Obesity, Type-2 Diabetes and Cancer:Mechanistic Insights

Abstract

Obesity leads to many diseases including hypercholesterolemia, type-2 diabetes, hypertension, cardiovascular disease, and cancer. It is the fastest-growing lethal disease in the Western and developing countries. The link between obesity and cancer is relatively underappreciated among the general population. Obesity represents the number one risk factor for type-2 diabetes and a considerable body of epidemiological studies supports the relationship between type-2 diabetes and many cancers. In this review, we examine the obesity-type-2-diabetes–cancer relationships from a mechanistic perspective, and where appropriate, we highlight potential pharmaceutical and dietary interventions.

I. INTRODUCTION

The notion that diet affects health has been known for more than 100 years. In 1825, Jean Anthelme Brillat-Savarin wrote, in Physiologie du Gout, ou Meditations de Gastronomie Transcendante: “Dis-moi ce que tu manges, je te dirai ce que tu es,” or “Tell me what you eat and I will tell you what you are.”¹ The German philosopher and anthropologist Ludwig Andreas von Feuerbach, in an essay titled Concerning Spiritualism and Materialism, wrote: “Der Mensch ist, was er iβt”: man is what he eats.^2,3 These phrases promote the notion that to be fit and healthy, you need to have a good diet.

According to the World Health Organization (WHO), prevalence of obesity across the globe has approximately doubled since 1980. In the United States, approximately one-third of the adult population is obese and an additional one-third is overweight.⁴ Obesity is the fastest growing lethal disease in the Western and developing countries. People do not die from obesity itself but from its complications, which shorten the lifespan.^5,6 Obesity leads to many other diseases including hypercholesterolemia, type-2 diabetes (T2D) and its complication, hypertension, cardiovascular disease, and cancer. The link between obesity and cancer is relatively underappreciated among the general population. As many as 20% of all cancers are due to obesity.^7,8 In the United States in 2014, overweight and obesity were estimated to cause 40% of all cancers,⁹ including cancers of the esophagus, colon, liver, pancreas, gallbladder, breast (postmenopausal), ovary, thyroid, prostate, multiple myeloma, kidney, and many others.¹⁰ It is very unlikely that a single mechanism would be at the forefront of all obesity-related cancers. Although the mechanisms linking increased adiposity to malignancy remain incompletely understood, growing evidence suggests that complex interactions between multiple pathways regulating steroid hormone synthesis, insulin resistance, insulin-like growth factor, adipokine and cytokine production, the immune responses, the gastrointestinal (GI) microbiota, and chronic local and systemic inflammation may collectively explain the link between overweight/obesity and carcinogenesis.^5,11 In this review, we examine the obesity-type-2-diabetes-cancer relationships from a mechanistic perspective and where appropriate we will highlight potential pharmaceutical and dietary interventions.

II. BODY MASS INDEX AND WHAT DOES IT MEAN?

Currently, the distinction between being overweight and obese is determined by the body mass index (BMI), which is calculated by weight in kilograms divided by height in meters squared.¹² BMI is used in assessing obesity, which could potentially be due to its ease of calculation and minimal cost. BMI is divided into four different categories: underweight, normal, overweight, and obese, with BMIs of < 18.5, 18.5–24.9, 25.0–29.9, and ≤ 30, respectively.¹³ An individual with an ‘obese’ BMI (≤ 30 kg/m²) is at a higher risk of developing cancer than an individual with a BMI of < 25 kg/m².¹² On a global scale, 1.4 billion adults meet the requirement for being overweight and nearly 500 million adults meet the requirement for being obese.¹⁴

BMI as a means in determining obesity in adults is extremely limiting and flawed.¹⁵ A better way to assess obesity and fat deposits in adults would be to use visceral adipose tissue (VAT) and computed tomography (CT).¹⁶ Another suggestion is to use waist circumference ratios to determine obesity, such as that in the waist-to-hip ratio and waist-to-height ratio.¹² Visceral fat is more strongly associated with adenocarcinoma in men than when using BMI alone.¹³ The location of the fat in the body of the individual plays a definitive role in the link between cancer mortality and obesity.¹⁷ A positive association was found between cancer mortality and obesity, specifically in the abdominal region.¹⁶ Colon, premenopausal breast, endometrium, and esophageal adenocarcinoma cancers have been associated with abdominal adiposity rather than with BMI alone.¹⁷

III. ADIPOSE TISSUE INFLAMMATION AND WAT VS. BAT

Adipose tissue inflammation is paramount in the promotion of cancer microenvironment and tumor progression.¹⁵ The inflammation sites closely resemble the microenvironment of a healing wound, promoting the production of proinflammatory mediators.^15,18 There are two main types of adipose tissue, visceral and subcutaneous, with visceral adipocytes being more metabolically active.¹⁹

White adipose tissue (WAT) is a type of subcutaneous adipose tissue that stores energy and excess fat.²⁰ In healthy individuals, WAT can comprise approximately a quarter of body mass^21,22 and is a major physiological fuel source. In normal-weight individuals, the adipose tissue microenvironment (ATME) is anti-inflammatory in nature²³ with resident macrophages that tend to be M2-polarized.²⁴ These macrophages are triggered by Th2 cytokines and are associated with tissue remodeling and immunosuppression. On the other hand, it has been suggested that M1-polarized macrophages, which are pro-inflammatory, are active in the inflamed obese adipose tissue.²⁵ These macrophages secrete proinflammatory mediators such as PGE₂, IL-1β, IL-6, and TNF-α.²⁴

All available data strongly suggest that assessing WAT inflammation status is important in determining whether a patient may be at risk of developing cancer.¹⁵ Thus, developing new interventions that reduce WAT has given rise to a new strategy to prevent and treat cancer in obese patients.¹⁵ Figure 1 visually depicts the flow of WAT inflammation as discussed by Iyengar et al.¹⁵ Adipose tissue outgrows its blood vessels, which leads to hypoxia, adipocyte stress, and death may occur.²⁶ This increases levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), which is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages.²⁷ MCP-1 stimulates proliferation of macrophages within adipose tissue,²⁸ which then leads to formation crown-like structures (CLS), which are essentially dead or dying adipocytes.²⁹ The macrophages that form CLS engage in phagocytosis of the dead or dying adipocyte and become lipid loaded, forming foam cells.³⁰ Free fatty acids (FFAs) are then released from the adipocyte and from other sources, which can activate toll-like receptor (TLR) 4 on the macrophage plasma membrane, leading to increased NF-κB-dependent expression of proinflammatory genes, including TNF-α, IL-1β, and COX-2.³¹ Lipolysis and release of FFAs are further stimulated by TNF-α and other cytokines, thereby sustaining WAT inflammation.¹⁵ This mechanism is consistent with elevated levels of proinflammatory mediators that are found within CLS in visceral fat.¹⁵

FIG. 1:

Process of white adipose tissue (WAT) inflammation as described in Iyengar et al.¹⁵

Brown adipose tissue (BAT) is a form of adipose tissue located predominantly in the cervical area that contains cells equipped with large numbers of mitochondria and the unique protein, uncoupling protein1 (UCP1).^20,32 BAT in newborn humans helps regulate energy expenditure by thermogenesis, but BAT in adult humans has been considered to have no physiologic relevance.³³ Research has shown that BAT of adult and geriatric humans is inversely correlated with BMI, suggesting that BAT may potentially play a role in the adult human metabolic systems.³³ Notably, WAT can convert to metabolically active fat (BAT) through the process of browning.²² However, the association between BAT activation with cancer progression is not well established.

IV. OBESITY AND CANCER

Excess weight is associated with an increased risk of multiple types of cancer. Almost 50% of cancers in postmenopausal women can be attributed to obesity.¹⁷ Obesity and overweight may increase the likelihood of dying from cancer.³⁴ Abdominal obesity has been shown to increase the risk of cancer mortality by 24%.³⁵ Here, we briefly highlight some of the cancers that are directly linked to obesity.

A. Breast Cancer

Obesity, defined by a BMI of ≥ 30 kg/m², has been associated with an increased risk of estrogen-dependent breast cancer, specifically in postmenopausal women.³⁶ Alternatively, obesity is associated with reduced breast cancer incidence in premenopausal women and is linked to the recurrence of breast cancer in both post- and premenopausal women.¹⁶ Obesity may be a risk factor for bala-like breast cancer regardless of menopausal status.¹⁶ In particular, it has been examined that the abundance of abdominal fat increases the risk for postmenopausal breast cancer.⁸ One study exemplified the link between obesity, inflammation, and aromatase in the mammary gland and visceral fat of mice.³⁷ Necrotic adipocytes were observed in the mammary gland and visceral fat of mice, which formed crown-like structures.³⁷ These crown-like structures are associated with proinflammatory mediators, such as TNF-α, IL-1β, COX-2, and were paralleled by elevated levels of aromatase expression and activity.^15,37 Inflammation of white adipose tissue detected by the presence of CLS may be a biomarker for increased risk of cancer.³⁷

B. Colorectal Cancer

Colorectal cancer (CRC) is one of the most common gastrointestinal malignant tumors in the world,¹² and it has the highest incidence and mortality among gasterointestinal cancers. This particular cancer also has one of the highest rates of mortality and morbidity worldwide. CRC has been associated with the consumption of red and processed meat.¹² After a CRC diagnosis, the consumption of carbohydrates in excess and high-sugar content beverages may increase the risk of recurrence and mortality.¹² Excess weight in teenagers is linked with a 200% increase of colon cancer in adulthood.³⁴ In the European Union, keeping a healthy weight was shown to reduce the annual incidence of CRC by up to 21,000 and the annual incidence of breast cancer by up to 13,000 in individuals.¹⁷ An increased risk of 60% for CRC has also been reported in men whose weight increased by more than 21 kg after reaching adulthood compared to those whose weight increased by only 1–5 kg.¹⁷ The correlation between relative risk of CRC in association with BMI is different in men and women. For men, the correlation is very good; however, in women, the relationship between BMI and the risk of CRC is complicated by the difference in fat distribution.^5,7 A better yardstick would be to use waist circumference and waste–hip ratios.³⁸ The mechanisms involved between obesity and CRC are likely to involve insulin and IGF-1 signaling, adipokines, and inflammation, all of which are discussed below.

C. Prostate Cancer

A large number of meta-analyses have indicated that obesity is associated with prostate cancer incidence.^7,39-41 Prostate cancer and obesity also have a geographic component.⁷ Prostate-specific antigen (PSA) levels are lower in obese men⁴²; thus, there is a lower likelihood of a PSA-driven biopsy. This is an important issue when comparing data from US studies, where PSA screening is prevalent, to data from other parts of the world, where PSA screening is less common.⁷ Notably, in the United States, prostate biopsies are guided by PSA screenings and because obese men have lower PSA levels, there is a reduced chance of undergoing biopsy compared to normal-weight men, lowering the detection rate of prostate cancer in obese men.¹⁶

Cytokines, such as IL-6, that are generated in inflamed WAT are known to activate the androgen receptor and promote cancer cell survival and proliferation in the prostate.¹⁵ Although only limited data are available, the increase in prevalence of prostate cancer is thought to be connected to lifestyle changes such as physical inactivity and higher intake of dietary fat and meat.⁴³ An increased risk of high-grade, aggressive prostate cancer is also thought to be associated with high BMIs.⁴⁴

D. Pancreatic Cancer

Obesity and pancreatic cancer (PC) are strongly associated. For example, there is a higher relative risk for PC for individuals whose BMI falls within the obese range (≥ 30), compared to those that are within of a healthy zone (< 25 )⁴⁴; this applies to both men and women.^45,46 In the US where there are a significant number of overweight adults, there is a two-fold increased risk of developing PC and mortality.^47,48 The underlying cause appears to be due to inflammation that is caused by excess triglycerides leading to an increase in adipocyte number and size, which leads to hypoxia as a result of devascularization, and macrophage infiltration.²⁰ This leads to local secretion of adiponectin, leptin, TNF-α, interleukins, and monocyte chemoattractant proteins^47,49; all of which are discussed further in other sections below.

E. Esophageal Cancer

In the United States, the incidence of esophageal adenocarcinoma has significantly increased over the past few decades, which may in part be due to the increasing weight trends.¹³ Association between esophageal adenocarcinoma and individuals with a BMI ≥ 30 kg/m² has been reported, and the risk increases as BMI increases.^50,51 Many studies have identified obesity as a risk factor for esophageal squamous cell carcinoma and adenocarcinoma (EAC) in men and women.⁵² Obese patients have a higher prevalence of gastroesophageal reflux disease, which can lead to Barrett’s esophagus (BE) and intestinal metaplasia, which are precursors to EAC.^5,53,54 A good correlation has been shown between abdominal fat/obesity and BE.⁵⁵ Notably, obesity early in life increases the risk of EAC.^5,56

F. Liver Cancer

Obesity has been recognized as a major independent risk factor for liver cancer, which has a 5-year survival rate of just 4%–8%.⁵⁷ As fat accumulates, leading to liver dysfunction, the liver synthesizes more triglycerides, but it does not transport them out, which leads to the development of fatty liver disease, defined as triglyceride content > 5% of the organ’s weight.^57,58 Fatty liver disease leads to the dysfunction of adipose tissue and creates a proinflammatory milieu and production of cytokines,⁵⁸ which makes the liver more susceptible to tumor formation and tumor growth.

V. OBESITY AND MOLECULAR TARGETS IN CANCER

Many factors appear to be important in linking obesity and cancer. However, three main factors are linked to endocrine and paracrine dysregulation of adipose tissue in obesity, which are considered to be the hallmarks: the insulin–IGF-1 axis, steroid hormones, and adipocyte-derived cytokines.^59,60

A. Insulin and IGF-1 Signaling

Insulin is an anabolic hormone secreted by the pancreatic β-cells; it is intimately involved in regulating carbohydrate, fat, and protein metabolisms. Its anabolic actions in the muscle, adipose tissue, and liver increase tissue mass, regulate glucose uptake, and synthesize nutrients. These anabolic effects are not directly related to carcinogenesis.⁵ In fact, in alloxan-induced diabetes, rats treated with the mammary tumor inducing carcinogen, 7,12-dimethylbenz(a)anthracene were completely free of tumors.^5,61 Moreover, induction of alloxan diabetes in tumor-bearing rats produced the rapid regression of 90% of the tumors.⁶¹ These data show that tumors that are insulin dependent have a stringent requirement for insulin to grow. Generally, obese patients have hyperinsulinemia independently of T2D, potentially as a result of higher energy needs.⁵ In a study of 695 middle-aged, nondiabetic, and normoinsulinemic men, those with a BMI of ≥ 26.7 kg/m² had a 6.6-fold increased risk of developing hyperinsulinemia, compared with men with body mass index of < 24.4 kg/m².⁶² In hyperglycemia, the availability of nutrients is plentiful, and cancer cells metabolize glucose via the Warburg effect, which is a metabolic shift in ATP generation from oxidative phosphorylation to glycolysis, which means that cancer cells can produce energy through high rates of glycolysis.⁵⁹

All available epidemiological data indicate a strong connection between T2D and certain cancers. The molecular basis for this association could involve the insulin-like growth factor 1 (IGF-1) signaling which is mitogenic under conditions of hyperglycemia and/or hyperinsulinemia, independently of the metabolic features of T2D.⁵

IGF-1, also called somatomedin C, is a hormone similar to insulin in its molecular structure⁶³ that has an important role in childhood growth and anabolic effects in adults. IGF-1 is transported in blood by insulin-like growth factor-binding protein-1 (IGFBP)-1. Insulin is exclusively produced and secreted by pancreatic β cells, whereas IGF-1 is mainly produced in the liver. Insulin binds to the insulin receptor (IR) and IGF-1 binds to the IGF-1 receptor (IGF-1R). IGF-1 signaling pathway is involved in promotion of cell growth and inhibition of apoptosis. These oncogenic properties are mediated through the signal transduction crosstalk between two IGF-R-activated pathways: Ras/Raf/MEK/ERK/MAPK (Ras pathway) and PI3K/AKT (AKT pathway). The Ras and AKT pathways have been shown to upregulate key cell-cycle checkpoint proteins.⁶⁴ Obesity can contribute to carcinogenesis by activating the insulin-IGF-1 pathway. Overweight individuals have elevated circulating levels of IGF-1,⁶⁵ and low serum levels of IGFBP-1, which could confer increased susceptibility to cancer development.^63,66,67 Notably, IGFBP has six iso-forms, and IGFBP-3 is the most abundant in humans.^5,59 Blocking the IGF-1R can inhibit the cellular actions of IGF-1. The antibody CP-751781 (Figitumumab), which blocks IGF-1R, was tested in a phase 1 dose-escalation study of 6 patients with CRC with acceptable tolerability, expected side effects of hyperglycemia, and preliminary evidence of efficacy.^68,69 In another phase 1 clinical trial assessing the safety and tolerability of dacomitinib-figitumumab combination therapy in patients with advanced solid tumors, the combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug with some indications in efficacy.⁷⁰ However, a number of studies have indicated that IGF-1R monoantibodies had no significant value in cancer treatment.^71-74 Three sets of data from the following relatively recent clinical trials (NCT00372996, 2015; NCT00887159, 2015; NCT00684983, 2016) have also indicated the insignificant cancer curative value of anti–IGF-1R agents.⁷⁵

B. Steroid Hormones

1. Estrogen

Hormonally driven cancers are increasing among postmenopausal women.¹¹ Increasing BMI and obesity are pivotal risk factors for the development of postmenopausal hormone receptor-positive breast cancer and for endometrial cancer.^76,77 In premenopausal women, the ovaries are the main organs responsible for estrogen production. However, in postmenopausal women, estrogen is produced locally within the adipose tissues and skin.⁷⁸ Peripheral conversion of androgens to estrogens is catalyzed by the enzyme cytochrome P450 aromatase, which is encoded by the CYP19 gene.⁷⁹ The rate of conversion of androgens to estrogens is elevated in postmenopausal women and with increasing BMI.^80,81 In obesity, aromatase gene expression can also be regulated by other factors such as cytokines, prostaglandins, and hormones. For example, PGE2 is elevated in obesity, and it promotes the expression of aromatase in breast adipose tissues.⁸² Furthermore, multiple other interactive signaling pathways involving estrogen, and its receptors, insulin and IGF-1, and adipokines are also implicated in breast carcinogenesis.¹¹

Inhibiting the enzymatic activity of aromatase to reduce estrogen production is an effective therapeutic strategy for management of estrogen receptor-positive breast cancer. A number of these agents are in clinical trials.^83-85

2. Androgens

In prostate cancer cell lines, inflammatory cytokine such as IL-6 and IGF-1 have been shown to modulate the androgen receptor (AR) signaling.⁸⁶ Also, IL-6 and other proinflammatory cytokines generated in inflamed WAT can activate the AR and promote cancer cell survival and proliferation in the prostate.¹⁵ Selective androgen receptor modulators (SARMs) have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, benign prostatic hyperplasia (BPH), hypogonadism, as well as breast and prostate cancers.⁸⁷

C. Adipocyte-Derived Cytokines

Adipokines are produced mainly by WAT, preadipocytes, and mature adipocytes. Adipokines such as leptin and adiponectin have a significant role in many cancers, including that of breast, colon, pancreas, and HCC. Adipokines are bioactive proteins that are synthesized and secreted from the adipose tissue. They have an important role in lipid metabolism, insulin sensitivity, inflammation, angiogenesis, and cell proliferation.^11,88,89 Metabolic homeostasis and the balance between cell proliferation and apoptosis are regulated in part by adipokines.¹¹ In obesity, adipokines are deregulated, which ultimately may lead to cancer progression and metastasis.⁹⁰

1. Leptin

Leptin is a 16 kD hormone that was first identified in adipocytes in 1994.^91,92 It is primarily known for its role in the mammalian central nervous system, where it regulates food intake.⁵⁹ Factors that alter leptin production and action include insulin, estrogen, and inflammatory mediators such as IL-1β, IL-6, and TNF-α.⁹³ Lipopolysaccharides (LPS) (membrane components of gram-negative bacteria) also increase leptin expression in WAT.⁹⁴ The actions of leptin in human cancer cell lines can be quite pleotropic. In a human colon-cancer cell line (HCT-116), leptin increased cell proliferation by activating the PI3K–AKT pathway; this effect was blocked by LY294002, a PI3K inhibitor.⁹⁵ Cell proliferation of colon cancer cells (HT-29) was also shown to be mediated through the Jak2–STAT3-activating capacity of leptin.⁹⁶ The proliferative and antiapoptotic effects of leptin were reduced by AG490, an inhibitor of JAK2, with LY294002, a phosphatidylinositol 3′-kinase (PI3 kinase) inhibitor, and by SP600125, a c-Jun NH₂-terminal kinase (JNK) inhibitor.⁹⁶ In vivo studies with Lep^ob/ob mice have shown less tumor formation when challenged with the carcinogen azoxymethane (AOM), suggesting a role for leptin in stimulating initiation of colon cancer.⁹⁷ The role of leptin in human colon cancer is quite controversial. Studies have shown that men with colorectal adenomas had elevated circulating leptin levels⁹⁸; other studies have indicated no correlation between leptin levels and increased in CRC when BMI and waist circumference were taken into account.⁹⁹

Elevated circulating levels of leptin have also been observed in women with breast cancer^100-102 and in some cases this has correlated with poorer prognosis.¹⁰³ Leptin was shown to increase proliferation of breast cancer cell lines by activating the JAK–STAT and PI3K signaling pathways.^104,105

Leptin has a role in pancreatic cancer (PC) pathogenesis. It binds to its receptors to mediate downstream signaling.¹⁰⁶ Leptin receptor and hypoxia inducible factor-1 (HIF-1) are coexpressed in PC cell lines, and this has been associated with poor prognosis, decreased overall survival, and increased metastasis in PC patients. Silencing of HIF-1 inhibited leptin receptor expression in PC cells, suggesting that a positive feedback loop between HIF-1 and leptin receptor mediates PC progression.^20,106 In PC, cell migration and invasion have been shown to involve Janus kinase 2 and signal transducer and activator of transcription 3 (JAK2/STAT3) pathway.^20,107

2. Adiponectin

Adiponectin, also known as AdipoQ, is a 30-kilodalton polypeptide with a C-terminal globular domain similar to TNF-α. It has a significant role in insulin sensitization of tissues such as muscle and liver.^20,108 It regulates carbohydrate as well as lipid metabolism through the adenosine monophosphate-activated protein kinase (AMPK) pathway, with its expression being decreased in obesity and diabetes. However, relatively recent studies strongly suggest that adiponectin modulates the activity of a ceramidase, which leads to decreased intracellular levels of ceramides, improved insulin sensitivity, and inhibition of apoptosis. These effects are mediated through activation of its cognate receptors AdipoR1 and AdipoR2.¹⁰⁹ In a murine model of nonalcoholic steatohepatitis, adiponectin-knockout mice had significantly more hepatic tumors.¹¹⁰ Adiponectin also increased caspase-3 activation and apoptosis in HCC cell lines, via inhibition of serine–threonine-protein kinase mTOR (mTOR), in a c-JNK dependent manner.^59,111 In vivo studies with nude mice, overexpression of adiponectin inhibited liver tumor growth and metastasis by suppression of tumor angiogenesis and downregulation of the ROCK/IP10/matrix metalloproteinase 9 pathway.¹¹² Epidemiological studies strongly suggest that obesity in association with low levels of adiponectin is correlated with increased incidence of breast cancer.¹¹³

The biochemical features of obesity include IGF-1 deregulation, alterations in metabolic enzymes, some proinflammatory cytokines, deregulation of the immune system, increases in the oxidative stress markers. All of these lead to cancer angiogenesis, migration, and proliferation, as depicted in a schematic diagram in Fig. 2.

FIG. 2:

Schematic diagram of the biochemical features of obesity. Reprinted from Martinez-Useros and Garcia-Foncillas,¹² with permission from Springer, Copyright 2016.

VI. DIABETES AND CANCER

The prevalence of diabetes is increasing, and in addition to 415 million adults who have diabetes, 318 million also have impaired glucose tolerance. Approximately 642 million people worldwide will have diabetes by the year 2040.^114,115 T2D which used to be referred to adult-onset or non–insulin-dependent diabetes, accounts for > 90%–95% of all diabetes. T2D is a complex metabolic disorder essentially characterized by alterations in lipid metabolism, insulin resistance, and pancreatic β-cell dysfunction.¹¹⁶ Obesity is the number one risk factor for T2D; it may lead to elevated serum triglycerides, hypertension, and insulin resistance.¹¹⁷

Compared to women of normal weight, those with a BMI of 30 kg/m² and 35 kg/m² have 28 times and 93 times greater risk of developing diabetes, respectively.^34,118 In normal-weight men, T2D occurred a rate of 1.6 per 1000 person years, whereas in obese men this number was 11.4,¹¹⁹ and obese men developed T2D 7 times more often than normal-weight men. The rate at which T2D is increasing in the youth is alarming. Between 2001 to 2016, the prevalence of T2D increased by ~ 35% among youth aged 10–19 years.¹²⁰

Patients with diabetes experience a roughly 20%–25% higher cancer incidence than individuals without diabetes, and they also have a higher mortality rate.^34,121 Both men and women with T2D were shown to have a two-fold increased risk of developing hepatocellular carcinomas (HCC), compared with nondiabetics.¹²² Furthermore, this risk appears to be independent of age, obesity, and sex.¹²³ Also, obesity and hepatic steatosis have been shown to be independent predictors of HCC, suggesting that metabolic derangements and diabetes work synergistically to increase HCC risk.¹²³ A considerable body of evidence supports an association between diabetes and an increased risk of breast cancer.^124,125

A considerable number of epidemiological studies support the relationship between T2D and colorectal cancer. Patients with T2D were shown to have a 27% increased risk of colorectal cancer compared to nondiabetics.¹²⁶ The evidence is even more overwhelming when it comes to pancreatic cancer. Based on data from 23 cohort and 13 case-controlled studies,⁵ the World Cancer Research Fund panel concluded that there is a “convincing increased risk” of pancreatic adenocarcinoma related to body adiposity and a “probable increased risk” with abdominal adiposity.¹²⁷ A comprehensive meta-analysis showed that individuals with T2D for < 4 years had a 50% increased risk of pancreatic cancer than did patients with diabetes for ≥ 5 years.¹²⁸ Although the connection between T2D and PC is convincing, with T2D patients having a two-fold increased risk in developing PC, the literature strongly suggests that insulin resistance, one of the hallmarks of T2D, and diabetes may in some cases be a consequence of PC.^128-130

VII. PHARMACEUTICAL INTERVENTIONS

A. Metformin

Metformin is a biguanide that is widely used as an insulin-sparing agent to treat diabetes. Some studies have indicated that those who used this drug, as a cohort had lower total cancer incidence.^131,132 However, there are also other studies that do not support these general observations.¹³³ A meta-analysis reported that metformin use was associated with reduced breast cancer incidence and mortality,¹³⁴ but other studies failed to demonstrate a protective effect of metformin on breast cancer incidence^133,135,136 or mortality¹³⁷ or a difference in the frequency of estrogen receptor (ER)-positive breast cancer.¹³⁸ In a tumor murine model of ER-positive breast cancer, metformin treatment slowed down tumor growth and this was shown to be through suppression of obesity associated adipokine levels and reduced Akt/mTOR pathway activation.¹³⁹ In a randomized clinical trial where patients were administered metformin for 1 month prior to breast cancer resection, the metformin-treated patients had reduced Ki67 expression, a cellular marker for proliferation, in HER2-positive resected tumors.¹⁴⁰ In preclinical studies, metformin suppressed overexpression of the HER2 protein by inhibiting the Akt/mTOR pathway¹⁴¹ and delayed the onset of adenocarcinoma in a transgenic murine model of HER2-positive breast cancer.¹⁴²

In diabetic men, a considerable body of data shows an inverse association between metformin use and prostate cancer risk^143-145 and prostate cancer-specific mortality.^146,147 Following primary therapy for prostate cancer, those receiving metformin had reduced risk of recurrence.¹⁴⁵

At the cellular level, metformin inhibited proliferation of the human prostate cancer cell lines, LNCaP, PC3, and DU145, causing G₀/G₁ or S phase cell cycle arrest via inhibition of cyclinD1, while having no effect on normal epithelial prostate cells. Also, in a xenograft mouse model of prostate cancer, metformin slowed tumor growth.¹⁴⁸

Metformin has been shown to prevent carcinogen-induced pancreatic cancer induction in hamsters maintained on a high-fat diet.¹⁴⁹ Notably, the growth of the pancreatic cell lines’ PANC1 and MIAPaCa-2 tumor xenografts were significantly reduced after daily intraperitoneal treatment with metformin.¹⁵⁰

Metformin use has also been associated with reductions in GI malignancies including gastric and CRC.^135,151,152 Interestingly, the use of metformin has been shown to improve traditional chemotherapeutic response rates.¹⁵³ The underlying anti-cancer action of metformin includes the inhibition of the mammalian target of rapamycin complex 1 (mTORC1) pathway, which plays an important role in metabolism, growth, and proliferation of cancer cells.¹⁵⁴ The mTOR pathway is activated through IGF-1 and insulin ligand binding to their respective receptors, which causes the insulin receptor substrate (IRS) signal to transmit to phosphoinositide 3-kinase (PI3K), and Akt/protein kinase B (PKB), which indirectly activate mTORC1.^34,155

B. Thiazolidinediones

Thiazolidinediones (also called glitazones, TZDs) are a class of orally available hypoglycemic medications that may be used for the treatment of T2D. They act by increasing insulin sensitivity through the peroxisome proliferator-activated receptor gamma, PPAR-γ. Attachment of the ligand to the PPAR-γ receptor activates a series of genes that are involved in glucose and fatty acid metabolism; the overall effect is an increase in insulin effect.¹⁵⁶ In a recent study using Umuc-3 and 5637 bladder cancer cells, rosiglitazone and pioglitazone markedly induced cell cycle G2 arrest and apoptosis, which resulted in inhibition of cell proliferation in vitro and suppression of tumor growth in vivo. The underlying mechanism involved marked inhibition of PI3K-Akt pathway.¹⁵⁷

Efatutazone is a novel third-generation thiazolidinedione that is at least 50 times more potent than rosiglitazone and 500 times more potent than troglitazone for PPAR-γ response element activation and the inhibition of cancer cell growth.¹⁵⁸ It has shown good activity in cell culture, inhibiting proliferation of human pancreatic and anaplastic thyroid tumor cell.¹⁵⁹

A recent meta-analysis indicated a protective association between TZDs use and CRC risk in patients with T2D.¹⁶⁰ PPAR-γ agonists suppress CRC cell growth in vitro and in vivo by inhibiting the mTOR and LKB-1 pathways.^161-163

C. Statins

Cholesterol comes from the diet and is also endogenously synthesized. It is an essential component of cellular plasma membrane in animals and has a crucial role in maintaining membrane fluidity.¹⁶⁴ Cholesterol is also a precursor of endogenous sex steroid hormones; thus, it has a potential role in breast and prostate cancers, two hormone-dependent tumors. Cholesterol that is derived from the diet can increase the risk of ER-positive breast cancer development,^165,166 and some data strongly suggest an increased risk of breast cancer with increasing serum cholesterol levels.¹⁶⁷ There is good correlation between high dietary cholesterol intake and increased risk of ER-positive, but not ER-negative, breast cancer.¹⁶⁷

Cholesterol content of normal prostate epithelial cells is relatively high, and this increases further during progression to cancer, suggesting a role in prostate cancer progression.¹⁶⁴ As reviewed in Allott and Hursting,¹⁶ elevated cholesterol levels may be associated with increased risk of aggressive prostate cancer^168-171 but not total prostate cancer,^171,172 although other studies have reported no association between cholesterol or its subfractions and prostate cancer risk.^173,174

In prostate cancer cell lines and in murine xenograft models, cholesterol has promoted cell growth.¹⁷⁵ Conversely, cholesterol reduction slowed tumor growth in xenograft murine models of human prostate cancer by lowering intratumoral androgen levels.¹⁷⁶

Statins are cholesterol-lowering drugs that are widely used in both men and women. As a class, they competitively and reversibly inhibit the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is the rate-limiting enzyme for cholesterol biosynthesis in the liver. This leads to decreases in serum low-density lipoprotein cholesterol (LDL-C), triglyceride, and cholesterol levels.¹⁶³

Statin use has been associated with reduced total cancer risk¹⁷⁷ and lower cancer-specific mortality.¹⁷⁸ However, there does not seem to be any association between statin use and total breast cancer risk,^179,180 although the UK Cancer Registry suggests a protective effect of statin use on breast cancer-specific mortality.¹⁸¹ One study reported lower rates of ER-negative breast cancer among statin users,¹⁸² but other researchers found no such association.¹⁸³ However, a strong inverse association between statin uses and risk of breast cancer recurrence and mortality has been reported.^184,185

In prostate cancer, there does not seem to be an association between statin use and total prostate cancer risk^186-189: however, an inverse association between statin use and risk of aggressive disease has been detected.^186,187 Postdiagnosis statin use has been associated with reduced risk of recurrence.¹⁹⁰

D. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Obesity is associated with subclinical chronic inflammation^88,191 and elevated levels of COX-2 expression.¹⁹² The anti-inflammatory properties of NSAIDs occur primarily through the inhibition of the COX pathway, which lowers PG levels.¹⁹³ Considerable evidence suggests that the long-term use of NSAIDs is associated with a significant reduction in many forms of cancer: colon,^194-197 breast,^198-200 pancreas,²⁰¹ bladder,^202,203 head and neck,²⁰⁴ esophageal,²⁰⁵ ovarian,^206,207 prostate,²⁰⁸ hepatocellular,²⁰⁹ and skin.^210-212 Of these, cellular and molecular mechanisms of CRC, which in many ways represent the prototypical case for cancer prevention, have been studied most extensively.

Some data support the upregulation of the aromatase pathway by COX-2-mediated PGE₂²¹³ and therefore support the notion that NSAIDs should be effective in the management of ER-positive breast cancer. NSAID use has been shown to reduce serum estradiol levels in women with breast cancer.²¹⁴ NSAIDs are also protective against breast cancer incidence and mortality.^215,216 COXIBs or COX-2 specific NSAIDs, such as celecoxib, may have a role in preventing HER2-positive breast cancer²¹⁷; however, the general impact of NSAIDs in this subtype of breast cancer needs to be investigated further.

In prostate cancer, COX-2 expression is also high relative to the normal adjacent tissue.²¹⁸ A meta-analysis reported an inverse association between NSAID use and aggressive prostate cancer risk.²¹⁹ However, regular NSAIDs use can lower PSA levels.²²⁰

VIII. OTHER MODES OF TACKLING OBESITY

A. Lifestyle Interventions: Diet

Research suggests that weight reduction aids in restoring pathways that were once deregulated due to obesity.^15,16 Restricting caloric intake for 28 days in a proof-of-principle study resulted in individuals having improved inflammatory gene expression signatures in the subcutaneous WAT.¹⁶ Caloric excess and diets that are rich in calories, overabundant in alcohol and animal fats, and/or lacking in plant products lead to increased cancer incidence.^16,17 There is an association between low-cancer risk and higher intake of fruits and vegetables,¹⁷ but more research should be conducted because this may only be relative to those eating high-protein, high-fat diets.¹⁷ Low levels of vitamin D in individuals may be responsible for 20% of the cancer risk association with an increased BMI.¹⁷ Dieting by restricting caloric intake may lead to WAT inflammation improvement and, in turn, to reduced incidence of cancer related to a high BMI.¹⁵

B. Physical Activity

To prevent the onset of chronic diseases, individuals should partake in daily exercise. Physical exercise can lower the risk of breast cancer and has been correlated to decreases in the risks of colon and breast cancer development.¹⁷ Men and women who are physically active have a 30%–40% decreased risk in developing colon cancer compared to those who are less active, with the risk declining at higher levels of physical activity.²²¹ Physically active women have a 20%–30% reduction in risk of developing breast cancer compared to women who are physically inactive.²²¹ Physical activity decreases the risk of pancreatic cancer in individuals who are overweight.⁴⁶ Figure 3 represents a schematic diagram linking obesity with cancer and the rationale for the use of various pharmacological agents.

FIG. 3:

Putative mechanisms linking obesity with cancer risk and progression: lessons from studies of chemopreventive agents. Reprinted from Allott and Hursting,¹⁶ with permission from Bioscientifica Limited.

IX. CONCLUSIONS AND FUTURE DIRECTIONS

Because the prevalence of obesity and T2D is on the rise, we need to achieve greater insight into the mechanisms that relate the obesity-T2D-cancer axis. Certainly there are links between obesity and T2D, between obesity and cancer, and between T2D and cancer. Collectively, these relationships are of public health interest; hence, more clinical studies are needed to decipher them. Patients that are clinically obese may require pharmacological interventions as well as lifestyle changes. To that end, more studies are needed to access the utility of agents such as metformin, statins, NSAIDs, and TZDs in the management of such patients. It would help if BMI measurements or at least another yardstick became routinely available in general medical practice. Considering that 1.6 million deaths occur internationally each year that are essentially obesity related, targeting this problem may ultimately decrease cancer-related deaths and also heart disease, stroke, and diabetes.

ABBREVIATIONS

T2D

type-2 diabetes

JAK2

Janus kinase 2

STAT3

signal transducer and activator of transcription 3

AMPK

adenosine monophosphate-activated protein kinase

MCP-1/CCL2

monocyte chemoattractant protein-1

FFA

free fatty acid

WAT

white adipose tissue

BAT

brown adipose tissue

CLS

crown-like structures

BMI

body mass index

CRC

colorectal cancer

PC

pancreatic cancer

HCC

hepatocellular carcinoma

IGFBP-1

insulin-like growth factor-binding protein-1

PI3 kinase

phosphatidylinositol 3′-kinase

PSA

prostate-specific antigen

HIF-1

hypoxia inducible factor-1

NSAIDs

nonsteroidal anti-inflammatory drugs

ATME

adipose tissue microenvironment

TNF-α

tumor necrosis factor-α

IL-1β

interleukin 1β

IL-6

interleukin-6

PG

prostaglandin

COX-2

cyclooxygenase-2

ER

estrogen receptor

PPAR-γ

peroxisome proliferator-activated receptor gamma

mTORC1

mammalian target of rapamycin complex 1