Abstract
Epidemiological studies suggest a positive association between obesity and type 2 diabetes mellitus (T2D) with the risk of cancer and cancer-related mortality. Insulin resistance, hyperinsulinemia, increased levels of IGF, elevated levels of steroid and peptide hormones, and inflammatory markers appear to play a role in the connection between these different diseases. Medications, such as metformin and exogenous insulin, used to treat T2D may affect the risk of cancer and cancer-related mortality. Newer therapies targeting the insulin and IGF1 systems are being developed for use in cancer therapy.
Introduction
Obesity and type 2 diabetes mellitus (T2D) have been demonstrated to have a positive association with both the risk of cancer and cancer-related mortality. Given the dramatic increase in the rates of obesity and T2D, this connection is of great public health concern. The link between obesity, T2D, and cancer appears to be related to insulin resistance, hyperinsulinemia, increased levels of IGF, steroid and peptide hormones, and inflammatory markers. Medications used to treat T2D can influence some of these factors and may affect the risk of cancer and cancer-related mortality. In this review, we present epidemiological evidence of the relationship between obesity, T2D, and cancer. We also review the available literature regarding the effects of exogenous insulin on the risk of cancer and cancer-related mortality in patients with T2D. Additionally, the proposed mechanisms that connect obesity, T2D, and cancer and the data on newer anticancer therapies that target metabolic pathways are discussed.
Epidemiological
Link between obesity, diabetes, and cancer
In the past several decades, there has been a dramatic increase in the rates of obesity (defined as a body mass index (BMI) ≥30 kg/m2). Currently, one-third of all adults in the United States are obese and similar trends have been observed worldwide. The World Health Organization (WHO) estimates that worldwide obesity has more than doubled since 1980. In 2008, 1.5 billion adults, aged 20 years and older, were overweight. Of these, over 200 million men and nearly 300 million women were obese (World Health Organization 2011a,b). Obesity has many associated comorbidities, including T2D and cancer. The association between obesity and cancer has been recognized and widely studied. The results of the Cancer Prevention Study suggested that 14% of cancer deaths in men and 20% in women could be attributed to obesity (Calle et al. 2003). More recent evidence suggests that about one-third of the 571 950 cancer deaths that were expected to occur in 2011 in the United States would be related to overweight or obesity, physical inactivity, and poor nutrition (American Cancer Society, Cancer Facts and Figures 2011 www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-029771.pdf). Meta-analyses of prospective studies from other parts of the world show similar findings (Bergstrom et al. 2001, Pan et al. 2004, Kuriyama et al. 2005).
With the worsening obesity epidemic, there has also been an increase in the rate of T2D. The CDC estimates that in the United States alone, there are 25.8 million people with diabetes, a number that comprises 8.3% of the population (Centers for Disease Control and Prevention, National diabetes fact sheet: national estimates and general information on diabetes and pre-diabetes in the United States www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf). Diabetes is estimated to affect 346 million people worldwide (World Health Organization 2011a,b) and is expected to continue to increase to 366 million by 2030, which is more than double the prevalence observed in the year 2000 (Wild et al. 2004). While a positive association between obesity and cancer has been observed, higher rates of cancer-related mortality have been seen in patients with T2D, regardless of BMI, suggesting that T2D may be an independent risk factor for cancer and cancer-related mortality (Calle & Kaaks 2004, Xue & Michels 2007). A recent meta-analysis of cohort and case–control studies examining the risk for specific cancers in patients with diabetes mellitus showed increases in the relative risk of liver, pancreatic, colorectal, bladder, endometrial, and breast cancers, and non-Hodgkin's lymphoma (Gallagher et al. 2010b). Insulin resistance, characterized by diminished responsiveness of the skeletal muscle, liver, and adipose tissue to insulin, and the subsequent hyperinsulinemia, or the compensatory rise in insulin levels in an attempt to maintain euglycemia, are key features of T2D (Kaaks & Lukanova 2001). Hyperinsulinemia, which often predates the diagnosis of T2D for many years and persists early in the disease process, has been shown to link obesity and T2D to cancer. Other endocrine and metabolic effects of obesity such as increased levels of bioavailable IGF1, through effects on IGF-binding proteins (IGFBPs), play a role. Additionally, bioavailability of steroid and peptide hormones and systemic inflammation may contribute to the greater cancer risk in obesity and T2D.
Mechanisms mediating increased cancer risk in obesity and T2D
Insulin and IGF1 receptors
Insulin is produced by pancreatic β cells, whereas IGF1 is produced in the liver. IGF1 is produced under the stimulus of GH acting on the GH receptor (GHR). Insulin and IGF1 mediate their intracellular effects via the activation of their cognate receptors, the insulin receptor (IR) and the IGF1 receptor (IGF1R) respectively. Both IGF1R and IR are heterotetrameric proteins (composed of one α–β dimer linked to a second α–β dimer by disulfide bonds) that possess intrinsic tyrosine kinase activity. IGF1R is expressed in nearly all the tissues of the body and activates mitogenic pathways resulting in cell proliferation (Frasca et al. 2008). Accordingly, increased IGF1R expression has been reported in several cancers (Gallagher & LeRoith 2011).
The IR, on the other hand, undergoes alternative splicing of exon 11 resulting in two isoforms, IR-A and IR-B, that show spatiotemporal differences in their expression and also exert diverse functions (Mosthaf et al. 1990, Sciacca et al. 1999). IR-A is overly expressed in fetal and tumor cells and has more antiapoptotic and mitogenic effects (Frasca et al. 1999). On the other hand, IR-B is expressed by differentiated tissues such as the liver, adipocytes, and muscle, where it exerts the metabolic effect of insulin (Belfiore et al. 2009). In vitro studies have shown increased expression of IR-A in cancer cells (Mathieu et al. 1997, Sciacca et al. 2002) and elevated IR-A levels have been associated with tumor progression (Vella et al. 2002). One possible explanation for the mitogenic effects of IR-A compared with IR-B could be its ability to bind to the fetal growth factor IGF2, which is an effective impetus of cell proliferation during gestation (Frasca et al. 1999, Sciacca et al. 1999). Furthermore, recent data show that upon binding to IR-A, IGF2 activates a unique signaling pathway that differs from that of insulin (Morcavallo et al. 2011).
There is a high degree of homology between IGF1R and IR, and thus, they can form hybrid receptors consisting of one α–β subunit of the IR and one α–β subunit of the IGF1R (Samani et al. 2007). IGF1 and IGF2 have high affinity for the hybrid receptors compared with insulin (Soos et al. 1993, Bailyes et al. 1997, Pandini et al. 1999), suggesting that cells that express increased quantities of hybrid receptors will have increased activation of mitogenic signaling pathways. In fact, increased levels of hybrid receptors have been observed in many cancer tissues (Belfiore et al. 1999, Pandini et al. 1999).
Insulin and IGF signaling
Ligand binding to the IR, IGF1R, and IR/IGF1R hybrid receptors results in autotransphosphorylation of the β-subunit tyrosine kinase domains. This is followed by phosphorylation of additional tyrosine residues and recruitment of adaptor proteins such as IR substrates 1–4. Tyrosine phosphorylation of the adaptor proteins results in the recruitment and activation of downstream effectors, among which the most predominant are the phosphotidyl inositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways. The MAPK signaling pathway is primarily responsible for cell growth and proliferation. On the other hand, the PI3K/AKT signaling pathway has diverse effects ranging from the regulation of metabolic processes, activation of antiapoptotic pathways, and the stimulation of protein synthesis (Belfiore & Malaguarnera 2011). In fact, activation of the PI3K/AKT pathway has been reported in many types of cancers (Gallagher et al. 2011). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which is a physiological inhibitor of the PI3K/AKT pathway and thus serves as a tumor suppressor, is very frequently mutated in cancer (LeRoith & Roberts 2003, Yakar et al. 2005, Levine et al. 2006). Another mechanism by which PTEN may serve as a tumor suppressor is by terminating IGF2 signaling. Studies on mice that overexpress IGF2 demonstrate the existence of a negative feedback loop wherein IGF2 activates PTEN, which in turn inhibits IGF2 signaling (Moorehead et al. 2003). Also, human breast cancer MCF-7 cells that have lost PTEN demonstrate increased IGF2 signaling through the IGF1R or IR-A (Perks et al. 2007).
One of the targets of the PI3K/AKT pathway is the activation of mammalian target of rapamycin (mTOR), which is involved in cell survival, growth, and metabolism, and is an actively pursued target for cancer therapy. In fact, activation of mTOR has been seen in breast cancer cells and has been linked to resistance to trastuzumab and tamoxifen, both chemotherapeutic agents (Yakar et al. 2005).
Insulin resistance
In obesity and T2D, insulin resistance leads to chronic hyperinsulinemia. Epidemiological studies as well as in vivo studies have demonstrated that insulin resistance can lead to enhanced tumor growth. In the Women's Health Initiative (WHI) Study, women with higher insulin levels had an increased risk of developing colorectal and endometrial cancers (Gunter et al. 2008a,b). Similar findings were observed in the Physicians' Health Study and the European Prospective Investigation into Cancer and Nutrition (EPIC), in which c-peptide levels were associated with a higher risk of developing colorectal and endometrial cancers and an elevated risk of mortality from prostate cancer (Ma et al. 2004, 2008, Jenab et al. 2007). In accordance with these observations, rats fed a high-fat diet (HFD) to induce insulin resistance developed more aberrant crypt foci, which are precancerous lesions, in the colon in response to the carcinogen azoxymethane than rats that were more insulin sensitive (Tran et al. 2003).
Hyperinsulinemia may affect cancer risk not only through the direct mitogenic effects of insulin but also indirectly via increased production of IGF1. GH activation of its receptor, the GHR, in the liver results in the activation of pathways that increase IGF1 production and secretion. In the presence of insulin, hepatic GHR expression is increased leading to increased production of IGF1. Therefore, chronic hyperinsulinemia is associated with elevated circulating IGF1 levels (LeRoith & Roberts 2003, Renehan et al. 2004). Insulin also suppresses IGFBP1 and -2, which serve to limit the bioavailability of IGF1 in the peripheral tissues (Calle & Kaaks 2004). Thus, a chronic elevation of insulin may lead to increased levels of bioavailable IGF1. Additionally, increased levels of insulin lead to increased formation of hybrid receptors and may lead to insulin binding to the IGF1R, thereby enhancing mitogenic potential (Vigneri et al. 2009).
IGFs and cancer
Higher levels of IGF1 have been correlated with an elevated risk of cancer, as evidenced by meta-analyses and prospective epidemiological studies (Chen et al. 2009, Rinaldi et al. 2010). For example, in the Rancho Bernardo Study, which included 18 years of follow-up, men who had a baseline IGF1 level above 100 ng/ml had a 1.82 risk of cancer mortality compared with men with lower levels. In men who had a baseline IGF1 level over 200 ng/ml, the risk was increased by 2.61 (Major et al. 2010). Samani et al. (2007) summarized several studies evaluating the expression level of both IGF1 and IGF2 in different human cancers and found an overall positive correlation.
Exogenous insulin and cancer
As the duration and severity of T2D progress, patients and physicians often turn to exogenous insulin as a means to control patients' hyperglycemia. Studies have shown an increase in cancer-related mortality in patients with T2D treated with insulin (Bowker et al. 2006). Currie et al. (2009) reported that patients treated with insulin had an increased risk of colorectal and pancreatic cancers compared with patients treated with metformin. Insulin analogs, developed as an alternative to human insulin, are commonly used in the treatment of T2D. In order to create the insulin analogs, human insulin has been modified to more accurately mimic the endogenous secretion of insulin. Altering the structure of the insulin molecule can alter and enhance its mitogenic activity (Zib & Raskin 2006). The potential for increased cancer risk in patients treated with insulin analogs became a cause of alarm after a German study showed a dose-dependent increase in cancer risk in patients treated with one such analog, insulin glargine, compared with human insulin (Hemkens et al. 2009). A positive association with breast cancer incidence was also observed in Swedish women using insulin glargine (Jonasson et al. 2009). However, the Scottish Diabetes Research Network Epidemiology Group reported that patients receiving insulin glargine had the same incidence rates of cancer as those not receiving insulin glargine, with the exception of the subgroup analysis of breast cancer. The authors concluded that this difference was due to selection bias as the patients who developed breast cancer were older and potentially more ill at baseline (Colhoun 2009). All the early studies linking insulin glargine and increased cancer risk had design flaws and thus were criticized and found inconclusive (Renehan 2011). Newer studies have sought to explore the relationship between insulin glargine use and cancer risk without these same design flaws and to conclusively define this relationship. Ruiter et al. studied a cohort of incident users of insulin in The Netherlands and found that of the 19 337 incident users of insulin, only 878 developed cancer. Interestingly, a lower risk of malignancy was observed in users of insulin glargine compared with human insulin. However, an increased risk in breast cancer was seen in users of insulin glargine compared with human insulin, and this association demonstrated a dose–response effect in the as-treated analysis (Ruiter et al. 2012). Suissa et al. (2011) specifically examined the long-term effects of insulin glargine on the risk of breast cancer and noted that while insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use, the risk increased after 5 years of use for women who had been on human insulin before starting insulin glargine (HR=2.7). As newer studies with improved methodology are being published, the association between insulin glargine and cancer risk is being explored. Further studies are necessary to better clarify this relationship.
Glucose, leptin, adiponectin, and inflammatory cytokines
While hyperinsulinemia is a predominant complication in obesity and T2D, several other factors (such as blood glucose levels) and the circulating profile of adipokines (such as leptin and adiponectin) and cytokines (such as TNFα and interleukins (IL)) are also abnormal in obesity and T2D, and their contribution to cancer risk and progression cannot be discounted. It has long been known that cancer cells take up more glucose, a phenomenon described as the Warburg effect (Herling et al. 2011). In fact, the increased glucose uptake by cancer cells is the basis for FDG-PET scans, which are currently used to visualize tumors in vivo (Vander Heiden 2011). However, most of the patients with T2D are both hyperglycemic and hyperinsulinemic, and thus, it is difficult to separate the effects of glucose and insulin. Nevertheless, increased intake of sugar and refined carbohydrates has been positively correlated with the risk of cancer (Krone & Ely 2005). One mechanism by which glucose could induce cancer progression is by the induction of oxidative stress, which has been associated with cancer (Brown & Bicknell 2001). Turturro et al. (2007) demonstrated that inducing hyperglycemia in the human breast cancer cell line MDA-MB-231 leads to increased expression of the oxidative stress-responsive gene, thioredoxin-interacting protein, and subsequent increased levels of reactive oxygen species. Thus, hyperglycemia in obesity and T2D could accelerate tumor growth and progression.
Leptin is produced primarily by white adipose tissue but can also be produced by cells of the mammary epithelium, ovary, placenta, brown adipose tissue, skeletal muscle, bone marrow, pituitary, liver, and fundal glands of the stomach (Maffei et al. 1995). Leptin levels correlate positively with white adipose tissue mass; therefore, leptin levels are increased in obesity (Paz-Filho et al. 2011). On the one hand, leptin regulates energy homeostasis by mediating food intake and expenditure through its action on the hypothalamus; on the other hand, it also stimulates cell growth, migration, and invasion (Garofalo & Surmacz 2006). Additionally, leptin can increase the production of cytokines by macrophages, which further stimulate cancer cells (Trayhurn & Wood 2004). Leptin expression is induced by hypoxia via the hypoxia-induced factor 1, and hypoxia frequently occurs in solid tumors (Ambrosini et al. 2002, Grosfeld et al. 2002). Furthermore, leptin can promote neoangiogenesis through the induction and activation of proangiogenic factors, such as vascular endothelial growth factor, fibroblast growth factor 2, and matrix metalloproteases 2 and 9 (Park et al. 2001). Leptin can enhance endothelial cell growth and suppress apoptosis through a BCL2-dependent mechanism (Bouloumie et al. 1998, Sierra-Honigmann et al. 1998, Cao et al. 2001, Artwohl et al. 2002). In hormone-dependent neoplasms, i.e. breast and endometrial cancers, leptin can stimulate cancer growth by activating aromatase, leading to increased estrogen synthesis (Boden et al. 1996). Studies on esophageal, breast, colorectal, and prostate cancers, cell lines demonstrate increased cell proliferation in the presence of leptin (Dieudonne et al. 2002, Onuma et al. 2003, Somasundar et al. 2004, Endo et al. 2011). In vivo studies also suggest a role for leptin in stimulating cancer development and growth. In fact, leptin-deficient ob/ob and leptin-resistant db/db mice do not develop transgene-induced mammary tumors (Cleary et al. 2003, 2004). More studies are necessary to further define the role of leptin in cancer promotion.
Adiponectin is produced exclusively by adipocytes and is involved in the regulation of energy homeostasis and glucose and lipid metabolism. Unlike leptin, adiponectin negatively correlates with body fat and BMI. Adiponectin production is inhibited by the inflammatory cytokines that are secreted by adipose tissue in obese individuals (Wozniak et al. 2009, Liu & Liu 2010). Adiponectin inhibits inflammation, atherogenesis, angiogenesis, and insulin resistance (Brakenhielm et al. 2004, Ahima 2006). In vitro studies show adiponectin to be an inhibitor of cell growth and proliferation in prostate, breast, and esophageal cancers (Bub et al. 2006, Konturek et al. 2008, Cleary & Grossmann 2009). Human studies appear to corroborate these findings. Serum adiponectin levels have been shown to inversely correlate with the risk, stage, and grade of colorectal cancer (Gialamas et al. 2011). In postmenopausal women, reduced serum adiponectin levels have been associated with increased breast cancer incidence (Mantzoros et al. 2004). Endometrial cancer has been linked to low adiponectin levels in premenopausal women (Cust et al. 2007). The molecular mechanism by which adiponectin suppresses cancer growth is by the activation of AMPK, which suppresses mTOR and thus hinders cell proliferation (Kelesidis et al. 2006, Reiling & Sabatini 2006, Kim et al. 2009). AMPK may also suppress tumor growth by upregulation of the p53 axis, reduction of cyclin D1 levels, and suppression of the cyclin-dependent kinases leading to G1 cell cycle arrest (Cazzaniga et al. 2009). Adiponectin also stimulates the tumor suppressor LKB1, which, in addition to inhibiting the metastasis, is also a physiological activator of AMPK (Saxena & Sharma 2010).
T2D and obesity are proinflammatory conditions and are associated with increased production of inflammatory cytokines such as IL6 and TNF-α by adipose tissue (Eltzschig & Carmeliet 2011). Elevated levels of IL6 have been observed in patients with breast cancer, prostate cancer, B-cell lymphoma, and myeloma (Gallagher et al. 2010a). TNF-α stimulates the development and advancement of many tumors by activating nuclear factor-κB (Szlosarek et al. 2006). Thus, while hyperinsulinemia could be one of the predominant factors driving cancer progression in obesity and T2D, the contributions of other factors mentioned earlier cannot be neglected.
Role of sex hormones
Increased adipose tissue, as seen in obesity, results in increased expression of the enzyme aromatase, which is responsible for converting androgens to estrogens (McTernan et al. 2000). Additionally, obesity and insulin resistance lead to decreased production of sex hormone-binding globulin (SHBG), resulting in increased bioavailability of estrogen. The increase in estrogen levels is thought to play a role in the development of endometrial cancer and postmenopausal breast cancer and epidemiological studies support this connection (Calle & Kaaks 2004). The estrogen receptor and the IGF1R can work together to activate MAPK, thus stimulating tumor cell proliferation (Lee et al. 1999). A recent study by Tworoger et al. (2011) demonstrated that women with increased estrogen levels had an elevated risk of postmenopausal breast cancer, which further increased in women with increased IGF1 and c-peptide. This suggests that it is the interplay of the increased estrogen and insulin and IGF1 that is involved in the development of postmenopausal breast cancer.
Multiple factors play a role in the link between obesity, T2D, and cancer. These include but are not limited to the intricate workings of the insulin and IGF systems, hyperinsulinemia and insulin resistance, hyperglycemia, elevated leptin, low adiponectin, increased inflammatory cytokines, and sex hormones.
T2D, obesity, and site-specific cancers
T2D and obesity have been associated with many different cancers. The Cancer Prevention Study II and the Million Women Study demonstrated an increased risk of cancer and cancer-related mortality from cancers of the esophagus, pancreas, colon, and rectum; non-Hodgkin's lymphoma; and multiple myeloma in women with elevated BMI (Calle et al. 2003, Reeves et al. 2007; Table 1). Results of meta-analyses show a higher risk of cancers of the liver, pancreas, colon and rectum, kidney, bladder, endometrium, and breast and non-Hodgkin's lymphoma in individuals with diabetes compared with those without diabetes (Huxley et al. 2005, Larsson et al. 2005, Vigneri et al. 2009, Gallagher et al. 2010b; Table 2). In this section, we will focus on the association between T2D, obesity, and cancers of the breast and prostate.
Obesity and relative risk of cancer and cancer mortality
| Study | Cancer site | Relative risk |
|---|---|---|
| The Million Women Study | ||
| Women (BMI>30 kg/m2) | All cancers combined | Incidence 1.12 (95% CI 1.09–1.14) |
| Cancer Prevention Study II | ||
| Men (BMI>40 kg/m2) | All cancers combined | Mortality 1.52 (95% CI 1.13–2.05) |
| Cancer Prevention Study II | ||
| Women (BMI>40 kg/m2) | All cancers combined | Mortality 1.62 (95% CI 1.40–1.87) |
Meta-analysis on the relative risk of cancer at different sites in patients with type 2 diabetes
| Study | Cancer site | Relative risk (case–control; cohort) |
|---|---|---|
| Larsson et al. (2007) | Breast | 1.80 (95% CI 1.05–1.32); 1.20 (95% CI 1.11–1.30) |
| Gallagher et al. (2010b) | Breast | 1.20 (95% CI 1.12–1.28) |
| Kasper & Giovannucci (2006) | Prostate | 0.89 (95% CI 0.72–1.11); 0.81 (95% CI 0.71–0.92) |
| Gallagher et al. (2010b) | Prostate | 0.84 (95% CI 0.76–0.93) |
| Gallagher et al. (2010b) | Liver | 2.51 (95% CI 1.90–3.20) |
| Huxley et al. (2005) | Pancreas | 1.94 (95% CI 1.53–2.46); 1.73 (95% CI 1.59–1.88) |
| Gallagher et al. (2010b) | Pancreas | 1.82 (95% CI 1.66–1.89) |
| Larsson et al. (2005) | Colorectal | 1.36 (95% CI 1.23–1.50); 1.29 (95% CI 1.16–1.43) |
| Gallagher et al. (2010b) | Colorectal | 1.30 (95% CI 1.20–1.40) |
| Gallagher et al. (2010b) | Bladder | 1.24 (95% CI 1.08–1.42) |
| Gallagher et al. (2010b) | NHL | 1.19 (95% CI 1.04–1.35) |
| Gallagher et al. (2010b) | Endometrial | 2.10 (95% CI 1.75–2.53) |
T2D, obesity, and breast cancer
Affecting one in every eight women in the United States, breast cancer is the most commonly diagnosed cancer (besides skin cancer) and has the highest rates of death among women. The link between T2D, obesity, and breast cancer has been studied well. The connection is thought to be due to the aforementioned factors, namely the insulin/IGF pathway via insulin resistance and hyperinsulinemia, dysregulation of sex hormones, inflammatory cytokines, and adipokines.
In vitro studies have established that proliferation of breast tissue and breast cancer cell lines is stimulated by insulin and IGF1 (Pollak et al. 1988, Arteaga & Osborne 1989, Ish-Shalom et al. 1997, Chappell et al. 2001). Blockade of the IGF1R-binding domain has been shown to inhibit the effect of IGF1R-induced growth in human breast cancer cell lines (Arteaga et al. 1989).
Rodent models of obesity have been utilized to better understand the connection between breast cancer and obesity. Rats fed a HFD develop increased breast tumors in response to the carcinogen 7,12 dimethylbenz(a)anthracene (Carroll & Braden 1984, Braden & Carroll 1986, Rose et al. 1993, Hakkak et al. 2005). Furthermore, transplanted tumor xenografts demonstrate more rapid growth in rodents on HFD (Nunez et al. 2008). HFD-induced obesity in rodents leads to insulin resistance, which in turn enhances tumor development. However, as stated earlier, inflammatory cytokines and adipokines may also play a role. Khalid et al. studied mice overexpressing the oncogene Her2/Neu (also known as Erbb2) in the mammary gland (under the murine mammary tumor virus promoter) on an HFD. These mice have higher body weights and increased body fat compared with regular chow-fed mice but demonstrate no evidence of insulin resistance. There is no difference in the time of first tumor presentation or tumor growth rates between the mice fed HFD and mice fed regular chow. However, the mice on the HFD present with a second tumor earlier and also have more tumors. Despite this, the tumors isolated from the HFD-fed mice do not show any differences in proliferative index relative to those isolated from the regular chow-fed mice. Thus, the authors concluded that in the absence of significant insulin resistance, HFD-induced obesity promotes tumor development and not tumor growth (Khalid et al. 2010). Thus, more studies are necessary to determine which components of obesity contribute to an increased risk of breast cancer and breast cancer mortality.
In vivo studies using rodent models have also been used to examine whether T2D is an independent risk factor for breast cancer. The lipodystrophic A-ZIP mice have reduced brown adipose tissue, absent white adipose tissue, elevated glucose, insulin, free fatty acids, and triglycerides and express increased levels of inflammatory cytokines. When A-ZIP/F-1 mice are crossed with the C3 (1)/T-Ag mammary tumor model, the result is increased tumor incidence and decreased tumor latency (Nunez et al. 2006). However, as with the previous studies, the A-ZIP mice also demonstrate hyperglycemia and increased cytokine levels, which could also affect tumor growth. Our laboratory has developed the nonobese, hyperinsulinemic MKR mouse model of T2D, and we have extensively studied the effect of hyperinsulinemia on breast cancer. In the MKR model, dominant-negative IGF1R is expressed specifically in skeletal muscle under the muscle creatine kinase promoter. The resultant is a mouse that is insulin resistant, glucose intolerant but not obese. Furthermore, the female MKR mice display mild dysglycemia and dyslipidemia, but normal levels of circulating inflammatory cytokines making them a good model to study the effects of T2D on mammary tumorigenesis independent of obesity. Female MKR mice injected orthotopically with mouse mammary carcinoma cells have enhanced tumor growth compared with control mice. Furthermore, tumors from the MKR mice demonstrate increased activation of the IR and IGF1R, as well as the PI3K/AKT/mTOR pathway. In fact, correcting the hyperinsulinemia in the MKR mice with a β3-adrenergic receptor agonist, treating with small-molecule IR/IGF1R tyrosine kinase inhibitors (TKIs), and pharmacologically inhibiting the PI3K/AKT/mTOR pathway result in reduction of tumor sizes in the MKR mice to the level of the control mice, further validating that hyperinsulinemia is the predominant factor mediating the accelerated tumor growth seen in the MKR mice (Fierz et al. 2010a,b, Novosyadlyy et al. 2010, Gallagher et al. 2011).
Epidemiological studies have also demonstrated an association between hyperinsulinemia and breast cancer (Michels et al. 2003, Jee et al. 2005, Rapp et al. 2006, Larsson et al. 2007). Gunter et al. (2009) reported on a case cohort study of postmenopausal women without diabetes and found that fasting insulin levels were positively correlated with breast cancer risk, irrespective of obesity. The Nurses' Health Study showed that postmenopausal women with T2D had an increased risk of breast cancer, with a hazard ratio of 1.17, which was independent of body adiposity (Michels et al. 2003). Larsson et al. (2007) performed a meta-analysis and found that women with T2D had a 20% increased risk of developing breast cancer compared with their nondiabetic counterparts.
While rodent models have focused on insulin resistance, hyperinsulinemia, and inflammatory cytokines and adipokines as the link between T2D, obesity, and breast cancer, it is important to also consider the role of sex steroids in the development of breast cancer. As discussed earlier, insulin can increase bioavailable estrogen by stimulating aromatase activity and inhibiting the production of SHBG. In postmenopausal women, SHBG levels have been negatively correlated with breast cancer risk (Toniolo et al. 1995, Key et al. 2002, Zeleniuch-Jacquotte et al. 2004, Kaaks et al. 2005).
Patients with T2D and obesity not only have an increased risk of developing breast cancer but also an increased risk of breast cancer mortality. In the Cancer Prevention Study II, increased BMI was strongly positively associated with increased mortality in individuals with breast cancer (Calle et al. 2003). Multiple studies have demonstrated that diabetic patients with breast cancer have lower survival rates than patients without diabetes (Yancik et al. 2001, Verlato et al. 2003). Patterson et al. (2010) reported a more than twofold risk of all-cause mortality in women with breast cancer and T2D compared with nondiabetic breast cancer patients. Erickson et al. (2011) analyzed archived baseline blood samples from the Women's Healthy Eating and Living Study for hemoglobin A1C, a measure of chronic glycemia, among women with early-stage breast cancer and found that the risk of all-cause mortality increased with increasing hemoglobin A1C. Schrauder et al. compared breast cancer patients with and without diabetes and found a higher risk for distant metastasis in the patients with diabetes (HR 2.28; 95% CI 1.31–1.97). Additionally, the patients with diabetes had an increased risk of mortality compared with their nondiabetic counterparts (HR 1.92; 95% CI 1.49–2.48; Schrauder et al. 2011). A recent meta-analyses of eight studies exploring the relationship between breast cancer and diabetes found that patients with breast cancer and preexisting diabetes had a significantly higher all-cause mortality risk (Peairs et al. 2011).
In vitro, in vivo, and epidemiological studies have suggested a connection between T2D, obesity, and breast cancer. Women with T2D and obesity appear to have an increased risk of both breast cancer and breast cancer-related mortality. Suggested mechanisms include the insulin/IGF pathway via insulin resistance and hyperinsulinemia, dysregulation of sex hormones, inflammatory cytokines, and adipokines. However, further studies are necessary to better define the association of T2D, obesity, and breast cancer.
T2D, obesity, and prostate cancer
Prostate cancer is the most commonly diagnosed cancer (besides skin cancer) in the United States, affecting approximately one in every six men. Its relationship with T2D and obesity differs from other types of cancer as many reports suggest an inverse association (Vigneri et al. 2009). In fact, two meta-analyses, one including studies from 1971 to 2002 and the second extending this analysis to 2005, reported a decreased risk of prostate cancer (9 and 16% respectively) in men with diabetes (Bonovas et al. 2004, Kasper & Giovannucci 2006).
The metabolic syndrome is defined by the presence of three out of five of the following factors: elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, increased blood pressure, and elevated fasting glucose (Alberti et al. 2009). A recently published Italian case–control study on risk factors for prostate cancer suggested that there was an increased risk of prostate cancer in men with the metabolic syndrome. However, when individual components of the metabolic syndrome were considered, the odds ratio of having prostate cancer was not significantly increased in the presence of elevated waist circumference or elevated fasting glucose, suggesting that prostate cancer risk is not enhanced by diabetes or abdominal obesity (Pelucchi et al. 2011).
Animal studies have yielded conflicting results on the effects of obesity on prostate cancer risk. HFD does not affect prostate carcinogenesis in Noble male rats (Leung et al. 2002). However, inoculation of human prostate carcinoma LNCaP cells into athymic mice fed a high carbohydrate/HFD results in increased tumor growth (Venkateswaran et al. 2007). Additionally, transgenic Hi-Myc mice fed a low-fat diet demonstrate a decreased incidence of prostate cancer (Kobayashi et al. 2008).
Elevated testosterone levels have been associated with an increased risk of prostate cancer (Shaneyfelt et al. 2000, Kasper & Giovannucci 2006). Men with T2D and obesity often have low testosterone levels and this may help to explain the decreased rates of prostate cancer in these men. In fact, studies have suggested that as many as 43% of men with T2D have reduced total testosterone levels and as many as 57% have decreased free testosterone levels (Grossmann et al. 2008). Thus, as prostate cancer is positively associated with testosterone levels and men with T2D and obesity have low testosterone levels, it is reasonable to conclude that men with T2D and obesity have a lower risk of prostate cancer than men without these conditions. And in fact, many studies do support this conclusion. Stocks et al. (2007) reported a prospective study and found that men with increased insulin resistance and worsening glycemic control had a decreased risk of prostate cancer. Baradaran et al. (2009) found that men with diabetes of longer duration had a lower risk of prostate cancer than men who had diabetes for a shorter period of time.
Patients with T2D and obesity have a lower risk of prostate cancer, but an increased risk of mortality and poor outcome once prostate cancer is diagnosed. Ma et al. (2008) demonstrated that higher c-peptide concentrations were predictive of prostate cancer-related mortality. T2D has been shown as a significant independent risk factor for a diagnosis of high-grade prostate cancer (Kang et al. 2011, Mitin et al. 2011). BMI has also been shown to correlate with the risk of a high-grade prostate cancer (Calle et al. 2003, Amling et al. 2004, Freedland et al. 2008, 2009, De Nunzio et al. 2011). Suggested explanations for this worse outcome and increased mortality include increased proliferation of tumor cells triggered by higher concentrations of insulin, IGF, and glucose (Barone et al. 2008).
Another explanation for the increased mortality and poorer outcomes in T2D and obesity could be under-diagnosis of prostate cancer. T2D has been associated with a lower level of prostrate-specific antigen (PSA) (Werny et al. 2006, Fukui et al. 2008). Similarly, PSA may be decreased in patients with obesity as a result of hemodilution (Wu et al. 2011). Often in clinical practice, prostate biopsy and subsequent cancer detection are initiated following an elevated PSA on screening tests. Thus, if patients with T2D and obesity have lower PSA levels, they are less likely to undergo biopsy and prostate cancer is less likely to be diagnosed at an earlier stage. However, when these patients present with prostate cancer, it is at a later stage when they are symptomatic or have more overt signs of disease. In order to answer this question, the authors of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, a 4-year international, multicenter double-blinded, placebo-controlled trial examined the relationship between diabetes and prostate cancer in 6427 men. In the REDUCE trial, all men underwent a prostate biopsy regardless of serum PSA. Results demonstrated that patients with diabetes were as likely to develop prostate cancer, both low and high grade, as individuals without diabetes. The authors suggest that the lower rates of prostate cancer in patients with diabetes may be partially due to lower serum PSA levels leading to fewer biopsies and less detection of disease in these men (Wu et al. 2011).
Studies suggest that men with T2D and obesity have a decreased risk of prostate cancer, but if men with these diseases develop prostate cancer, they are more likely to have poor outcomes and to die from their prostate cancer. Suggested explanations for this include lower testosterone and PSA levels in men with T2D and obesity. Other factors may also play a role. Thus, further studies in both animals and humans are necessary to further elucidate the complicated relationship between T2D, obesity, and prostate cancer.
Targeted therapeutics
The involvement of the insulin and IGF1 signaling pathways in cancer development and progression has led to the development of new cancer therapies that target these systems (Fig. 1). In this section, we review some of these therapies.
Schematic representation of anticancer therapies targeting insulin and IGF1 signaling. IGF1 and IGF2 bind to the IGF1R. Monoclonal antibodies directed at IGF1 and IGF2 have been developed and they prevent IGFs from interacting with the IGF1R. Monoclonal antibodies that block the IGF1R, thereby preventing the binding of insulin and IGF1 have also been developed. TKIs bind to the tyrosine kinase of the IGF1R and inhibit phosphorylation and subsequent activation of the receptor. Insulin can also bind to the IGF1R. As the IGF1R and IR are homologous, there is a cross-reactivity between the TKIs and the IR, which is why hyperglycemia is a common side effect of these medications. The IGF1 Ab and IGF2 Ab can cause hyperglycemia by inducing a compensatory increase in GH following IGF1 blockade and may also affect the IR by binding with hybrid receptors. Metformin is an insulin sensitizer and thus reduces insulin levels, providing less substrate for binding. Metformin also has a more direct inhibitory effect on cancer development and proliferation. Metformin activates LKB1, a tumor suppressor that activates AMPK, leading to mTOR inhibition, resulting in inhibited cell growth. Recombinant IGFBPs bind IGF1 and IGF2 without influencing the IR and are under development for use in cancer therapy. IGF1R, IGF1 receptor; IR, insulin receptor; IGF1 Ab, IGF1 antibodies; IGF1R Ab, IGF1R antibodies; IGFBPs, IGF-binding proteins; TKIs, tyrosine kinase inhibitors; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin.
Citation: Endocrine-Related Cancer 19, 5; 10.1530/ERC-11-0374
Metformin and cancer
Epidemiological studies have suggested a protective role for metformin in cancer development. Studies on patients with T2D on metformin have demonstrated a lower risk of cancer (Evans et al. 2005, Currie et al. 2009, Jiralerspong et al. 2009). In vitro studies corroborate these findings (Alimova et al. 2009, Kisfalvi et al. 2009, Cantrell et al. 2010, Rattan et al. 2011). Human breast cancer cells treated with metformin demonstrate inhibited proliferation and colony formation and increased cell cycle arrest (Alimova et al. 2009). It has been postulated that the effect of metformin on cancer development and progression may be a result of decreased levels of insulin and insulin resistance; however, studies have shown that metformin has a direct effect on tumor cell proliferation (Ben Sahra et al. 2010).
As stated previously, metformin activates AMPK. The AMPK/mTOR axis is modulated by liver kinase B1 (LKB1). LKB1 is a tumor suppressor that activates AMPK, leading to mTOR inhibition, resulting in inhibited cell growth (Ben Sahra et al. 2010). Zakikhani et al. (2006) demonstrated that metformin both upregulates AMPK activity and reduces general protein synthesis in MCF-7 human breast cancer cells, thereby functioning as a growth inhibitor. Additionally, Dowling et al. (2007) reported that metformin-mediated AMPK activation results in mTOR inhibition and reduced translation initiation. On the other hand, several studies have suggested an AMPK-independent effect of metformin on cancer cells (Guigas et al. 2006, Ben Sahra et al. 2008). Therefore, it is possible that metformin has an AMPK-dependent effect on some cancer cell lines and an AMPK-independent effect on others (Ben Sahra et al. 2010).
In vivo studies suggest an antineoplastic effect of metformin. Female transgenic Her2/Neu mice treated with metformin demonstrate decreased incidence and size of mammary adenocarcinomas. Additionally, the mean latency of tumor development is increased with metformin treatment (Anisimov et al. 2005). Algire et al. (2008) studied the effect of metformin on high-energy diet-induced tumor progression. A higher tumor volume was observed in mice receiving the high-energy diet than control mice that was attenuated in the presence of metformin treatment.
Human studies have shown similar results. Evans et al. demonstrated that treatment with metformin leads to a decreased risk of cancer in patients with T2D. A dose–response relationship was observed, as patients with the most exposure to metformin had the lowest rates of cancer (Evans et al. 2005). This dose–response relationship was confirmed by a more recent study that demonstrated that long-term use of ≥40 prescriptions (>5 years) of metformin was associated with an odds ratio of 0.44 (95% CI 0.24–0.82) for developing breast cancer compared with no use of metformin (Bodmer et al. 2010). Currie et al. (2009) reported that patients with T2D treated with metformin had decreased rates of cancer compared with those on other antidiabetic treatments. In a nested case–control study from Denmark, women with T2D on metformin were less likely to develop breast cancer than women who were not taking metformin, OR 0.77 (95% CI 0.61–0.99; Bosco et al. 2011).
Epidemiological studies have suggested that women who receive metformin for treatment of T2D not only have lower rates of breast cancer but also have better treatment response rates and lower rates of mortality from breast cancer (Jiralerspong et al. 2009, Landman et al. 2010). Jiralerspong et al. (2009) found that patients with early-stage breast cancer and T2D patients receiving metformin, in addition to neoadjuvant chemotherapy, had an increased rate of complete pathological response compared with patients with early-stage breast cancer and T2D not receiving metformin. In the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study in The Netherlands, patients with T2D taking metformin had a lower hazard ratio for cancer mortality, 0.43 (95% CI 0.23–0.80), and the hazard ratio with every 1 g increase in metformin was 0.58 (95% CI 0.36–0.93; Landman et al. 2010). Several clinical trials are now being conducted to determine whether metformin has clinically significant anticancer effects in patients without T2D. Additionally, the positive results seen with metformin have led to the development of other AMPK inhibitors that are currently under investigation (Park et al. 2009, Zhou et al. 2009).
IGF1- and IGF1R-targeted receptors
Monoclonal antibodies targeting the IGF1 peptide and the IGF1R have been studied for use in cancer treatment. Administration of antibodies to IGF1 (KM3168) and IGF2 (KM1468) to transgenic mice with a predisposition toward development of colon polyps results in reduced polyp formation. When combined, these two antibodies demonstrate an additive effect (Matsunaka et al. 2010). Treatment with these antibodies also leads to inhibition of bone metastases in prostate cancer cells (Goya et al. 2004). Similar agents are in phase I clinical trials.
Monoclonal antibodies directed at the IGF1R target the IGF1 system by binding to the α receptor of the IGF1R, thereby preventing the binding of IGF1 and IGF2. They also increase the internalization of the IGF1R, hence decreasing the number of receptors available for binding IGF1 and IGF2. The overall result is inhibition of the IGF1R signaling cascade (Heidegger et al. 2011). In vitro and in vivo studies with the monoclonal antibody robatumumab lead to inhibition of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor cells and xenografts (Wang et al. 2010). Studies using the IGF1R antibody AVE1642 demonstrate an inhibition of metastasis in metastatic breast cancer cell lines (Sachdev et al. 2010). Several of these agents are undergoing preclinical testing and are in clinical trials for the treatment of both hematological and sold malignancies (Haluska et al. 2007, Lacy et al. 2008, Heidegger et al. 2011). As early clinical studies have appeared promising, several phase II and III trials were initiated to evaluate these agents. The most common side effect observed is hyperglycemia, which is likely caused by a compensatory increase in GH following IGF1 blockade, however, and may also affect the IR by binding with hybrid receptors (del Rincon et al. 2007). Studies have been disappointing as limited efficacy and a high degree of side effects have led to cessation of several of these trials and concern over the continued use of these agents (Heidegger et al. 2011). Thus, more studies are necessary in order to optimize the therapeutic benefit of these medications, while minimizing their toxicities in cancer therapy.
Tyrosine kinase inhibitors
As the IR and the IGF1R are tyrosine kinase receptors that require tyrosine kinase activity for effective signal transduction and these receptors have been demonstrated to play a role in cancer development and progression, TKIs have been evaluated for use in cancer therapy. TKIs compete for the ATP-binding site on the tyrosine kinase, blocking insulin and IGF1 signaling (Clemmons 2007). In vitro studies using the TKI BMS-554417 demonstrate inhibition of the IGF1R and IR kinase activity and proliferation of various cancer cell lines. Treatment with this agent also leads to reduced tumor xenograft size in vivo (Haluska et al. 2006). The TKI BMS-754807 inhibits the growth of osteosarcoma, rhabdomyosarcoma, neuroblastoma, liposarcoma, breast, lung, pancreatic, colon, gastric tumors, and multiple myeloma and leukemia cell lines. In addition, treatment with this agent in xenograft tumor models leads to tumor growth inhibition (Carboni et al. 2009). Treatment of female MKR mice with the TKI BMS-536924 also results in diminished tumor growth (Novosyadlyy et al. 2010). The TKI OSI-906 has been shown to have antitumor activity in adrenocortical carcinoma and is currently undergoing a phase III trial (NCT00924989). Phase I and II trials using TKIs in cancers of the lung and breast and other solid tumors are ongoing (Heidegger et al. 2011). The most common side effect observed with use of the TKIs is hyperglycemia as the binding site is conserved between the IR add IGF1R and insulin signaling can be inhibited (Heidegger et al. 2011). Thus, further study of these agents is necessary.
Conclusion
Epidemiological studies suggest that obesity and T2D are positively correlated with both the risk of cancer and cancer-related mortality. The link between obesity, T2D, and cancer is related to insulin resistance, hyperinsulinemia, and increased levels of IGF1, as well as augmented levels of steroid and peptide hormones and inflammatory markers. Medications used to treat T2D may affect the risk of cancer and cancer-related mortality. Hyperinsulinemia and augmented insulin and IGF1 signaling can enhance tumor development and growth. Newer therapies targeting these systems are being studied and show great promise as cancer treatments; however, further studies are necessary to better define their optimal utility.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Acknowledgements
The authors would like to thank Archana Vijayakumar for her careful review of the manuscript.
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