The role of selected adipokines in tumorigenesis and metabolic disorders in patients with adrenal tumors
Anna Babinska, Piotr Kmieć, Krzysztof Sworczak
| Department of Endocrinology and Internal Medicine, Medical University of Gdansk, | Corresponding author: |
|---|---|
| Gdansk, Poland | Anna Babinska MD |
| Department of Endocrinology | |
| Submitted: 30 April 2019; Accepted: 12 August 2019 | and Internal Medicine |
| Online publication: 4 March 2020 | Medical University of Gdansk 7 Dębinki St |
| Arch Med Sci 2023; 19 (2): 467-477 | 80-288 Gdansk, Poland |
| DOI: https://doi.org/10.5114/aoms.2020.93486 | Phone: +48 58 349 28 40 |
| Copyright @ 2020 Termedia & Banach | Fax: +48 58 349 28 41 |
| E-mail: a.mail@wp.pl |
Abstract
Recently, more and more attention has been directed to the role of adi- pose tissue and adipocytokines in the pathogenesis of metabolic and in- flammatory disorders in humans. Excess fat tissue has also been associated with a higher risk of malignancies. Advances in the research on the role of adipokines in adrenal tumors may elucidate the relationship between various types of adipose tissue (visceral, subcutaneous, and periadrenal) and metabolic disorders observed in hormonally active adrenal tumors, as well as associations with adrenal cortex cancer. In patients with active or cured Cushing syndrome, increased leptin and resistin concentrations as well as release of pro-inflammatory cytokines can be associated with car- diovascular risk. Also, the renin-angiotensin-aldosterone system in patients with primary hyperaldosteronism may affect the metabolic activity of the adipose tissue. Elevated resistin concentrations in this group of patients are associated with morphological changes of the myocardium independently of the effects of the metabolic syndrome. Further, it has been suggested that hypoadiponectinemia comprises an additional factor in the pathogenesis of carbohydrate metabolism disorders and the risk of cardiovascular com- plications in pheochromocytoma patients. Understanding the mechanisms of action of adipokines may be important in developing prophylactic and therapeutic strategies in hormonally active and malignant tumors of the adrenal glands.
Key words: adipokines, adipokine receptors, subclinical Cushing syndrome, Cushing syndrome, pheochromocytoma, primary hyperaldosteronism, adrenocortical carcinoma.
Introduction
Obesity is a major social problem. The number of obese people in the United States in 2010 was 78 million [1]. Obesity increases the risk of hypertension (HT), dyslipidemia, type 2 diabetes (DM2), coronary artery disease (CAD), stroke, gallbladder disease, osteoarthritis, and sleep ap- nea. Also, the relationship between obesity and many human cancers has been proven: in all malignancies, obesity was associated with an increased mortality rate - by 52% in men and 88% in women [1-3].
Apart from its role in the storage of lipids, the adipose tissue (AT) is considered the largest endocrine gland in humans. It regulates energy homeostasis, metabolism, inflammatory processes, immunity, hormonal equilibrium, and bone turnover [4-7]. Concerning metabolic homeo-
AMS
stasis, physiologically, hormones secreted by the AT (adipokines) signal functional status to other organs. In this respect, the crucial peptides are leptin and adiponectin. What is more, substances produced by the fat tissue are also involved in im- munity and inflammation. Obesity and adipocyte dysfunction induce production of inflammatory cytokines (commonly, and also here, referred to as adipocytokines together with adipokines), the secretory profile of the AT becomes pathologic. Adipocytokines likely contribute to metabolic dis- eases and inflammation [8, 9].
Adipose tissue is considered to be involved in the pathology of rheumatoid arthritis (RA), sys- temic lupus erythematosus, and Behçet’s disease [10]. In active arthritis peri-articular fat and syno- vial tissue were shown to release leptin, resistin and adiponectin, and the secretion of proinflam- matory adipokines was increased [10]. Excessive expression of adipokines was also demonstrated in the intestinal mesenteric fat tissue in patients with Crohn’s disease. Research on the effect of adipokines on acute pancreatitis is ongoing: it seems that serum concentrations of resistin and leptin are elevated in this disease and may con- stitute its marker [11]. Kumar et al. [12] described increased adipogenesis and increased expression of adiponectin and leptin in the orbital tissue of patients with active thyroid orbitopathy.
Chronic inflammation that takes place in the adipose tissue may affect the development of metabolic disorders related to obesity. In many studies, a relationship has been demonstrated between adipocytokine secretion observed in obesity and the development of insulin resistance, DM2, hypertension (HT), non-alcoholic steatohep- atitis, and adverse lipid profile [8, 9].
Furthermore, a relationship has been investi- gated between various adipocytokines and hu- man neoplasms, including benign and malignant tumors of the endocrine system. The main mecha- nisms underlying the association between obesity and the risk of malignancy include:
- insulin resistance and the insulin-like growth factor 1 (IGF1) system (insulin inhibits apoptosis and stimulates IGF1 synthesis, which is a growth factor and promotes cancer; in obesity IGF1-bind- ing protein synthesis in the liver is reduced, as a result, IGF-1 bioavailability increases),
- impact of adiposity on the biosynthesis and bio- availability of endogenous sex hormones,
- obesity-induced low-grade chronic systemic in- flammation,
- alterations in the levels of adipocyte-derived fac- tors [3, 5, 13, 14].
In many human cancers (mainly those relat- ed to obesity) the role of leptin, which promotes carcinogenesis, as well as adiponectin, has been
investigated. In humans, leptin has been shown to increase the growth of tumor cells associated with obesity, but it has also been proven to affect cancers not associated with obesity, for example, central nervous system tumors - gliomas and me- ningiomas [15].
Adiponectin, on the other hand, has a pro- tective effect and anti-proliferative properties. Decreased adiponectin concentration has been demonstrated in cancers of the stomach, pros- tate, endometrium and breast [5].
There are a few reports concerning the role of adipose tissue in endocrine diseases. In this re- view the role of adipokines in oncogenesis and metabolic disorders in the course of human adre- nal gland tumors is discussed.
Methods
This review was based on an electronic search of literature using the PubMed database. Associa- tions between adipokine and cytokine levels and the risk of cancers and metabolic disorders in ad- renal tumors were investigated.
Characterization of selected adipokines
Adiponectin
The best known adipokine is adiponectin [4, 5]. Adiponectin is believed to be a mediator of obe- sity-related cancers and exerts direct anticancer effects via its receptors [5, 16]. Adiponectin is mainly synthesized in the white adipose tissue; secretion in the brown adipose tissue is low [7, 17]. Researchers also noted the presence of adi- ponectin in other animal tissues: skeletal muscles [18], liver [19], colon [20], cardiac tissue [21], sal- ivary glands [22], bone marrow [23], fetal tissue and placenta [24], as well as cerebrospinal fluid [25], and breast milk [26]. Its expression in various tissues may indicate its para- and autocrine ac- tion [4, 5]. Adiponectin is a 247-amino acid mono- mer protein that circulates in the form of trimers, low molecular weight hexamers (LMW), or mul- timeric form with high molecular weight (HMW). Various spatial forms have different physiological properties, and the HMW and trimeric forms have the highest biological activity [4, 5]. It seems that the key factor in exerted biological effects of adi- ponectin is not its total concentration but the ra- tio of the HMW fraction to total adiponectin [4, 5].
The effects of adiponectin are mediated via its receptors, which are present in various organs and tissues. Yamauchi was first to isolate adi- ponectin receptors in human and mouse tissues in 2003 [27]. To date, three adiponectin receptors have been identified: two main, i.e. AdipoR1 and AdipoR2, and one receptor similar to that in the cadherin family [5, 28]. Receptor expression cor-
relates with insulin concentration, and decreases in diabetic mice [29]. Obesity seems to reduce the expression of AdipoR1/AdipoR2, thus reduc- ing the sensitivity to adiponectin, which in turn leads to a vicious cycle of insulin resistance [30]. Aging and long-term consumption of high-fat foods were reported to reduce the concentration of adiponectin and increase the expression of its receptors [31].
Adiponectin, through its receptors, activates several intracellular signaling pathways, mainly AMPK, but also mammalian target of rapamycin (mToR), nuclear factor KB (NF-KB), c-Jun N-termi- nal kinase (INK), and signal transducer and activa- tor of transcription proteins, STATs [32, 33].
The negative correlations between circulat- ing adiponectin and obesity (especially central), insulin resistance and DM2 are well known [34]. A meta-analysis of prospective studies involving a total of 14,598 participants and 2,623 DM2 cases showed that higher adiponectin concen- tration was associated with a lower risk of DM2 [34]. Higher adiponectin levels were also associat- ed with a moderate reduction of coronary artery disease risk in men with DM [35]. In addition, hypoadiponectinemia was associated with an ad- verse atherosclerotic lipid profile [36]; the risk of cardiovascular complications was inversely pro- portional to adiponectin concentrations [37].
Adiponectin has insulin-sensitizing action and reports by some authors indicate that hypoadi- ponectinemia is associated not only with insulin resistance, DM, and CAD [38-40], but also with malignant tumors [6]. The anti-inflammatory effect of adiponectin is primarily conveyed by inhibition of T-cell activation and proliferation, and blocking of tumor necrosis factor a (TNF-a) release. Adi- ponectin also inhibits the synthesis of interferon y (IFN-y), a molecule that stimulates cytotoxicity of natural killer (NK) cells. Adiponectin induces the synthesis of interleukin (IL)-10, an anti-inflamma- tory molecule, and receptor antagonist for IL-1. It also increases monocyte apoptosis and phagocyto- sis by macrophages, and inhibits the expression of TNF-a-induced adhesion molecules [25].
The protective effect of adiponectin in cancer is based on its anti-proliferative properties. It inhibits angiogenesis and intracellular signaling associated with carcinogenesis [41]. Adiponectin reduces the proliferation of tumor and endothe- lial cells in the breast and prostate by binding mitogenic growth factors [41]. Several cancer cell lines express receptors for adiponectin, sug- gesting its possible direct effects on these cells. Expression of adiponectin receptors has been demonstrated in breast, prostate, liver, stomach, colorectal, pancreatic, and lung carcinoma [5, 16, 42-45].
Chou et al. analyzed the relationship between AdipoR1 and AdipoR2 expression in various hu- man neoplasms and cancer progression assessed as presence of local lymphatic and distant metas- tases. A statistically significant relationship was found between AdipoR1 expression and kidney cancer with and without metastasis. In the course of kidney cancer, a neoplasm strongly associated with obesity, lower serum adiponectin levels and significantly higher expression of AdipoR1 recep- tors in tumor tissue are found than in non-obe- sity-associated neoplasms [16]. In breast cancer, high expression of AdipoR1 was associated with vascular invasion. In contrast, in gastric cancer, high AdipoR1 expression was associated with lon- ger survival [16].
Leptin
Leptin is the second well-known human ad- ipokine. It is mainly produced by differentiated adipocytes, and its effects are contrary to those of adiponectin [46]. Leptin suppresses appetite and induces energy expenditure, although in the obese elevated leptin levels are present presum- ably due to resistance to the hormone [8].
Leptin is a pro-inflammatory adipokine. It en- hances the formation of free oxygen radicals and induces proliferation of endothelial cells and expression of metalloproteinases within the ex- tracellular matrix. It also activates neutrophils, monocytes and cytotoxic NK cells, stimulates pro- duction of proinflammatory cytokines by mono- cytes and lymphocytes, increases proliferation of T-lymphocytes and monocytes, and promotes angiogenesis. Leptin acts via its receptor, Ob-R (located on the surface of endothelial cells and leukocytes) [4], regulates many intracellular path- ways: JAK (Janus kinase), STAT (signal transducer and activator of transcription) protein, PI3K (phos- phatidylinositol 3-kinases), AKT (protein kinase B), and MAPK (mitogen-activated protein kinase). In addition, leptin increases proliferation via a vari- ety of growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), and IGF-1 [47, 48].
A positive relationship between leptin con- centration and coronary artery calcification was demonstrated in 860 healthy adults, who had neither diabetes nor established cardiovascular risk factors [49]. Leptin induced C-reactive protein (CRP) secretion, which is a well-known marker of cardiovascular risk [49].
Leptin is one of the most potent adipokines in metabolic regulation. It regulates body weight by signaling the state of nutrition to other organs - in particular to the hypothalamus, which produces neuropeptides and neurotransmitters that affect energy delivery and expenditure. Leptin also plays
an important role in the regulation of homeosta- sis. It improves insulin sensitivity in the liver and skeletal muscles and regulates the function of pancreatic ß cells. Interactions between leptin and inflammation are bi-directional: proinflammatory cytokines increase the synthesis and release of leptin, which in turn contributes to chronic inflam- mation in obesity [8].
Leptin was shown to increase the growth of breast, esophageal, stomach, pancreatic, prostate, ovarian, and lung cancer cells [50-52]. A rela- tionship between leptin concentration and colon cancer cell proliferation was also suggested [53]. Further, it was indicated that leptin promotes the proliferation of some breast tumors in vitro as well as tumor invasiveness and angiogenesis in some animal models [53, 54]. The oncogenic effects of leptin have not been elucidated yet. It is believed this protein activates intracellular signal transduc- tion pathways [55]. In addition to receptor effects of leptin, e.g. in gastric cancer, its direct paracrine and autocrine action not mediated by its recep- tor was proposed [51]. It seems that oncogenic effects of leptin are exhibited more prominently in obesity-related cancers (esophageal, breast, stomach, colon and pancreatic) compared to those in which obesity plays a smaller role [56]. In epidemiological studies, an association between serum leptin concentrations and tumor progres- sion was suggested. The strongest relationship was demonstrated for colon, prostate and breast cancers [57-59].
The effect of leptin on endocrine tumors is very poorly understood. Ob-R presence was demon- strated in the human adrenal glands [60]. Asso- ciations between leptin levels and adrenocortical and adrenal medullary neoplasms have not been investigated yet.
Resistin
Resistin was first discovered as an obesity hor- mone in animal studies. In obesity, an increase in serum resistin concentration was observed [61]. In experimental studies, resistin was demon- strated to act antagonistically to insulin [62, 63]. It seems that in humans resistin acts on insulin signaling pathway, causing dephosphorylation of 3-phosphorylated phosphoinositide [64]. Recent research in humans also indicates its role in the pathogenesis of atherosclerosis. Its concentra- tion was demonstrated to be independently as- sociated with an increased risk of myocardial in- farction and ischemic stroke in a large cohort of middle-aged subjects and in the Women’s Health Initiative Observation Study [65]. Also, high re- sistin concentration was associated with morpho- logical changes in the heart independently of the presence of metabolic syndrome [66].
Recent reports indicate that high serum resistin levels are an important risk factor for heart failure in the elderly, independently of CRP, insulin resis- tance or obesity [67, 68].
Resistin is mainly produced by monocytes and macrophages (whichisstimulatedbyTNFaandIL-6), and its synthesis is induced during adipogenesis [69-71]. In turn, resistin activates the NF-KB path- way and, as a result, induces TNF-a, IL-6, and IL-12 production. Resistin stimulates expression of adhe- sion molecules: vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in endothelial cells, and induces endo- thelin 1, a strong spasmogen.
Epidemiological studies in humans showed a relationship between elevated resistin concen- tration and higher risk of DM2, myocardial infarc- tion, and atherosclerosis. It seems that resistin concentration may serve as a marker of metabolic diseases in humans [8].
Other proinflammatory cytokines secreted by the adipose tissue
Associations between a pathologic adipocyto- kine profile (reduced adiponectin and increased leptin as well as resistin levels) and the develop- ment of insulin resistance, DM, and the risk of car- diovascular diseases have been reported by many researchers [4, 72, 73]. In studies of the patholo- gies of cardiovascular and metabolic diseases as well as malignancies cytokines secreted by the AT other than the three adipokines above have also been investigated.
Pro-inflammatory cytokines, including IL-6, TNF-a, and monocyte chemoattractant protein 1 (MCP-1), are involved in many pathological pro- cesses including inflammation, endothelial dam- age, atherosclerosis, insulin resistance, HT, and bone remodeling [4, 74].
Interleukin 6 is a cytokine that plays an import- ant role in the development of insulin resistance in obesity. Adipose tissue contributes to 10-35% of circulating IL-6 in humans. Hyperglycemia caus- es an increase in IL-6 concentration. Expression of IL-6 in the adipose tissue correlates positively with insulin resistance both in vivo and in vitro [8]. In a cohort of 1293 healthy elderly subjects followed prospectively for a mean of 11.6 years, elevated IL-6 levels were associated with a doubling of car- diovascular risk and all-cause mortality [36]. Also, elevated IL-6 concentrations were shown to con- stitute a risk factor of DM2 and myocardial infarc- tion [34, 37].
Tumor necrosis factor a is part of the inflammatory system, capable of initiating a cy- tokine cascade including synergistic and inhibi- tory reactions that control the synthesis and ex- pression of other proinflammatory cytokines [8].
TNF-a promotes the expression of adhesive mol- ecules in endothelial cells and synthesis of endo- thelin 1 and angiotensinogen, which contributes to HT. Pro-inflammatory effects aside, TNF-a and IL-6 lower adiponectin secretion [23, 27, 39].
Adipocytokines in benign human adrenal cortex tumors
Wide use of thoracic and abdominal imaging studies results in an increased prevalence of ad- renal tumors, which amounts to 10% among the elderly [75]. Most of the discovered tumors are hormonally inactive; rarely they have subclinical or overt hormonal activity [75]. All hormonally active tumors may lead to many metabolic disor- ders and an increased risk of cardiovascular dis- eases [76-80]. There are also reports indicating increased risk of these diseases in non-functional adrenal incidentaloma patients (NFAI) [81].
Adipokines were shown to be secreted by the periadrenal fat tissue surrounding adrenal tumors and their receptors to be present in tumor tissues [16, 82, 83]. Researchers’ interest has been direct- ed at a potential effect of adipokines on hormonal activity and metabolic disorders in hormonally ac- tive adrenal tumors.
Adrenal Cushing’s and subclinical Cushing’s syndrome
Endogenous Cushing’s syndrome (CS) is a con- sequence of chronically increased serum gluco- corticoid concentrations. Authors of many studies have shown that glucocorticoid overproduction in both overt and subclinical Cushing’s syndrome (CS and SCS) increases the risk of metabolic diseases and cardiovascular events [72, 74, 81, 84-87]. In patients with CS, the mortality rate due to com- plications of metabolic diseases increases fourfold compared with the healthy population [72, 88].
In a number of studies a relationship has been shown between concentrations of cortisol and adipocytokines [72]. Wagenmakers et al. showed that an adverse adipokine profile (i.e. low adi- ponectin and high leptin and resistin levels) per- sisted even after CS patients had been cured [89]. Persisting central distribution of the AT negatively affects the adipocytokine profile and likely con- tributes to sustained increased cardiovascular risk, independently of active hypercortisolemia [89]. The authors of the current review observed higher TNF-a and IL-6 concentrations as well as lower adiponectin levels in 20 SCS patients com- pared to healthy volunteers [90].
Dogruk Unal et al. demonstrated that low ad- iponectin concentration is a valuable determinant of SCS in patients with accidentally discovered ad- renal tumors [87]. Barahona et al. recorded lower concentrations of adiponectin in clinically active
CS female patients as well as those treated for CS (over the preceding 11 +6 years) compared to healthy volunteers, although this difference was not significant when age was taken into account [91].
Concerning another adipokine, resistin, in a study by Krsek et al. [92], its concentration was higher in 10 female CS patients compared to healthy volun- teers. Resistin levels positively correlated with body mass index (BMI). Resistin level reduction did not reach statistical significance 9 months after surgical treatment, although the amount of visceral fat de- creased among enrolled patients.
Although hyperleptinemia has been repeat- edly confirmed in CS patients, a relationship be- tween cortisol and leptin levels is unclear [72, 93]. Gavrila et al. showed that cortisol and leptin circadian profiles are strongly related: their peak concentrations occur during morning hours. Peak leptin concentration followed that of cortisol with a 2-hour time difference, which suggests a rela- tionship between these hormones [94]. Also, in human studies, administration of dexamethasone resulted in an increase in leptin in obese subjects, which was independent of sex, age, and insulin sensitivity [94]. Further, Widjaja et al. recorded a significant reduction in leptin concentration 2.5 years after transsphenoidal surgery for ACTH-dependent Cushing’s syndrome. In their small group of patients (n = 9), insulin, cortisol concentrations, and BMI returned to reference values for sex and age [95].
In contrast, Weise and co-authors found that diurnal leptin profile was normal in 18 patients with CS, and observed no correlation between leptin and cortisol levels. This lack of association between both hormones in CS was also under- lined by the fact that corticotropin-releasing hor- mone (CRH) administration before and 10 days after surgical treatment of hypercortisolemia in 12 CS patients did not affect leptin concentration (despite significant differences in cortisol levels, i.e. basally and in response to CRH both before and after surgery) [96].
A possible explanation for these findings is the fact that so far no studies have investigated the relative amount of specific body fat stores (namely visceral and subcutaneous fat) and leptin concen- tration in CS patients. This distinction in tissue type is crucial because subcutaneous fat produces two to three times more leptin than visceral fat [97].
Although the pathogenesis of hypoleptinemia in CS patients is unclear, it is thought to be a com- pensatory mechanism for excess glucocorticoids, due to which food intake is inhibited (via suppres- sion of neuropeptide Y and stimulation of proop- iomelanocortin (POMC), which has anorectic ef- fects) [72, 98].
Central obesity, a typical feature of CS, is as- sociated with altered secretion of adipocytokines,
which contributes to metabolic and cardiovas- cular complications [5, 85, 88]. In CS patients, serum concentrations of leptin and resistin, as well as proinflammatory cytokines such as TNF-a and IL-6, are increased [72]. It is possible that a pathological adipocytokine profile constitutes an additional risk factor of metabolic and cardio- vascular diseases in CS patients. The situation is not so clear in patients with SCS, in whom obesity and overweight are less frequent and less severe than in patients with overt CS [72, 86]. Probably, even small but chronic exposure to excess gluco- corticoids in both CS and SCS can lead to central accumulation of adipose tissue, which results in a persistent, unfavorable profile of adipokines and cytokines. Despite reports on the influence of ad- ipocytokines on the risk of metabolic diseases in CS and SCS patients, literature data are often con- tradictory [81, 99, 100]; therefore, future studies including larger patient populations are required.
Primary hyperaldosteronism
In primary hyperaldosteronism (PA) patients compared to primary hypertensives the risk of cardiovascular diseases and the frequency of met- abolic syndrome are increased [101-104]. Resec- tion of an aldosterone-producing adenoma leads to regression of these disorders. The role of ad- ipocytokines in primary aldosteronism has been poorly studied.
A relationship between hyperaldosteronism and fat tissue function is indicated by reports on the presence of the mineralocorticoid receptor (MR) in the AT, which mediates actions of both al- dosterone and glucocorticoids in adipocyte differ- entiation, adipocytokine secretion, and lipid accu- mulation [105]. The RAAS may be involved in the modulation of adipocytokines in individuals with excessive serum aldosterone [106, 107].
Letizia et al. showed that mineralocorticoids, such as aldosterone, play an important role in adipose tissue function, regulating differentia- tion of preadipocytes to mature adipocytes, and inducing inflammatory adipocytokines [108]. In their study, higher secretion of leptin and low- er secretion of adiponectin in adrenal fat tissue surrounding aldosterone-producing tumors were observed [108].
Rossi et al. analyzed AdipoR1 and AdipoR2 re- ceptor expression in normal adrenal glands (which were removed during renal cell carcinoma surgery) and aldosterone-secreting adenomas [109]. Sig- nificantly higher expression of adiponectin recep- tors in aldosteronomas compared to normal adre- nal cortex was revealed. The authors speculated that adiponectin modulates aldosterone secretion by affecting adiponectin receptor subtypes in the adrenal cortex [109].
In another report, Iacobellis et al. compared adi- pocytokine levels in PA and essential hypertension patients. Higher concentrations of resistin were found in the former group, while leptin levels were higher and adiponectin lower after accounting for the presence of metabolic syndrome in both pa- tient groups [66]. It is possible that high resistin concentrations in PA may be the result of abnormal adipocyte function due to exposure to prolonged high concentrations of aldosterone [66]. However, a direct effect of aldosterone on resistin concentra- tion has not been demonstrated yet [66].
Similarly, lower adiponectin levels in PA pa- tients compared to low renin essential hyperten- sives were also found by Fallo et al. [110]. Low adiponectin levels may contribute to endothelial dysfunction [66].
On the other hand, Haluzik et al. found that leptin concentrations were not different between PA and matched healthy controls at baseline; however, a significant increase in leptin levels was observed in PA patients after treatment (both surgical and pharmacological) [111]. The same observation concerning pre- and post-surgery leptin levels for PA was made by Torpy et al., who suggested that improved insulin secretion due to correction of hypokalemia may be the underlying reason for increase in leptinemia [112].
The few studies, in which only selected adi- pokines in PA patients were investigated, and in light of the presence of adipocyte receptors in the tissue of adenomas secreting aldosterone, indi- cate the need for further studies on larger groups of patients to explain the influence of the fat tis- sue on metabolic disorders observed in this group of patients.
Adrenocortical carcinoma
Research on the relationship between the ad- ipose tissue and human neoplasms is largely ob- servational, and there are limited data on rare ma- lignancies, including those of the adrenal glands.
Chou et al. investigated expression of adiponec- tin receptors in various, including non-obesity-as- sociated human neoplasms, and were the first to show their presence in adrenocortical cancer (ACC) [16]. The authors showed that AdipoR1 expression was much higher in obesity-associated neoplasms compared to those in which the influence of obe- sity as an etiological factor was not proven [16].
The authors of the current review evaluated differences in the expression of adiponectin re- ceptors in benign and malignant adrenal tumors by immunohistochemistry. In an analysis of 128 resected adrenal tumors both AdipoR1 and Adi- poR2 expression levels were significantly higher in ACC compared to benign adrenal hyperplasia and adrenocortical adenomas [82]. It seems that
higher adipokine receptor expression in malignant adrenal tumors can be explained by down-regula- tion, which is present in epithelial breast cancer as well as Barrett’s adenocarcinoma [113, 114]. It can be assumed that low serum adiponectin levels are associated with tumorigenic effects, resulting in increased expression of AdipoR1 and R2 recep- tors in adrenal tumor tissue [82, 83].
An attempt to evaluate the proliferative effect of leptin in adrenal tumors was undertaken by Glasow et al. in 1999 [60]. The researchers exam- ined normal and neoplastic adrenocortical tissue and found that leptin does not regulate the prolif- eration of adrenocortical tumors despite the pres- ence of its receptor in the tumors [60].
In the above-mentioned study conducted by the authors of this review (resected adrenal tu- mors from 128 patients), it was demonstrated that leptin receptor expression was absent or minimal in half of examined benign tumors (nod- ular hyperplasia and adrenocortical adenomas), while being much higher in ACCs [82, 83]. We also sought for a relationship between the expression of adipokine and leptin receptors in ACC tissue and the progression of this rare human tumor [83], but none was demonstrated. Effective radical surgical treatment remains the established prog- nostic factor [115].
Considering the role of adipokines in neoplasia and the presence of adipokine receptors in adre- nal tumors, it can be hypothesized that adipokines play a role also in human adrenocortical cancers, which are non-obesity-associated neoplasms.
Pheochromocytoma
Pheochromocytoma (PHEO) is a neoplasm that arises from chromaffin cells of the neural tube of the sympathetic and parasympathetic nervous system. It comprises approximately 1-8.7% of in- cidentally discovered adrenal tumors according to various reports [116-118]. PHEOs produce one or more catecholamine (epinephrine, norepinephrine, dopamine, which are metabolized to metaneph- rines, normetanephrines, and 3-methoxytramine, respectively), as well as other active substances, all of which lead to various clinical symptoms [116-118].
Obesity is rare in patients with PHEO due to the catabolic effect of excessive catecholamine secre- tion, which stimulates lipolysis [75, 119, 120]. How- ever, adrenal glands are embedded in fat tissue, which has been shown to secrete adipokines that can affect PHEO [108]. There are reports assessing the influence of the adipose tissue on PHEO tumor metabolism that suggest its effect on metabolic disorders in this group of patients [119, 120].
Glucose metabolism disorders including DM are a relatively common feature in patients with
PHEO. According to the literature, impaired glu- cose tolerance was observed in 25% to 75% of patients with PHEO and about 33% developed DM [116, 119, 120]. Supraphysiological catecholamine concentrations reduce insulin secretion and are the main cause of DM in PHEO patients. Wiesner et al. reported that glucose intolerance in PHEOs is caused by increased insulin resistance [121]. Pos- sibly, insulin resistance is another factor in the de- velopment of DM in pheochromocytoma patients.
In some studies, lower adiponectin concen- trations compared to controls were observed in PHEO patients [119, 122]. Elenkova et al. suggest- ed that hypoadiponectinemia was the missing link in the pathogenesis of carbohydrate metabolism disorders in these patients, and that it may be an additional risk factor for cardiovascular and meta- bolic complications [119].
Epinephrine up-regulates the expression of adiponectin receptors. It seems that high cate- cholamine concentrations present in PHEO, i.e. the cause of glucose intolerance and DM, induce compensatory expression of adiponectin recep- tors, particularly AdipoR1, in PHEO tumor tissue, probably due to decreased serum adiponectin concentration [122].
In the available literature, Isobe et al. specu- lated that, contrary to epinephrine, high levels of norepinephrine induce adiponectin secretion. It was suggested that this mechanism is protective against occurrence of DM in PHEO patients with excess norepinephrine secretion [122].
The authors of the current review investigated adipokine and leptin receptor expression in tumor tissues of 40 adrenal PHEO patients. AdipoR1 and R2 receptor expression was significantly higher in PHEO compared to both benign and malignant adrenocortical tumors [82]. Also, leptin receptor expression in PHEO tumors was higher than in ad- renocortical tumors [82].
In studies by other authors, serum leptin con- centrations in patients with PHEO tumors were evaluated [122]. It was shown that chronic over- production of catecholamines that occurs in PHEO did not suppress leptin secretion in these patients. This may be related to the development of toler- ance to a chronic excess of catecholamines in the adipose tissue [123].
The interplay between fat tissue surrounding PHEO and possible stimulation of leptin secretion by catecholamines may be associated with higher expression of Ob-R in this type of tumor. In fact, in our previous studies, expression of leptin recep- tor was significantly higher in PHEO compared to ACC. Higher expression of adiponectin and leptin receptors in PHEO may result from a significantly stronger effect of catecholamines on adipokine secretion by the AT in comparison to the effect of adrenocortical hormones [82].
Presence of adipokine receptors in PHEO tu- mors in humans as well as the relationship be- tween low adiponectin concentration and in- creased risk of DM and insulin resistance in PHEO patients indicates the role of adipose tissue in metabolic disorders in this pathology.
Conclusions
The role of adipocytokines in hormonally active adrenal tumors and their possible effect on met- abolic disorders and cardiovascular risk has been investigated scarcely. Elucidating the interplay be- tween excess hormone levels and adipocytokines remains a challenge for future studies.
Presence of adipokine receptors in adrenal cor- tex and medulla tumors, and, particularly, their high expression in malignant tumors, suggest the possible effect of adipokines on neoplasia in these non-obesity-related neoplasms. Under- standing the mechanisms linking adiponectin and leptin with proliferation may be important in the development of anticancer prophylaxis and ther- apy not only in obesity-associated malignancies. The pathophysiological significance of adipokine receptors and their potential prognostic value in assessment of the risk of cancer incidence, recur- rence and treatment results in obesity-related can- cers warrant the necessity of future studies. It is possible that treatment with adiponectin receptor analogues or clinical use of adiponectin may have direct beneficial effects in many human cancers. However, currently, lifestyle modifications remain the most important factor in the prevention of cancer and metabolic disorders related to obesity.
Conflict of interest
The authors declare no conflict of interest.
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