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The human prostate gland is an endocrine organ in which dysregulation of various hormonal factors plays a key role in the development of non-tissue transformation and leads to the formation of prostate cancer. Existing epidemiological data confirm the role of the components of the metabolic syndrome, namely obesity, hypercholesterolemia, diabetes, and hyperinsulinemia, in the development and/or progression of prostate cancer. Although the exact mechanisms underlying the relationship between metabolic syndrome and prostate cancer remain largely unknown, it has been shown that various “in vitro” and animal experiments with models of the metabolic syndrome contribute to survival, mitogenesis, metastasis, and treatment resistance pathways through various adaptive reactions, such as intracellular steroidogenesis and lipogenesis. Although the exact biopathophysiological mechanisms between metabolic syndrome and prostate cancer have yet to be studied, drugs that target specific components of the metabolic syndrome have also provided evidence for the relationship between metabolic syndrome, its components, and prostate cancer. The appearance of “in vitro” results and molecular genetic research data will bring us closer to using this knowledge to determine specific ways of cancer-specific survival and improve treatment outcomes in patients with this disease.
Academy of Postgraduate Education under FSCC of FMBA of Russia, Russia
Galina P. Peshkova
FSBEI HE I.P. Pavlov RyazSMU MOH Russia, Russia
Igor V. Reshetov
Academy of Postgraduate Education under FSCC of FMBA of Russia, Russia
*Address all correspondence to: drpeshkov@gmail.com
1. Introduction
Metabolic syndrome (MS) describes a group of comorbidities including central obesity, high serum glucose, dyslipidemia, and systemic hypertension. Over the past decade, various definitions have been proposed for MS. The International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute have resolved differences in definitions of metabolic syndrome (Table 1) [1].
Criteria for diagnosing metabolic syndrome
I. Main criterion
Central (abdominal) type of obesity—waist circumference (white men)
>94 cm
II. Additional criteria
High blood pressure (BP)
BP level >140 and 90 mm Hg or treatment of previously diagnosed arterial hypertension with pharmacological drugs
Elevated triglyceride levels
>1.7 mmol/L or specific treatment for this lipid abnormality
Decreased HDL cholesterol levels
<1.0 mmol/l
Increasing the level of LDL cholesterol
>3.0 mmol/l
Impaired glucose tolerance (IGT)
Elevated plasma glucose 2 hours after loading 75 g of anhydrous glucose with OGTT >7.8 and <11.1 mmol/l, provided that the fasting plasma glucose level is less than 7.0 mmol/l.
Impaired fasting glycemia (IFG)
Elevated fasting plasma glucose >6.1 and <7.0 mmol/l, provided that plasma glucose after 2 h with OGTT* is less than 7.8 mmol/l**.
Combined CGI/IGT disorder
elevated fasting plasma glucose ≥6.1 and <7.0 mmol/l in combination with plasma glucose after 2 h with OGTT ≥7.8 and <11.1 mmol/l.
Table 1.
Criteria for metabolic syndrome (The International Diabetes Federation) [1, 2].
OGTT—oral glucose tolerance test.
Reliable MS is considered in the presence of three criteria: one main and two additional.
Metabolic syndrome is considered a growing public health problem and an emerging risk factor in the etiology of several cancers, including prostate cancer (PCa).
The influence of individual MS components, such as hypertension, obesity, and dyslipidemia, which were associated with PCa, was revealed [3].
Metabolic syndrome is a group of risk factors for cardiovascular disease, including hypertension, central obesity, hypertriglyceridemia, hyperglycemia, and low HDL-C, with insulin resistance (IR) as the main feature. The definition of metabolic syndrome by the International Diabetes Federation [2] is shown in Table 1. In IC, normal glucose levels are insufficient for a normal response to insulin from fat, muscle, and liver cells, often with central obesity as a physical manifestation of this condition. CI in fat cells causes hydrolysis of stored triglycerides and an increase in free fatty acids (FA). These free fatty acids are taken up by the liver, leading to an increase in triglycerides, low-density lipoprotein cholesterol, and a decrease in HDL. In addition, CI causes a decrease in glucose uptake in the muscles and a decrease in the accumulation of glucose in the liver, which leads to the development of hyperglycemia [4].
Metabolic syndrome (also known as syndrome X, Riven's syndrome [5], insulin resistance syndrome) is defined by a cluster of lipid and non-lipid metabolic risk factors for cardiovascular disease with central insulin resistance.
With insulin resistance (IR), there is an increased response of insulin to carbohydrates entering the body, especially with a high glycemic index (GI). Insulin acts on fat cells to hydrolyze stored triglycerides, which increases plasma free fatty acid levels. These free fatty acids are taken up by the liver, resulting in increased production of triglycerides and very-low-density lipoprotein (VLDL) cholesterol and decreased production of high-density lipoprotein (HDL) cholesterol. Insulin acts in the muscles to decrease glucose uptake, while in the liver it reduces glucose accumulation, both of which increase blood glucose levels. High levels of insulin cause increased sodium absorption in the kidneys, spasm of the arteries, and hence hypertension. Endothelial effects of elevated insulin levels are also observed, mediated by the action of nitric oxide. In addition, there is a violation of cellular repair with an increased level of pro-inflammatory cytokines. In the blood serum, the concentration of bound and free serum testosterone, sex hormone-binding globulin (SHBG), and the androgen receptor is reduced [6].
In the past two decades, the prevalence of metabolic syndrome has increased markedly, coinciding with the global epidemic of obesity [7] and type II diabetes [8]. Studies using the Third National Health and Nutrition Survey (NHANES III) database showed that the prevalence of metabolic syndrome increased from 29.2% in 1988–1994 to 32.3% in 1999–2000 [9, 10]. The prevalence varies by race and gender and increases with patient age [11].
3. The influence of metabolic syndrome on the development of prostate cancer
There is strong evidence showing that the metabolic syndrome may contribute to oncogenesis and that the individual components of the metabolic syndrome have a synergistic effect, increasing the risk of tissue neotransformation [12]. Evidence for a causal relationship between metabolic syndrome and prostate cancer is conflicting (Figure 1).
Figure 1.
Mechanisms of influence of metabolic syndrome factors on the development of prostate cancer.
The presence of factors such as elevated body mass index (↑BMI), arterial hypertension (↑BP), and low HDL levels increases the risk of developing PCa. Hyperinsulinemia (↑ insulin) and low testosterone levels are interrelated and may contribute additionally. An increase in pro-inflammatory cytokines can lead to the development of the aggressive properties of a prostate tumor through an increase in the activity of NF-kB (↑ NF-kB). However, the lower IGF-1 activity seen in metabolic syndrome reduces the risk of PCa. The presence of a low prognostic risk tumor in stage T2 may be secondary to a hypoinsulinaemic condition.
The story goes on to present the impact of individual metabolic syndrome factors on the risk of developing prostate cancer.
In a study by Laukkanen et al. [13], the association between insulin resistance (IR) and the development of prostate cancer was assessed in 1880 patients, 19% of whom had insulin resistance. After a mean follow-up of 13 years and adjusted for age, lifestyle, and diet, the relative risk of prostate cancer was 2 (95% CI 1.07.3.53; p = 0.03). In insulin-resistant patients who were also obese, the relative risk (RR) approached three (95% CI 1.22.7.34; p = 0.02). In patients with metabolic syndrome and BMI ≥ 27, the risk of developing PCa is three times higher [13].
The relationship between diabetes mellitus and prostate cancer risk is unclear, diabetes is commonly associated with obesity, and obesity is associated with an increased risk of disease recurrence [14] and higher cancer-specific mortality [15].
Smith et al. [16] evaluated the relationship between diabetes mellitus and mortality in patients with locally advanced prostate cancer after radiotherapy and ADT. The study cohort included 1554 patients receiving radiotherapy and adjuvant therapy with goserelin for locally advanced prostate cancer. Median follow-up was 8.1 years; a total of 765 deaths were recorded, of which 210 (27%) were associated with prostate cancer. Diabetes is associated with a lower risk of prostate cancer. Most men with diabetes are obese, and obesity is associated with more deaths from prostate cancer. Whether diabetes affects outcomes after verification of prostate cancer remains unclear. After adjusting for age, race, tumor stage, Gleason score, PSA level, weight, and treatment, being overweight (>89.5 kg) was associated with more prostate cancer mortality (HR = 1.77 [95% CI 1.22–2.55]; p = 0.002), while there was no overt diabetes (HR = 0.80; 95% CI, 0.51–1.25; p = 0.34). Elevated levels of insulin and IGF-1 observed in obese patients may be responsible for this association [17] rather than all of the metabolic consequences of diabetes.
Kasper J.S. and colleagues [18] demonstrated in a multivariate analysis that diabetes mellitus was associated with a 17% reduction in the risk of developing generalized PCa, a 28% reduction in the risk of localized PCa, a 31% reduction in the likelihood of developing high-risk PCa, and a 24% reduction in the incidence of PCa. low risk of progression. Further analysis showed that overweight patients with diabetes (BMI ≥ 30) had a 19% lower risk of PCa than overweight patients without diabetes [18]. A further prospective multivariate analysis of 72,670 patients showed that 4 years after the diagnosis of diabetes mellitus, the incidence of prostate cancer decreased by 37% [19]. Similar data from the CPSII NC cohort showed that diabetes mellitus was less likely to develop nonaggressive tumor type (stages I and II with Gleason < 8) and aggressive tumor type (stages III and IV with Gleason ≥ 8) PCa (RR 0.71 and 0.51, respectively) [19]. An inverse correlation has been reported between triglyceride levels and the incidence of PCa [20].
Mistry et al. [21] suggested that obesity and adipokines may play a role and promote the progression of established prostate cancer based on their study of leptin and adiponectin, two adipokines that, at high circulating levels, respectively, stimulate and inhibit the development of prostate cancer. In addition, there is evidence from in vitro studies suggesting that unsaturated fats specifically affect prostate cancer signaling [22]. Prostate cancer cells perceive adipocytes as an energy source during early bone marrow metastasis in vitro [23], since the cell and prostate cancer usually migrate to bone marrow adipocytes rather than subcutaneous fat, indicating that adipocytes have different effects [24]. The use of statins reduces mortality from prostate cancer by ~50% [25].
Univariate analysis also showed positive associations with PCa prevalence and hyperglycemia (OR, 7.31), low HDL (high-density lipoprotein) cholesterol (OR, 9.93), increased waist-to-hip ratio (WHR), systolic arterial pressure, and diastolic blood pressure heart rate [26]. Another study found that every 12 mm Hg increase in diastolic blood pressure was independently associated with an 8% increase in the incidence of PCa [27].
According to the Helsinki study, patients with elevated BMI (>28) and systolic blood pressure (>150 mmHg) are more than two times more likely to have PCa and more than three times more likely to have low HDL (≤1.05 mmol/l) [28].
In a prospective cohort study of 950,000 patients, age stratification showed that in an obese man aged 50–59 years, the incidence of prostate cancer increased by 50% compared with patients with a normal BMI [29]. In addition, a significant positive correlation has been shown between BMI and the incidence of PCa [29]. A meta-analysis of 56 studies with 68,753 cases showed an overall increase in the risk of PCa by 5% for every 5 kg/m2 (BMI) [30].
Some research suggests that components of the metabolic syndrome may also lead to more aggressive PCa. In the previously mentioned meta-analysis [30], each increase in BMI by 5 units significantly increased the risk of a more advanced stage of PCa (relative risk [RR]—1.12). A recent retrospective study found that white men with a BMI ≥ 35 were approximately two–three times more likely to experience pathologic features during radical prostatectomy (including Gleason score ≥ 7, positive surgical margin, extraprostatic extension, and seminal vesicle invasion) than lean men analogues (BMI < 25) [31].
Hammarsten and Högstedt [32] demonstrated that the stage and grade of PCa are directly related to BMI, waist measurement, fasting triglycerides, and fasting plasma insulin and indirectly to HDL. A prospective study also demonstrated that higher plasma insulin levels were noted in those who died compared with those who survived after PCa, and moreover, PCa mortality was significantly related to the number of metabolic syndrome features present [33]. The researchers also reported a positive relationship between waist-to-hip ratio (WHR), diastolic blood pressure (DBP), and serum PSA in patients with PCa, as well as a negative feedback between high-density lipoprotein (HDL) levels and serum PSA levels [26, 34].
Low testosterone levels associated with metabolic syndrome are associated with a poorer prognosis for prostate cancer. In a retrospective analysis, patients with low plasma total testosterone (<3 ng/mL) were more likely to develop high-risk PCa (Gleason score ≥ 7; OP 2.59) [35]. Other researchers have found no relationship between testosterone levels and the risk of developing PCa or a more aggressive form of PCa [36].
A number of mechanisms can play both a positive and a negative role in the occurrence of PCa. Low testosterone levels disturb the hormonal balance, leading to tissue neotransformation and the appearance of tumor cells that proliferate independently of androgens and to a more aggressive phenotype [37]. Angiogenesis is critical for tumor survival, and androgens have been shown to regulate sustained expression of vascular endothelial growth factor (VEG-F) in PCa models [38].
Schatzl and colleagues [39] demonstrated that intratumoral microvascular density (MVD) is inversely proportional to serum testosterone levels in men with newly diagnosed PCa. Low testosterone levels are also closely associated with hyperinsulinemia, but the etiology of this relationship is not fully understood [40]. Insulin is known to have promitotic and anti-apoptotic effects, and elevated insulin levels have been associated with increased growth of the PCa cell line (LNCaP) [41]. It has been established that the activity of 5α-reductase androgen receptor (AR) is increased in patients with DM-2 and obesity [42] and may increase the risk of cancer due to greater stimulation of the prostate [43, 44].
There is sufficient evidence that IGF-1 is associated with the metabolic syndrome and that it may influence the development of PCa. An increasing number of components of the metabolic syndrome were inversely correlated with serum IGF-1 levels, as well as with the IGF-1/insulin-binding growth factor-3 (IGFBP-3) ratio, a marker of IGF-1 bioavailability [45, 46, 47].
Significant direct associations have been reported between IGF-1 levels and an increased risk of development of prostate cancer, as well as between the levels of low and high levels of prostate cancer [48, 49]. In PCa cell lines, IGF-1 has been shown to induce proliferation and inhibit apoptosis [18].
Prostate epithelial cells have also demonstrated the ability to synthesize low levels of VEG-F in response to IGF-1 stimulation, providing a mechanism for enhanced angiogenesis [18]. The relationship between SD-2 and PCa initially seems paradoxical. CD-2 is associated with hyperinsulinemia, which itself is associated with a reduced risk of developing PCa. However, CD-2 has been shown to protect against high severity diseases. This phenomenon may be related to the time factor. Although T2DM is associated with insulin resistance and initial hyperinsulinemia, islet cell desensitization and insulin depletion (the so-called depletion of released insulin - an “over-worked’’ or “exhausted’’ b-cell) can develop over time, which contributes to a decrease in insulin levels [50]. The proposed concept is confirmed by the previously mentioned data of Rodriguez and colleagues [19], who demonstrated a decrease in the incidence of prostate cancer 4 years after diagnosis.
Chronic inflammation associated with metabolic syndrome increases the risk of developing PCa. We previously mentioned that IL-1β, IL-6, TNF-α, CRP, and IL-8 are elevated in metabolic syndrome. TNF-α, IL-6, and IL-8 have been associated with an increased risk of PCa and PCa stage, as well as with metastasis [51]. IL-1β has also been associated with metastasis [52].
IL-8 has chemotactic and angiogenic activity and can stimulate androgen-independent growth of LNCaP cells [51]. Both IL-1β and TNF-β have been shown to induce IL-8 expression in androgen-dependent (LNCaP) and androgen-independent (DU-145 and PC-3) PCa cell lines [51]. These cell lines also demonstrated the ability to secrete IL-6, which can function as a paracrine signal in LNCaP cells and an autocrine signal in DU-145 and PC-3 cell lines [53]. In vivo, PCa cells have demonstrated the ability to secrete TNF-α, and the ability of TNF-α to reduce androgen receptor expression and sensitivity to DHT in LNCaP cells suggests that this may contribute to the development of androgen insensitivity in PCa [54].
IL-1β, IL-6, IL-8, and TNF-stim are known to stimulate the nuclear factor-B (NF-kB) pathway, and this has been suggested as a possible link between increased levels of inflammatory cytokines and the development of PCa [55].
Increased activity of the transcription factor NF-kB is associated with PCa. In both PC-3 and DU-145 cell lines, NF-kB was shown to be constitutively activated [56]. Inverse correlations between NF-kB activity and androgen receptor sensitivity in PCa models suggest a role for NF-kB in the androgen-independent pathogenic pathway of PCa [57]. Indeed, inhibition of NF-kB in metastatic PC-3M cell lines of PCa leads to a decrease in the expression of VEG-F and IL-8, which correlates with a decrease in revascularization and metastasis to the lymph nodes in native mice [56].
Lessard L and colleagues [58] showed that in tissue samples after radical prostatectomy, the localization of nuclear NF-kB was directly related to the degree of invasion into the lymph nodes. IGF-1 appears to modulate pro-inflammatory cytokines as it has been shown to stimulate IL-8 expression in DU-145 cells independently or in synergy with IL-1β [51].
IGF-1 can also induce the expression of IL-6, IL-8, and TNF-β in human immune cells [51]. Interestingly, IL-6 and TNF-β themselves have been shown to decrease serum IGF-1 levels while increasing hepatic CRP synthesis [45], explaining the aforementioned feedback between CRP and IGF-1.
The low levels of IGF-1 seen in metabolic syndrome may be associated with decreased levels of these pro-inflammatory cytokines, thereby reducing the risk of developing PCa. However, it is important to note that some researchers have not found a correlation between these adipokines and the risk of developing PCa [47, 59].
Metabolic syndrome is a complex disease consisting of many interrelated pathophysiological entities, including obesity, hypertension, dyslipidemia, hyperglycemia/insulin resistance, and endothelial dysfunction. The main approach to cancer prevention in patients with metabolic syndrome is the prevention of risk factors. Lifestyle changes, including weight loss and a healthy diet, are known to reduce the risk of cancer in the general population.
In conclusion, it should be noted that the recent pandemic, metabolic syndrome and obesity lead to an increase in the number of oncological and cardiovascular diseases and, as a result, to a decrease in life expectancy. The single most effective preventive method is lifestyle modification. Preventive initiatives aimed at preventing the development of the metabolic syndrome and its components are measures of primary and secondary prevention of the development of oncological diseases, including neotransformation of prostate tissue.
Financing the work. Review and analytical work on the preparation of the manuscript was carried out at the personal expense of the author.
Conflict of interest. The author declares the absence of obvious and potential conflicts of interest related to the publication of this article.
Participation of the authors: Peshkov M.N. was involved in collection and analysis of literature data and wrote the article, and Peshkova G.P. and Reshetov I.V edited the article. All authors read and approved the final version of the manuscript before publication.
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Written By
Maxim N. Peshkov, Galina P. Peshkova and Igor V. Reshetov
Open access peer-reviewed chapter
