Prostate Cancer
frequent abnormalities are collectively grouped and identified as metabolic syndrome, the onset and duration of the single components may differentially influence the risk of PCa. Available data on metabolic syndrome and PCa are contradictory and insufficient to suggest a link between metabolic syndrome and PCa.63,64
Leptin and Adiponectin
The dual control by adipose tissue of energy metabolism and the immune system is well demonstrated by two adipokines with opposite functions, leptin and adiponectin. In recent years, both adipokines have received particular interest for their capacity to modulate cancer cell phenotype directly.
Leptin is a small adipokine produced predominantly by adipocytes. Circulating leptin levels are higher in obese individuals with respect to lean subjects. Leptin exerts a complex control of energy homoeostasis, modulating different organs and systemic metabolism. During fasting, when plasma leptin levels decline, neural pathways in the hypothalamus cause appetite to increase and energy expenditure to decrease, an attempt to restore body fat stores.65
Leptin suppresses
the appetite through the production of anorexigenic peptides by the hypothalamus. In animal models the central anorexigenic action of leptin is clearly diminished in ageing, most probably due to the impaired signal transduction in hypothalamic neurons. Because aged obese rats are leptin-resistant, these data predict that they will also have a delayed normalisation of caloric intake and exacerbated weight gain when provided with a high-fat diet. These results demonstrate that aged rats are more susceptible to the detrimental effects of a high-fat diet.66
effects that save energy during nutritionally lean times.68
and inhibits the reproductive axis, both Importantly,
concentration is predictive of high-grade disease and more advanced tumours.73,74
Results from in vitro studies support such a relationship. In fact, leptin treatment of PCa cells determines the activation of intracellular signalling pathways associated with proliferation, migration and invasion.74,75
Adiponectin is the most abundant circulating adipokine in lean individuals. In contrast to other adipokines, serum levels of adiponectin are negatively correlated with central obesity. Adiponectin possesses several physiological functions including modulation of glucose metabolism and energy homoeostasis through the enhancement of insulin activity. Studies in ageing humans revealed that enhanced adiponectin values are a distinctive feature of centenarians. Much evidence from experimental models indicates that adiponectin protects against obesity-linked metabolic dysfunction, including type 2 diabetes and metabolic syndrome. Adiponectin is an effective immunosuppressor both at the systemic level and in adipose tissue. Plasma adiponectin levels are negatively correlated with C-reactive protein levels in obese or diabetic patients, and the administration of adiponectin in obese animals improves inflammation-associated pathological outcomes.76,77
In adipose tissue adiponectin can interfere in
the differentiation of macrophages towards a pro-inflammatory M1 subtype, reducing the production of reactive oxygen species.78 Adiponectin receptors are expressed in PCa cell lines and in benign and malignant human prostate tissues,79 reduction in the risk of PCa.80
and it is associated with a marked Lower adiponectin levels are
Whether a similar mechanism is also valid in humans remains to be proven. In addition, the fall in plasma leptin diminishes thyroid hormone production67
The leptin receptor is expressed on prostatic epithelial cells, and thus leptin may directly modulate the development and homoeostasis of prostatic tissue. Maturation of the prostate gland continues while embryonic testosterone levels are high; however, as testosterone levels fall during the third trimester of gestation, the gland enters a quiescent state. The quiescent state persists until puberty, when testosterone levels increase again and the epithelium proliferates, giving rise to the mature gland. It is plausible that leptin may exert a role in this phase of gland reactivation just prior to the increase in testosterone levels. In fact, current evidence suggests that leptin plays a permissive role in timing sexual development.70
leptin has been indicated as a key factor in the development and maintenance of murine and human reproductive tissues, including the prostate.69
The
leptin dependence in prostatic epithelial cells can be reactivated in elderly men following the tumour transformation. In fact, the expression of the leptin receptor is significantly higher in PCa than in both benign prostatic hyperplasia and normal prostatic tissue.71
The
The available data do not unequivocally indicate a positive correlation between blood leptin levels and PCa risk. On the contrary, there are more convincing indications that elevated plasma leptin
higher the blood leptin concentration, the greater the negative effect on cellular differentiation and the positive one on cancer progression in PCa.72
1. Wan H, Sengupta M, Velkoff VA, DeBarros KA, 65+ in the United States. In: US Census Bureau (ed.), Current Population Reports, Washington, DC: US Government Printing Office, 2005;23–209.
2. Flegal, KM, Carroll, CL, Ogden, et al., Prevalence and trends in obesity among US adults, 1999–2000, JAMA, 2002;288:1723–7. 3. Wang Y, Beydoun MA, The obesity epidemic in the United
independently associated with high-grade PCa.81 Conclusions
The recent growing prevalence of overweight and obesity among older adults has synergised with a substantial change in demographic curves in industrialised countries towards an elderly population. This synergy will have an important impact in the prevalence of chronic health conditions as well as disability among future generations of older adults. Obesity in older adults could affect the health and medical care demands of the elderly population for at least the next several decades, and even today it is only because of pharmacological tools that obesity and its comorbidities have not decreased the lifespan. PCa is one of the age-associated diseases that may be nourished by obesity. The evidence of an association of obesity with increased risk of high-grade cancer could determine in the near future an escalation of non-treatable life-threatening PCa cases. There is growing evidence that dysregulation in adipose tissue homoeostasis plays a key role in adverse metabolic changes associated with both obesity and old age. The well-known modification in adipose tissue during obesity may, in the elderly population, worsen the physiological condition of frailty due to a higher susceptibility of adipose cells to various stresses. The resulting dysregulation in adipokines may represent one of the interpretation keys for understanding pathological consequences at the systemic level. However it is critical to better recognise the complex relations existing between abdominal obesity and metabolic changes taking place in the elderly population. In order to dissect these mechanisms, a clearer understanding of the cellular and molecular changes in adipose tissue is needed. n
States—gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta- regression analysis, Epidemiol Rev, 2007;29:6–28.
4. Alwan A, Agis T (eds), Global status report on noncommunicable diseases 2010, Geneva: World Health Organization, 2011;176.
5. Cancer Facts & Figures 2010, Atlanta: American Cancer Society, 2010.
6. Hotamisligil GS, Shargill NS, Spiegelman BM, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science, 1993;259:87–91.
7. Bray GA, Medical consequences of obesity, J Clin Endocrinol Metab, 2004;89:2583–9.
8. Kim JY, van de Wall E, Laplante M, et al., Obesity-associated
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