Abstract
Many studies have provided observational data on the association of obesity and thyroid cancers, but only few of them propose mechanisms that would permit a better understanding of the causal molecular mechanisms of this association. Considering that there is an increasing incidence of both obesity and thyroid cancers, we need to summarize and link recent studies in order to characterize and understand the contribution of obesity-related factors that might affect thyroid cancer development and progression. Adipose tissue is involved in many vital processes, including insulin sensitivity, angiogenesis, regulation of energy balance, activation of the complement system, and responses such as inflammation. Although these processes have their own molecular pathways, they involve the same molecules through which obesity and adipose tissue might exert their roles in carcinogenesis, not only affecting MAPK and PI3K or even insulin pathways, but also recruiting local inflammatory responses that could result in disease formation and progression. This review describes five important issues that might explain the link between excessive weight and thyroid cancer: thyroid hormones, insulin resistance, adipokines, inflammation, and sexual hormones.
Introduction
Overweight and/or obesity have been consistently related to the development and progression of different types of cancers during the last decades. An extensive review published a few years ago estimated that approximately 20% of all cancers might be caused by excessive weight (overweight or obesity) (Wolin et al. 2010). Both the International Agency for Research on Cancer (IARC) and the World Cancer Research Fund (WRCF) recognize solid evidence that postmenopausal breast cancer, endometrial cancer, colon cancer, esophageal adenocarcinoma, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, thyroid cancers, leukemia, non-Hodgkin lymphoma, and myeloma are related to overweight and obesity with respect to development, treatment, and progression of the disease (IARC 2002, World Cancer Research Fund & American Institute for Cancer Research 2007, Wolin et al. 2010, De Pergola et al. 2013). However, because of the differences in the etiological factors related to different types of tumors and the variety of mechanisms involved in excessive weight conditions, cancers might be related to weight variations by distinct and complex pathways.
Many efforts have been made to understand the possible mechanisms underlying these associations, and it has been strongly suggested that endometrial and postmenopausal breast cancers are linked to obesity by endogenous estrogen levels (Begg et al. 1987, Kaaks et al. 2002, Renehan et al. 2008, Hvidtfeldt et al. 2012, Strong et al. 2013), whereas cancers of the gallbladder, and esophagus, lymphomas, and myelomas might be influenced by inflammation, which, itself, is very closely related to obesity (Renehan et al. 2008, Lodh et al. 2012, Kavanagh et al. 2013, Li et al. 2013, Wang et al. 2013). In patients with pancreatic and colon cancers, the evidence indicates a major role of insulin pathways linking the development of the disease with obesity (Renehan et al. 2008, Sun et al. 2013, Wolpin et al. 2013).
Concerning thyroid tumors, although many observational studies have been reporting a correlation between excessive weight and thyroid malignancy (Zhao et al. 2012), the mechanisms behind this correlation are not fully understood and a causal mechanism has not yet been established. In this review, we aim to present clinical data regarding the association of obesity and overweight with thyroid cancer and the latest findings on the possible pathophysiological pathways that underlie this association.
Obesity, BMI, and thyroid cancer
Epidemiological data
The World Health Organization (WHO) uses the BMI, a measure of weight relative to height (kg/m2) to indicate body fat, and recommends a median BMI in the range of 21–23 kg/m2 for optimal health. The general indication for subjects is to maintain the BMI in the range of 18.5–24.9 kg/m2, as a large number of studies have proved that there is an increased risk of comorbidities for BMIs ranging from 25.0 to 29.9 kg/m2, and moderate to severe risk of comorbidities for subjects with a BMI of over 30 kg/m2 (WHO 2009). In fact, the WHO estimates that, at the present time, 65% of the world's population live in countries where overweight and obesity cause more diseases and deaths than malnutrition (WHO 2009). The worldwide prevalence of obesity has almost doubled between 1980 and 2008 (Ogden et al. 2006), and although more recent studies have shown a tendency towards stabilization of the growing rates of obesity (Flegal et al. 2012, Perez Rodrigo 2013), the general rates of overweight and obesity remain very high in the population (Perez Rodrigo 2013). The WHO reported that over 50% of the population of America, the Eastern Mediterranean, and Europe were overweight in 2008 (Perez Rodrigo 2013).
Obesity and overweight have long been recognized as triggers for many diseases, such as hypertension, hypercholesterolemia, diabetes, insulin resistance (IR), and different types of cancers. Like obesity, thyroid cancer has been showing a worldwide increase in incidence during the last decades (Davies & Welch 2006, Chen et al. 2009, Agate et al. 2012, Jung et al. 2012, Wang & Wang (In Press)). This increase is mainly due to differentiated thyroid carcinomas (DTCs), and more specifically due to papillary thyroid carcinomas (PTCs) (Pellegriti et al. 2013). PTCs are indolent cancers, and most of them are not likely to progress or cause death (Brito et al. 2013). Although the incidence of thyroid cancers has presented a marked increase, the mortality rates have remained stable indicating that a pool of formerly undiagnosed tumors would possibly never present a clinical evolution (Davies & Welch 2006). However, the reasons why DTC incidence has been increasing are still controversial (Ward & Graf 2008). A series of studies have claimed that this was only a matter of diagnosis (Davies & Welch 2006, Grodski et al. 2008, Sprague et al. 2008), but the increasing incidence does not comprise only tumors less than 1 cm of extent favored by better imaging tests, but also larger tumors, making it difficult to believe that changes in incidence are exclusively due to improvements in diagnosis and health access (Enewold et al. 2009). Thus, it is possible to propose the hypothesis that we are dealing with an increasing exposure to risk factors that might contribute to this noticeable surge. Among the well-documented and recognized risk factors for DTCs are previous radiation exposure, iodine intake, familial history of thyroid disorders, hormonal and reproductive factors, TSH levels, and, more recently, the genetic profile; presence of inflammation and also BMI have been included to the list of potential risk factors for thyroid cancers (Agate et al. 2012).
Association between overweight and thyroid cancer: observational studies
The relationship between overweight and cancers has long been investigated, and the first available studies date back to the 1940s. In 1987, during the decade when the first obesity boom was reported, Albanes (1987) reviewed a series of studies concerning the relationship between overweight and different cancer types and observed that subjects with high relative body weight or high caloric intake were at a higher risk of developing breast, colon, rectum, prostate, endometrium, kidney, cervix, ovary, thyroid, and gallbladder cancers. But in the case of thyroid cancers, it was only after the year 2000 that larger studies started to appear with the first solid evidence (Pappa & Alevizaki 2013).
There are two different types of observational studies concerning the relationship between obesity and thyroid cancer: in the first one, thyroid cancer prevalence has been looked for in obese patients and, in the second one, patients with thyroid cancer are searched for obesity. These approaches give different information and pictures, but it is important to observe that obesity can be an epiphenomenon of the thyroid cancer disease, reducing therefore the relevance of the second type of studies, although there is no evidence that thyroid cancer induces important metabolic alterations. Most of the observational studies quoted in this revision are large cohorts of obese subjects.
Dal Maso et al. (2000) analyzed 12 case–control studies performed during the 1990s, including 2056 females and 417 males with thyroid cancer, and found a weak relationship of the BMI at diagnosis and an increased risk of thyroid cancer in females (OR=1.2), but no association in males. Although some other authors have shown associations of food intake with the risk of thyroid cancers (Franceschi et al. 1990, 1991, Shah 1999), this first review only considered anthropometric factors, not including any data regarding eating habits or other possible factors that could be related to obesity and cancer risk. However, it provided the rationale for further studies. Back at that time, there were scarce studies focusing on the mechanisms of obesity-related thyroid cancers.
During the next decade (2001–2010), many studies investigated the relationship between excessive weight and cancers and, although a considerable number of them were not specifically designed for thyroid cancers, many authors presented data on the relationship between DTCs and obesity. These studies included larger cohorts and, by the end of the decade, the mechanisms that would link DTCs and overweight/obesity started to appear as objects of investigation. Samanic et al. (2004) investigated a large cohort of US male veterans (3 668 486 whites and 832 214 blacks) with a diagnosis of obesity and their risk for the development of different types of cancers over almost 30 years. The primary goal of the authors was to identify differences in the risk of cancers between white and black subjects, and the authors reported that both white and black obese men presented a higher risk of developing thyroid cancers (RR=1.4; 95% CI=1.09–1.81 and RR=1.92; 95% CI=1.09–3.4 respectively) (Samanic et al. 2004). In an interesting study, Boru and colleagues analyzed an Italian cohort of 1333 obese patients who were considering bariatric surgery. Out of these patients, 43 (3.2%) presented with different types of cancer either before, during, or after the obesity treatment. Thyroid cancer was the second most frequent, affecting 8 (18.60%) out of the 43 patients with malignancies, indicating that severely obese subjects are at a higher risk of developing thyroid carcinomas (Boru et al. 2005).
Engeland et al. (2006) analyzed a very large cohort of subjects (2 000 947) followed for an average of 23 years. During this time, 3046 thyroid cancer cases were diagnosed and 1415 of them were either overweight or obese. The risk of thyroid cancer (all the types together) increased moderately with an increase in the BMI of one unit in both women (RR=1.02; 95% CI=1.01–1.03) and men (RR=1.03; 95% CI=1.00–1.05). The authors verified that obese women were at a higher risk of PTCs (RR=1.19; 95% CI=1.01–1.41) or follicular thyroid carcinomas (FTCs) (RR=1.63; 95% CI=1.24–2.15), but at a lower risk of medullary thyroid carcinomas (MTCs) (RR=0.35; 95% CI=0.16–0.79), demonstrating, for the first time, to our knowledge, that the association of obesity with thyroid cancers was stronger for DTCs. Men did not present a higher risk of DTCs, probably because the number of cases included was limited (Engeland et al. 2006). As a matter of fact, several studies have reported these differences between obese men and women and their risk of thyroid cancer, allowing speculation regarding hormone effects or the insufficiency of male cases analyzed, as thyroid cancer incidence is higher in women (Pappa & Alevizaki 2013). Other subsequent studies showed associations of weight, BMI, body surface area, and/or overweight/obesity and DTCs, demonstrating that these parameters elevated the risk of developing these cancers (Brindel et al. 2009, Mijovic et al. 2009, Clero et al. 2010, Leitzmann et al. 2010). However, as stated by Wolin, Carson, and Colditz in a great review of the association of obesity and cancers, by the year 2010, there were still only a few inconclusive studies about the mechanisms linking overweight/obesity and thyroid cancer (Wolin et al. 2010), although some authors had started outlining insulin-related pathways (Haddad et al. 2002, Rezzonico et al. 2008, 2009, Akinci et al. 2009, Cheng et al. 2010a).
During the current decade, several authors have been studying the relationship between excessive weight and cancer and trying to propose mechanisms underlying this relationship, based on the advances made by molecular biologists. Kitahara et al. (2011) published three large pooled analyses of cohort studies on the roles of obesity, the amount of exercise performed, and waist circumference (Kitahara et al. 2012a,b,c) in thyroid cancers. In these studies, all including very large cohorts, the authors demonstrated that overweight and obese subjects, compared with normal-weight subjects, presented a higher risk of developing thyroid cancers (HR=1.20; 95% CI=1.04–1.38 and HR=1.53; 95% CI=1.31–1.79 respectively) (Kitahara et al. 2011). In addition, subjects with a BMI of 25 kg/m2 or more who declared the greatest amount of physical activity presented a higher risk of thyroid cancer (HR=1.34; 95% CI=1.09–1.64) (Kitahara et al. 2012a,b). Studying some anthropometric parameters, Kitahara and colleagues demonstrated that a large waist circumference (over 102 cm in men and over 88 cm in women) increased the risk of thyroid cancer not only in men (HR=1.79; 95% CI=1.21–2.63) but also in women (HR=1.54; 95% CI=1.05–2.26) (Kitahara et al. 2012c), indicating that central adiposity might exert an effect on hormonal balance and metabolism which might increase the risk of thyroid cancer. In 2012, two other studies with very large cohorts demonstrated the association of excessive weight with thyroid cancers as well. Rinaldi et al. (2012) studied 343 765 females and 146 824 males, with 566 incident thyroid cancers, demonstrating an association of obesity with thyroid cancer risk in women (HR highest versus lowest quintile=1.41; 95% CI=1.03–1.94), but not a significant one for men. Zhao, in a meta-analysis of five studies, including a total of 809 941 subjects and 5154 thyroid cancer patients, demonstrated that excessive weight was associated with an increased risk of thyroid cancers (OR=1.18; 95% CI=1.11–1.25). Both overweight and obesity were risk factors for thyroid cancers, although overweight represented a slightly smaller risk than obesity (OR=1.13; 95% CI=1.04– 1.22 – for overweight and OR=1.29; 95% CI=1.18–1.41 for obesity) (Zhao et al. 2012). During the same year, our group demonstrated that excessive weight (BMI >25 kg/m2) was associated with an increased risk of DTCs (OR=3.787; 95% CI=1.12–6.81) and that this increased risk could be due to the excess calorie ingestion (OR=5.89; 95% CI=3.12–11.10), characterized by the excessive ingestion of proteins (OR=4.60; 95% CI=1.63–12.95) and carbohydrates (OR=4.90; 95% CI=2.59–9.28) (Marcello et al. 2012a).
In 2013, Kim and colleagues showed that obesity was not only associated with an increased risk of thyroid cancers, but could also exert an influence on tumor presentation. They reported that a 5-kg/m2 increase in the BMI was associated with PTCs >1 cm (OR=1.31; P<0.001), microscopic extrathyroidal invasion (OR=1.23; P=0.006), and advanced tumor/node/metastases (TNM) stage (OR=1.30; P=0.003) (Kim et al. 2013a). Some other authors have been reinforcing the data on the relationship between obesity and thyroid cancer, and the most recent studies have focussed on the possible links for this association, such as diabetes and/or IR (Shih et al. 2012, Tseng 2013), cytokines (Cheng et al. 2012, 2013, Di Cristofano 2013), diet (Kim et al. 2013b), anthropometric factors (Kim et al. 2013c), and even genetic variants that might affect susceptibility to thyroid cancers (Kitahara et al. 2012a,b). The main results presented in this section are summarized in Table 1.
Summary of observational studies relating excess weight and thyroid cancer risk
| References | Study design | Population studied | Main findings |
|---|---|---|---|
| Dal Maso et al. (2000) | Pooled analysis of 12 case–control studies | 2056 female and 417 male patients, 3358 female and 965 male controls | The heaviest women and men were at a higher risk of thyroid cancer (OR=1.2 and OR=1.5 respectively) |
| Weight at diagnosis was a risk factor (OR=1.20) in women | |||
| BMI at diagnosis increased the risk of thyroid cancer by 1.2 in women | |||
| Samanic et al. (2004) | Cohort study | 4 500 700 US male veterans (3 668 486 whites; 832 214 blacks) diagnosed as obese | White and black obese veterans were at a higher risk of developing thyroid cancer when compared with non-obese subjects |
| White: HR=1.4 | |||
| Black: HR=1.9 | |||
| Boru et al. (2005) | Cohort | 1333 severely obese patients (369 males and 964 females) | Thyroid cancer as the second most common malignancy (18.6% of the malignant cases) |
| Engeland et al. (2006) | Cohort | 2 000 947 persons (963 523 men and 1 037 424 women) 3046 cases of thyroid cancer | Obese women were at a higher risk of PTCs (RR=1.19) or FTCs (RR=1.63), but at a lower risk of MTCs (RR=0.35) |
| Brindel et al. (2009) | Case–control | 219 thyroid cancer cases (195 women/24 men) and 359 controls (315 women and 44 men) | Increased risk only in women |
| Highest quartile of BMI before diagnosis: 2.3 more risk for thyroid cancer | |||
| Higher risk in overweight or obese women at age 18 compared with normal lifelong weight women (OR=6.2) | |||
| Mijovic et al. (2009) | Cross-sectional | 253 patients with indeterminate FNABs | Women <45 years had higher malignancy rates when obese (65%) versus 54% (non-obese) |
| Clero et al. (2010) | Pooled analysis | 554 cases (65 men and 489 women) and 776 controls | Patients with a greater body surface area presented more risk of thyroid cancer. OR for women=3.97 and for men=4.06 |
| Leitzmann et al. (2010) | Cohort | 484 326 men and women from the USA, 352 cases of thyroid cancer | Higher risk in obese compared with normal-weight men (HR=1.89), especially for PTCs (OR=1.49) |
| Kitahara et al. (2011) | Pooled analysis of five prospective studies | 413 979 women and 434 953 men. 768 women and 388 men with thyroid cancer | Overweight and obesity compared with normal-weight increased the risk of thyroid cancer (HR=1.20 and HR=1.53 respectively) |
| Kitahara et al. (2012a,b) | Pooled analysis of five prospective studies | 362 342 men, 312 149 women. 308 men and 510 women with a primary thyroid cancer | Subjects with excess weight with the greatest amount of physical activity presented a higher risk of thyroid cancer (HR=1.34) |
| Kitahara et al. (2012c) | Cohort | 125 347 men and 72 363 women. 106 men and 105 women with thyroid cancer | Large waist circumference increased the risk of thyroid cancer not only in men (HR=1.79) but also in women (HR=1.54) |
| Rinaldi et al. (2012) | Cohort | 343 765 female and 146 824 male participants 566 thyroid cancer patients | Association of obesity with thyroid cancer risk in women (HR=1.41) |
| Zhao et al. (2012) | Meta-analysis | 809 941 subjects and 5154 thyroid cancer patients | Excessive weight (overweight and obesity) increased the risk of thyroid cancers (OR=1.18) |
| When the groups were separated: | |||
| Overweight: OR=1.13 | |||
| Obese: OR=1.29 | |||
| Marcello et al. (2012a) | Case–control | 115 DTC cases and 103 controls | Excessive weight increased the risk of DTCs by more than three times (OR=3.78) |
| Kim et al. (2013a) | Retrospective | 2057 patients with PTCs | Increase in the BMI was associated with PTCs >1 cm (OR=1.31), microscopic extrathyroidal invasion (OR=1.23), and advanced TNM stage (OR=1.30) |
PTC, papillary thyroid cancer; HR, hazard ratio; OR, odds ratio; FNAB, fine needle aspiration biopsy; FTC, follicular thyroid carcinoma; MTC, medullary thyroid carcinoma.
Understanding the underlying mechanisms: where do we stand?
Five important factors might explain the connection between excessive weight and thyroid cancer: thyroid hormones, IR, adipokines, inflammation, and sexual hormones (Fig. 1), but do we understand how they interfere with thyroid cells and tissue biology?
Schematic representing the main factors that might explain the relationship between obesity and thyroid cancer and the possible interactions among them.
Citation: Endocrine-Related Cancer 21, 5; 10.1530/ERC-14-0070
Thyroid hormones
Some studies with euthyroid subjects have shown evidence that regional obesity and a tendency to weight gain are associated with slight variations in thyroid function (Knudsen et al. 2005, Fox et al. 2008). A negative association between BMI and serum free thyroxine (T4) levels was reported (Knudsen et al. 2005), with lower T4 levels being associated with fat accumulation (Knudsen et al. 2005, Alevizaki et al. 2009). A moderate increase in triiodothyronine (T3) levels observed in obese subjects (Reinehr et al. 2006, De Pergola et al. 2007, Nannipieri et al. 2009) has been explained by a higher conversion of T4 to T3 as a compensatory mechanism for fat accumulation to improve energy expenditure (De Pergola et al. 2007). Positive associations were also observed between free T3 level and both waist circumference and BMI in obese patients (De Pergola et al. 2007). Some cross-sectional studies in euthyroid subjects demonstrated a positive association between serum TSH and BMI (Manji et al. 2006, Fox et al. 2008). Potential stimulators of TSH production, explaining the increase in TSH in obese patients, include hormonal mediators of adipose tissue, especially leptin (Rosenbaum et al. 2000, Sari et al. 2003). Apart from modulating food intake and energy expenditure, leptin acts as a neuroendocrine regulator of the hypothalamic–pituitary–thyroid axis by regulating the expression of TRH in the paraventricular nucleus; leptin secretion by adipose tissue will then be stimulated by TSH (Menendez et al. 2003, Oge et al. 2005, Feldt-Rasmussen 2007, Santini et al. 2010). Leptin may also affect deiodinases, activating the T4 to T3 conversion (Zimmermann-Belsing et al. 2003, Reinehr 2010).
In addition to the association between TSH and BMI, there is a clinical association between higher serum TSH levels and an increased risk of malignancy in human thyroid nodules (Fiore & Vitti 2012) and advanced stage of the disease (McLeod et al. 2013). As TSH is the major stimulator of thyrocyte proliferation, this hormone could be directly involved in thyroid carcinogenesis in obese subjects (Hard 1998). In fact, the binding of TSH to its receptor (TSHR) increases the intracellular levels of cAMP and activates proliferation pathways, including PI3K–AKT and RAS–BRAF pathways (Takada et al. 1990, Xing 2013). Mitogenic effects of TSH on follicular thyroid cells have been demonstrated using in vitro and animal models (Farid et al. 1994, Zielke et al. 1999, Rivas & Santisteban 2003). TSH also interacts with other growth factors such as insulin (Rapp et al. 2006). In IR, a clinical condition frequently present in obesity, insulin stimulates TSH production promoting proliferation of thyroid cancer cells (Hard 1998, Hursting et al. 2008).
Based on the important role of TSH in thyroid cell proliferation, a recent study has evaluated the serum TSH levels in two mouse groups that spontaneously develop thyroid cancer: one fed on a high-fat diet and another on a low-fat diet. However, no significant difference in serum TSH levels between the two groups was found, indicating that the tumor growth and anaplastic change observed in the obese mouse group occur independent of alterations of TSH level (Kim et al. 2013b).
Clinical studies also did not show an association between serum TSH and thyroid cancer. Two prospective studies evaluated serum TSH levels in obese and non-obese subjects. One study showed an increased risk of thyroid cancer in obese subjects, but this risk was unrelated to serum TSH levels (P=0.831) (Han et al. 2013). Another study, aiming to evaluate the prevalence of thyroid nodules in morbidly obese women, showed significantly higher TSH levels in this group when compared with a group of normal-weight and/or slightly overweight women (P<0.0001), but the prevalence of thyroid nodules was significantly lower in obese women (P<0.0001) (Cappelli et al. 2012).
In summary, the existing data neither support nor rule out the involvement of TSH hormone as an etiopathogenic element in the association between obesity and thyroid cancer.
IR and the role of IGF1
Back in 1992, Vassilopoulou-Sellin and colleagues reported the case of a girl with thyroid cancer and severe IR also associated with acanthosis nigricans (Vassilopoulou-Sellin et al. 1992), but it was only after the year 2000 that studies relating IR and thyroid cancer started to appear. IR is a condition in which the body produces sufficient insulin to take up and use glucose, but the sensitivity to this insulin is impaired or selective, thus causing pancreatic β-cells to upregulate insulin production as a compensatory mechanism, which results in hyperinsulinemia. There are several studies linking hyperinsulinemia and the risk and/or aggressiveness of colorectal, pancreatic, liver, esophageal, breast, and endometrial cancers (Gunter et al. 2008, Arcidiacono et al. 2012, Inoue & Tsugane 2012, Qiu et al. 2012, Zhan et al. 2013). Thyroid nodules follow the same trend (Rezzonico et al. 2008). Rezzonico and colleagues studied 111 euthyroid women divided into four groups: G1, subjects with IR and obesity; G2, obese women without IR; G3, normal-weight subjects without IR; and G4, normal-weight women without IR. Subjects with IR (G1 and G3) presented a higher frequency of thyroid nodules (50 and 61% respectively) when compared with members of groups G2 and G4 (23.8 and 16.1% respectively). In addition, about 30% of the subjects in G1 and G3 presented with larger nodules (>1 cm), whereas only 5 and 7% of the subjects in G2 and G4 presented with such nodules (Rezzonico et al. 2008). In order to verify if IR would specifically be increased in DTC patients, apart from other thyroid nodules, the same group further investigated 20 DTC women and 20 euthyroid subjects, observing that 50% of DTC patients but only 10% of the control group presented with IR; they suggested that IR could be an important risk factor for DTCs (Rezzonico et al. 2009). Not only the Argentinean group has reported the association of IR with thyroid nodules, but other studies in Turkish and Italian populations have also shown that nodular thyroid disease might be related to higher HOMA-IR (an index to measure IR) and metabolic syndrome (MetS) (Ayturk et al. 2009, Yasar et al. 2011, Rendina et al. 2012, Balkan et al. 2014). Rezzonico et al. (2011) investigated the effect of metformin, an anti-diabetic medication, on thyroid hyperplasia. The authors followed 66 women with hyperplasia and IR for 6 months and divided them into four groups: G1 (n=14), for those who received only metformin as treatment; G2 (n=18), subjects who received both l-T4 and metformin; G3 (n=19), patients treated only with l-T4; and G4 (n=15), women who did not receive any kind of medication. After 6 months, subjects in G1 and G2 presented a significant reduction in nodular size, while the G3 and G4 patients did not present with size-altered nodules (Rezzonico et al. 2011). These results reinforced the importance of IR in nodular thyroid disease and also provided evidence that IR diagnosis and its concurrent treatment may be beneficial. But what could be the molecular mechanisms involved?
The insulin signal transduction is dependent on two insulin receptors: IR-A (which has greater affinity for insulin-like growth factors 1 and 2 (IGF1 and IGF2), although it also recognizes insulin), and IR-B (insulin specific) (Artim et al. 2012). Blood glucose homeostasis in healthy subjects requires a very delicate adjustment of insulin production by pancreatic β-cells and insulin-mediated glucose uptake in tissues (Kern et al. 1990, Dimitriadis et al. 2008). The first step in insulin receptor activation results in the phosphorylation and recruitment of several molecules which ultimately lead to the downstream upregulation of the AKT/mTOR/PI3K and ERK/RAS/MAPK pathways, the two main signaling cascades involved in cancer proliferation and survival (Guo 2013). Hence, insulin receptors are also directly involved in the expression and effects of IGF1 and IGF2, both already related to thyroid cancers (Vella et al. 2001).
The stimulation of the IGF1 axis may cause different effects, as it is involved in inflammation, IR, diabetes, and cancer (Djiogue et al. 2013). IGF1 is a protein with a high level of conservation through species, probably due to its participation in vital processes such as the regulation of cell proliferation according to food availability (Longo & Finch 2003). Like TSH, IGF1 is also essential for thyroid cell growth and thyroid formation (Eggo et al. 1990). There are several reports associating the overexpression of IGF1 and IGF1 receptor (IGF1R) with thyroid enlargement and goiter development, supporting the hypothesis of an effect of IGF1 on thyroid cells (Cheung & Boyages 1997, Clement et al. 2001, Kimura et al. 2001, Volzke et al. 2007). In a recent report, Ock and colleagues have shown that in the absence of the IGF1R, neither TSH-induced thyrocyte hypertrophy occurs nor is goitrogen administration effective in promoting thyroid hypertrophy. The authors also observed that short-term treatment using IGF1 induces AKT activation, which may induce the TSH-stimulated IGF1R/mTOR/S6 signaling pathways in cultured thyrocytes (Ock et al. 2013).
While IGF1 is related to many events beyond IR, IGF2 plays its role through its binding to insulin receptors and the participation in the above-mentioned pathways (Djiogue et al. 2013). IGF2 receptor (IGF2R) may also play an important role in human cancers. In fact, mutations that cause loss of function of IGF2R gene have already been reported for breast, ovarian, lung, oral epithelial, and squamous cell carcinomas (Cheng et al. 2009).
Inflammation
For many years, adipose tissue was considered as a measly deposit of fat in our body. Today, adipose tissue is understood as a dynamic gland and the diverse range of molecules produced by adipocytes includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular hemostasis, blood pressure regulation, angiogenesis, the regulation of energy balance, and acute-phase response, as well as inflammation (Trayhurn & Wood 2004). Adipose tissue may be considered a component of the immune system, as it expresses receptors for many immune molecules (Fruhbeck 2006, Schaffler & Scholmerich 2010) in addition to producing immune molecules that can be released into circulation. These molecules may provide favorable conditions that support a pro-tumor immune microenvironment, indicating that obesity-dependent inflammation may be the link between obesity and cancer. But what are these molecules? How do they associate with obesity and cancer?
In addition to adipocytes, adipose tissue contains stromovascular cells that are active producers of molecules that may influence the immune response. Aiming to characterize changes that happen in adipose tissue with increasing adiposity, Weisberg and colleagues profiled the transcript expression in adipose tissue from several groups of mice. They found that the expression of 1304 transcripts correlated significantly with body mass and many of these transcripts were characteristic of macrophages. In fact, immunohistochemical analysis of adipose tissue revealed that the percentage of cells expressing macrophage markers was significantly and positively correlated with both adipocyte size and body mass, indicating an association between macrophage infiltration and development of obesity (Weisberg et al. 2003).
It has been proposed that pro-inflammatory T-lymphocytes are present in visceral adipose tissue and may contribute to local inflammatory cell activation before the appearance of macrophages, indicating that these cells could play an important role in the initiation and perpetuation of adipose tissue inflammation (Kintscher et al. 2008). Both M1 and M2 macrophages can be found in adipose tissue. M1 macrophages are stimulated by IFNγ or lipopolysaccharide and are able to produce pro-inflammatory cytokines. Conversely, M2 macrophages are related to humoral immune response and are able to produce anti-inflammatory cytokines, such as IL10 (Gordon & Taylor 2005). In this scenario, local hypoxia in obesity may promote the M2 to M1 switching (Catalan et al. 2013). Interestingly, these macrophages are responsible for almost all adipose tissue TNFα (TNF) expression and significant amounts of iNOS (NOS2) and IL6 expression (Weisberg et al. 2003).
TNFα is a cytokine that is believed to mediate tumor cytotoxicity and is a potent inducer of new blood vessel growth (angiogenesis) (Leibovich et al. 1987). Liu et al. (2012) demonstrated that diet-induced obesity produces an elevation in colonic TNFα levels and instigates a number of alterations in the key components within the Wnt signaling pathway, which have a pro-transformational nature, indicating that the Wnt pathway could be the mechanism by which obesity increases the risk of colorectal cancer. TNFα has an anti-proliferative action in a human PTC cell line through a receptor-mediated mechanism (Pang et al. 1994). Exposure of PTC cell lines to TNFα resulted in the development of progressively increasing loss of the TNFα-induced anti-proliferation, termed resistance (Pang et al. 1996). Probably, the high TNFα exposure provided by obesity may induce TNFα resistance that facilitates thyroid tumor progression.
IL6 is a pleiotropic cytokine. It interferes with growth and differentiation and some results indicate that IL6 might increase the risk of certain cancers such as those that originate from breast, liver, prostate, colon, and esophagus (Ghosh & Ashcraft 2013). However, the role of IL6 in thyroid cancer is still confusing. Using human thyroid cancer-derived cell lines, Couto and colleagues determined that IL6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 deficiency led to more proliferative and larger tumors, indicating that, at least in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth (Couto et al. 2012). An anaplastic thyroid cancer cellline secretes high levels of IL6 (Chang et al. 2003). Despite only a few results linking IL6 directly to thyroid cancer, IL6 may be important for the inflammatory microenvironment in thyroid carcinogenesis, and this microenvironment has already been proven to have an influence on DTC development and progression (Lumachi et al. 2010, Cunha et al. 2013).
Adipokines: the link among obesity, IR, and inflammation?
Our body produces cytokines in order to respond to aggressive or non-proper features. These molecules influence activation, growth, and differentiation of several different target cells. Adipokines or adipocytokines are a subset of cytokines produced by the adipose tissue (Cunha et al. 2013). They are involved not only in immune responses, but also in the regulation of appetite and energy balance, insulin sensitivity, angiogenesis, blood pressure regulation, and lipid metabolism (Kwon & Pessin 2013). Obesity, per se, is already related to an inflammatory state, but the presence of IR might enhance this inflammation, by decreasing the production of anti-inflammatory molecules, such as adiponectin, and producing pro-inflammatory adipokines, such as leptin and resistin, which will lead to the stimulation or blockage of several other immunological molecules, thus, promoting an optimal environment for tumor growth and development (Catalan et al. 2013).
Adiponectin is an adipokine with strong anti-inflammatory properties. It is produced exclusively by adipocytes; pro-inflammatory factors such as TNFα, IL6, and ROS can exert a regulatory effect on adiponectin expression (Li et al. 2009). This adipokine is able to improve insulin sensitivity, influence cell proliferation, and regulate the balance of anti- and pro-inflammatory molecules and cells, such as TNFα, IL10, macrophages, T-cells, and NK-cells, always aiming to control inflammation (Yokota et al. 2000, Kumada et al. 2004, Takemura et al. 2007). In order to develop these functions, adiponectin binds to two different receptors: AdipoR1 and AdipoR2. These receptors have an important role in improving the insulin signaling on target cells, through the increase in AMPK activity and PPARα and PGCα, also indirectly leading to a reflex on the AKT/mTOR/PI3K and MAPK pathways, well known due to their regulation of cell proliferation (Hall et al. 2009). In addition, during this process, adiponectin also influences the immune system through NFκB regulation (Obeid & Hebbard 2012). Owing to its complex anti-proliferative and inflammation-restraining functions, adiponectin has been suggested to have anti-neoplastic properties in some types of cancers. In recent years, several authors have been demonstrating association of adiponectin with breast, endometrial, prostate, colorectal, liver, pancreatic, and gastric cancers, as well as some hematological types of leukemia, lymphoma, and myeloma (Obeid & Hebbard 2012). In 2011, Mitsiades and colleagues demonstrated that adiponectin levels are in serum inversely correlated with DTCs, exerting a protective effect against the development of this cancer. Furthermore, the authors demonstrated that thyroid tissues express ADIPOR1 and ADIPOR2, facilitating the entrance and the functioning of adiponectin in the thyroid (Mitsiades et al. 2011), indicating that adiponectin is not only expressed, but also functional in thyroid cells. Another recent study has demonstrated that adiponectin receptors might be important for DTCs. Comparing tissues of primary PTCs with metastatic tissues, Cheng et al. (2013) reported that 27% of primary tumors expressed ADIPOR1 and 47% expressed ADIPOR2. When tissues were negative for both receptors, tumors were significantly associated with extrathyroidal invasion, multicentricity, and higher TNM stage, indicating that the expression of adiponectin receptors is associated with a better prognosis.
Leptin is another adipokine predominantly secreted by adipose tissue, although it can also be produced by skeletal muscle, stomach, and plasma (Piya et al. 2013). Leptin is structurally similar to other cytokines, such as IL2, IL6, and granulocyte-colony-stimulating factor (G-CSF), a characteristic that makes leptin capable of participating in similar cellular and organic processes, such as the control of food intake through satiety sensation, regulation of energy expenditure, the activation of monocytes and macrophages, stimulation of VEGF, angiogenesis, cell proliferation, and the suppression of anti-inflammatory cytokines (Kwon & Pessin 2013). The induction of leptin responses and effects involves its binding to leptin receptor b (ObR), leading to the activation of intracellular signals through JAK2, STAT3, and AMPK (Kwon & Pessin 2013). These molecules will then regulate several pathways of pivotal importance to cancers, such as the AKT/mTOR/PI3K and ERK/MAPK pathways, involved in cell growth and survival; COX2, IL1, and NFκB, related to inflammation; and VEGFs, involved in angiogenesis (Surmacz 2013). Thus, leptin interacts with several factors that participate in diverse carcinogenic stages, and its relationship with breast, prostate, colorectal, hepatocellular, pancreatic, and lung cancers, as well as thyroid cancer, has consistently been demonstrated in the literature (Dutta et al. 2012, Vansaun 2013). Concerning thyroid cancers, and more specifically DTCs, leptin and OBR (LEPR) expression were first demonstrated by Cheng et al. (2010b), who found them associated with a high risk of lymph node metastases. Other groups have also reported the involvement of leptin in the clinical phenotype of DTCs, and it has been suggested that leptin may affect the migration of thyroid cells, collaborating for a worse prognosis and metastasis formation (Cheng et al. 2010a, 2011, 2012, Kim et al. 2013b, Zhang et al. 2013).
Resistin is an adipokine produced by human monocytes and macrophages, as well as adipocytes (Kwon & Pessin 2013). Its name is derived from the fact that it was primarily related to IR by the suppression of insulin-mediated signaling in rat adipocytes (Steppan et al. 2005), but in humans this association is not always present. Actually, in humans, resistin has diverse functions in proliferative, anti-apoptotic, pro-inflammatory, and pro-angiogenic events (Hlavna et al. 2011, Piya et al. 2013). Inflammatory cytokines such as IL1β, IL6, TNFα, and LPS may induce resistin expression, but, conversely, resistin has been demonstrated to stimulate the production of IL6 and TNFα through the NFκB signaling pathway (Bokarewa et al. 2005). In addition to its action on the immune system molecules, resistin can also bind to TLR4, activating JNK and p38 MAPK, to induce IR (Benomar et al. 2013). Owing to its ability to regulate immune molecule production and its indirect regulatory effect on the MAPK pathway and other proliferative events, resistin has been investigated in human cancers. Its expression has been linked to the increased proliferation of prostate cancer by the stimulation of the AKT/mTOR pathway (Kim et al. 2011). Resistin has also been linked to breast, endometrial, colorectal, hepatocellular, pancreatic, and lung cancers (Hlavna et al. 2011, Jiang et al. 2012, Dalamaga et al. 2013, Duan et al. 2013, Kuo et al. 2013, Stewart et al. 2013).
Preliminary data from our group indicate that quantification of serum leptin, adiponectin, resistin, and ghrelin might provide an excellent tool for diagnosis malignancy in thyroid nodules (Marcello et al. 2012b). We observed that DTC patients had lower levels of adiponectin in serum (2.46±0.84) when compared with patients with benign nodules (3.03±1.73; P<0.0001). Leptin, on the other hand, was higher in DTCs (9.82±0.70) than in benign cases (1.95±0.67; P<0.0001). Similarly, resistin levels were higher in patients with DTCs (14.80±1.53) than in patients with benign nodules (1.99±0.66; P<0.0001). Ghrelin levels differed between DTC (84.56±24.02) and benign patients (133.57±18.00; P<0.0001). The receiver operating characteristic (ROC) curves for all the cytokines showed that the concentrations of serum adiponectin, leptin, resistin, and ghrelin distinguished benign from malignant nodules with 76, 100, 100, and 96% accuracy respectively (Marcello et al. 2012b; Fig. 2). In a deeper investigation, we were able to show that these cytokines helped to discriminate follicular patterned lesions. The follicular variant of PTC (FVPTC) could be distinguished from follicular adenomas (FA) by adiponectin (P<0.05), leptin (P<0.001), and ghrelin levels; and from goiters by serum leptin (P<0.001), resistin (P<0.001), and ghrelin (P<0.001) levels. FA differed from follicular carcinomas and the classic PTCs (CPTCs) with respect to leptin (P<0.001) and ghrelin (P<0.001) levels. The CPTCs differed from FA with respect to leptin (P<0.01) and ghrelin (P<0.01) levels and from goiters with regard to leptin (P<0.001), resistin (P<0.001), and ghrelin (P<0.01) levels. These results indicate that the peripheral blood measurement of serum adiponectin, leptin, resistin, and ghrelin levels, using simple and reliable ELISAs, may represent a new alternative approach to the diagnosis and management of thyroid nodules MA Marcello, A Calixto, LL Cunha, MB Martins, AC Vasques, BC Geloneze and LS Ward, unpublished observations).
Box plots showing the serum concentrations of the adipokines studied and ROC curves showing the very high specificity and sensitivity of these adipokines.
Citation: Endocrine-Related Cancer 21, 5; 10.1530/ERC-14-0070
Gender
The relationship between thyroid cancers and gender is long known, as all the available literature have reported a higher thyroid cancer incidence among women. In fact, the Brazilian National Cancer Institute (INCA) estimates that 2.9% of the new cases of cancer (do not include skin cancers – not melanoma) affecting women in Brazil in 2014 will correspond to thyroid cancers. This incidence rate drops to only 0.4% in men (INCA 2014). In a recent review, Pellegriti et al. (2013) have shown that the incidence rates of thyroid cancer among women have grown considerably more than that for men in countries such as Denmark, Finland, France, Israel, Italy, Japan, Spain, Switzerland, United Kingdom, and the USA.
In 1979, considering the follow-up of 600 patients, Cady et al. (1979) observed that women who had thyroid cancers before menopause presented with less aggressive tumors, in comparison with women diagnosed after menopause. Several subsequent studies with large cohorts have proven a strong association of thyroid diseases and, more specifically, thyroid cancers with female gender; in addition, many reports describe differences in thyroid cancer comportment in men and women (McTiernan et al. 1984, Ron et al. 1987, Galanti et al. 1996, Truong et al. 2005, Leux et al. 2012). But how do estrogen and/or reproductive hormones influence thyroid cancers?
Even though the thyroid carcinogenesis model that is widely accepted and consolidated indicates a major role of mutations in members of the MAPK and PI3K/AKT pathways, accumulating evidence indicates that these inherited or somatic alterations are not sufficient to characterize tumors, and the microenvironment where this tumor is inserted is of extreme importance for tumor phenotypes (Cunha et al. 2013). Estrogen might influence this microenvironment.
Banu et al. (2001) first demonstrated that both testosterone and estradiol had effects on the proliferation of human PTC and FTC cell cultures and that these two cell lines presented receptors (ERα and ERβ) for the studied hormones. These receptors are responsible for the functions of estrogen, and they have opposite functions with respect to cell proliferation and survival. ERα acts as a stimulator of proliferation and suppressor of apoptosis, whereas ERβ acts as an adjuvant for cell differentiation and stimulates apoptosis (Di Vito et al. 2011). Investigations with thyroid cancer cell lines and also some human thyroid tumors have demonstrated the expression of ERs in thyroid tumor cells, both neoplastic and non-neoplastic, indicating that thyroid cells are likely to experience effects of estrogen or ERs (Lee et al. 2005, Zeng et al. 2007, 2008). In fact, the administration of estrogen has been associated with thyroid cell growth and proliferation and also with some changes in other markers of proliferation, growth, and angiogenesis, demonstrating not only the intracellular role of estradiol and ERs, but also their role in the transcription of other genes (Tangjitgamol et al. 2005, Zeng et al. 2007, Chen et al. 2008, Ranks et al. 2009, Kavanagh et al. 2010, Kumar et al. 2010, Rajoria et al. 2010, Kamat et al. 2011). A recent study has demonstrated crosstalk between ER and PPARγ, indicating that levels of expression of ERα (ESR1) and ERβ (ESR2) are related to PPARγ levels in the cell. Chu and colleagues demonstrated that there is an inverse relationship between PPARγ and ERs. Also, these authors demonstrated that while cells that presented ERα activation were able to control the inhibitory effect of PPARγ on cellular functions, activation of ERβ led to apoptosis. When the interaction between ERβ and PPARγ was tested, molecules such as caspase 3 and apoptosis-inducing factor were expressed, indicating that the crosstalk between ERβ and PPARγ could be a target for DTC therapy (Chu et al. 2013).
It is certainly important to understand these complex molecular mechanisms, but how do they relate to obesity and obesity-related cancers?
Although the molecular relationship between estrogen and thyroid cancers has been largely investigated, the literature is a lot scarcer when obesity is involved. The relationship between obesity and waist circumference is a crucial point for the understanding of the relationships between obesity, estrogen and cancer. The National Institute of Health (NIH) in the USA, following the WHO recommendations, considers that overweight or obese subjects presenting waist circumference over 102 cm (men) and over 88 cm (women) are at an extremely high risk of developing several types of disease, especially the ones related to metabolism of glucose (WHO 2011). After the first sexual differentiation, during the teenage years, two other very important aspects also contribute to body fat distribution: reproductive status and age, which can be connected in women. Pregnancy, for example, is associated with gains in central and visceral adiposity post partum, augmenting women's waist circumference and dislocating fat accumulation to the upper part of the body (Lassek & Gaulin 2006). In the same way, menopause is associated with an increase in fat mass and a redistribution of fat to the abdominal area, indicative of two important protagonists: hormones and aging (Toth et al. 2000). Although steroid hormones may have more influence in women than in men, the age factor is of extreme importance for both. Ford et al. (2003) demonstrated that the waist circumference increases with the age in both genders, indicating that after a certain moment in time, waist changes will be nearly equivalent and the differences between men and women will disappear. Kitahara et al. (2012c) described an influence of the large waist circumferences on DTCs, but this is the first association of waist circumference with thyroid cancers. This association might be justified by the fact that fat accumulation, specifically in the abdominal region, might lead to a hypertrophy of adipocytes or even impair their functions.
Adipose tissue is involved in many vital processes, including insulin sensitivity, angiogenesis, regulation of energy balance, activation of the complement system, and responses such as inflammation (Trayhurn & Wood 2004). Although these processes have their own molecular pathways, they involve the same molecules through which obesity and adipose tissue might exert their role in carcinogenesis, not only affecting MAPK and PI3K or even insulin pathways, but also recruiting local inflammatory responses that could result in disease formation and progression.
Summary/conclusions
In this review, we attempted to summarize and discuss available data in order to better understand obesity-related thyroid cancers. Although recent reports have described a slight decrease in the prevalence of obesity, these data might be considered with caution, as methodologies for the evaluation of these data are different from the ones used in the past. Furthermore, the incidence of thyroid cancers is still rising and a better characterization of the relationship between obesity and thyroid cancers could help in the establishment of new preventive measures and also in identification of new specific targets for cancer therapy, improving not only the quality of health services but also patients' quality of life, which remains our main goal.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
We thank the National Council for Scientific and Technological Development (CNPq) – Brazil for the grants 141299/2011-8 and 475673/2013-1, which allowed the realization of this paper.
Author contribution statement
All authors of this review have directly participated in the planning, analysis, and writing of the article. All authors of this review have read and approved the final version submitted.
Acknowledgements
We thank Etna Macário of the Faculty of Medical Sciences for her valuable suggestions and insights in the English review. We also thank Murilo Meneghetti for his help with the tables and figures.
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