of kappa B-α (IκB-α) is degraded, allowing NF-κB to translocate to the nucleus and initiate gene transcription.58 Activation of NF-κB is associated with insulin resistance and is upregulated in many types of cancers.39

Metabolic hormones, such as leptin, insulin, and IGF-1, have also been shown to modulate NF-κB signaling when their systemic levels are altered in response to energy balance modulation. Once bound to their cognate receptor, IGF-1, insulin, and leptin activate Akt, which is an established upstream kinase of the IKK complex. Subsequently, the activated IKK complex targets IκB-α for degradation and allows the p50/p65 subunits to translocate to the nucleus and initiate gene transcription. Leptin-stimulated activation of NF-κB has been demonstrated in vitro in human preneoplastic and neoplastic colonic epithelial cells.57,59 Insulin has been shown to activate NF-κB signaling in vitro and in vivo in HEK293 kidney cells and in aged kidneys harvested from overweight rats; furthermore, this activation was attenuated in rats administered a 40% CR diet.60 Mitsiades and colleagues61 showed that IGF-1 increased NF-κB DNA binding activity comparable to that of TNF-α, and induced expression of FLIP, XIAP, cIAP-2, Al/Bfl-1, and survivin, all downstream genes mediated by NF-κB.61

Inflammation and cancer

The link between chronic inflammation and cancer development was first noticed over 100 years ago by Rudolph Virchow when he observed an abundance of leukocytes in neoplastic tissue.62 Since then, the role of chronic inflammation as a precursor to cancer development has been observed in multiple cancer types, some of which include gastritis and gastric cancer, inflammatory bowel disease (IBD) and colon cancer, and pancreatitis and pancreatic cancer.63,64 In various mouse models of human cancers, inflammation has also been shown to influence tumor promotion and progression.65–67

Like adipose tissue, tumor microenvironments are composed of multiple cell types including epithelial cells, fibroblasts, mast cells, and cells of the innate and adaptive immune system that favor a proinflammatory, protumorigenic environment.68–70 Furthermore, tumor cells as well as stromal cells increase expression of COX-2 in neoplastic tissues. COX-2 is considered an indicator of poor prognosis in multiple cancer types,71 and population-based studies have shown that long-term use of nonsteroidal anti-inflammatories (NSAIDS) and COX-2 inhibitors decreases colon cancer risk by 50%, gastric and esophageal cancer risk by 40%, and breast cancer risk by 20%.72 TNF-α is produced by tumor cells and stromal cells and is believed to enhance tumor development through NF-κB–induced gene transcription.73 TNF-α has been linked to the development of skin, liver, and colon cancer, and treatment with a TNA-α antagonist during the promotion stage inhibited the progression of hepatocellular carcinoma.73 IL-6 promotes cell growth, inhibits apoptosis, and is associated with the development of Kaposi sarcoma, multiple myeloma, and Hodgkin's lymphoma. In addition, high circulating levels of IL-6 are correlated with IBD and risk for colon carcinogenesis.74

Contributing to the proinflammatory tumor environment is the presence of tumor-associated macrophages (TAMs). The recruitment of TAMs to the tumor microenvironment is largely dependent on the MCP-1. Levels of MCP-1 in tumor tissue are highly correlated with the accumulation of TAMs in ovarian, breast, and pancreatic cancer.75 TAMs are capable of polarizing into what is known as an M1, a classically activated cytotoxic macrophage, or an M2, an immunosuppressive macrophage. The cytokines produced by each type of macrophage are what distinguish an M1 from an M2, and tumor tissue typically contains a larger quantity of M2 type macrophages.75 In addition to producing cytokines and chemokines, TAMs also produce growth factors that enhance proliferation, angiogenesis, and contribute to deposition and dissolution of connctive tissue.76 There is also some evidence to suggest that NF-κB plays a role in mediating TAM transcriptional programs and by extension, protumorigenic effects of TAMs.76–78

Targeting inflammation for cancer prevention

Current approaches to inhibit inflammation center on targeting various intermediates of the NF-κB pathway and sensitizing tumors to chemotherapeutic agents. NSAIDS such as aspirin have been studied extensively for their ability to modulate NF-κB activity. Prolonged treatment of colon cancer cells with aspirin has been shown to inhibit translocation of NF-κB to the nucleus resulting in apoptosis.79 Experimentally, the use of COX-2 inhibitors has proven to be effective at preventing pancreatic lesions in a transgenic mouse model of pancreatitis and pancreatic dysplasia,80 as well as inhibiting growth and promoting apoptosis in pancreatic cancer cells.81 However, results from human studies suggest combining COX-2 inhibitors with the standard chemotherapeutic drugs Gemcitabine or Cisplatin does not increase the therapeutic response relative to the chemotehrapeutic drugs used alone.82 Sulindac (another NSAID) has been shown to decrease colon cancer cell proliferation, and sulindac combined with parthenolide has been demonstrated to inhibit NF-κB and pancreatic cancer cell growth.83,84

The proteasome inhibitor, PS-341, more commonly known as Bortezomib, is currently approved for clinical use in the treatment of mantle cell lymphoma and multiple myeloma through increased stabilization of the IκBα subunit and decreased NF-κB activity. It has been shown to facilitate growth arrest and apoptosis in lung cancer cells and has been shown to increase effectiveness of chemotherapy drugs in patients with multiple myeloma.85 In addition to pharmacological inhibitors, dietary components have also been studied for their ability to inhibit inflammation. Curcumin is a spice often used in Asia that has potent antioxidant, antiinflammatory, and anticancer effects.86 Multiple studies have shown in vitro and in vivo that curcumin inhibits NF-κB signaling in various cell types. In genetically obese mice, curcumin was shown to prevent macrophage accumulation in adipose tissue in addition to inhibiting NF-κB activation in the liver.87 Experimentally, curcumin has been shown to decrease cancer proliferation in breast.88 and pancreatic cancer cells, as well as to decrease DNA binding of NF-κB, reduce COX-2 protein levels, and inhibit PGE2 production in multiple pancreatic cancer cell lines.89 In mouse models, curcumin has been shown to inhibit cancers of the skin,90 breast,91 liver,92 and colon.60 Curcumin inhibits TNF-α–induced phosphorylation and degradation of the IκBα subunit and also prevents hydrogen peroxide–mediated activation of NF-κB activation.93 Curcumin can also suppress steady-state signaling through the mTOR pathway in multiple tissues, which, as discussed above, likely contributes to the anticancer effects of cucumin. The main obstacles that prevent broader use of curcumin as a therapeutic or preventive agent are its low water solubility and limited bioavailability.94

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Obesity-related hormones, growth factors, and their signaling pathways
  5. Lessons from calorie restriction research
  6. Obesity and chronic inflammation
  7. Conclusion
  8. Conflicts of interest
  9. References

Multiple signals associated with the obese state contribute to inflammatory and growth factor signaling, and components of these interacting pathways represent promising targets for breaking the obesity–cancer link.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Obesity-related hormones, growth factors, and their signaling pathways
  5. Lessons from calorie restriction research
  6. Obesity and chronic inflammation
  7. Conclusion
  8. Conflicts of interest
  9. References