Review – Prostate CancerObesity and Prostate Cancer: A Role for Adipokines
Introduction
Prostate cancer is one of the most commonly diagnosed malignancies in men and the second leading cause of cancer-related death worldwide. In Europe 2.6 million new cases are diagnosed each year and prostate cancer accounts for 9% of all cancer deaths among men within the European Union [1]. The incidence and disease-specific mortality of prostate cancer demonstrate marked geographic variation, being greatest in North America and western European countries. Even within Europe, there is a notable difference between northern and southern countries, with prostate cancer incidence and mortality being highest in England and Wales and lowest in Mediterranean countries such as Spain, Italy, and Portugal [2]. Worldwide, the lowest incidence of prostate cancer is in Asian men, but recent studies have shown that rates have risen rapidly in the past two decades in most Asian countries [3]. Furthermore, the differences in prostate cancer incidence between the indigenous American population and Asian immigrants are reducing, reflecting a potential influence of environmental risk factors on Asian immigrants [3]. However, the possibility that these changes may partly be attributable to recent improvements in diagnostic methods cannot be excluded. Differences in prostate cancer incidence among ethnic populations undoubtedly have a genetic component, but the contribution of environmental factors in the pathogenesis of this disease, in particular the influence of diet and the “Western lifestyle,” is gaining recognition.
Obesity is reaching epidemic proportions in Western populations and is commonly attributed to the high fat consumption and the sedentary lifestyles of Western populations. It is a significant public health concern, being linked with diseases such as type 2 diabetes and cardiovascular disease. Visceral (central) obesity, in particular, is associated with insulin resistance, hyperglycaemia, hyperinsulinaemia, dyslipidaemia, hypertension, and prothrombotic and proinflammatory states [4]. The term “metabolic syndrome” encompasses these biochemical abnormalities and clinical conditions that may or may not be associated with central obesity.
Thus, a geographic correlation exists between areas of high prostate cancer and obesity incidence. Numerous studies have been performed to examine the association between obesity and prostate cancer, but they have yielded inconsistent results [5]. This may, in part, be due varying methods of anthropometric measurement, such as body mass index (BMI) and the waist-to-hip ratio (WHR). However, a recent study has shown visceral fat accumulation, as quantified by computed tomography (CT), is a specific risk factor for prostate cancer [6]. More consistent results have been obtained with studies looking at obesity and progression of prostate cancer. Indeed, it has recently been suggested that obesity may reduce the risk of nonaggressive disease while concurrently increasing the risk of aggressive disease [5]. Therefore, it is possible that rather than increasing the absolute risk of prostate cancer development, obesity may be associated with the progression of latent or microscopic prostate cancer to clinically significant and metastatic prostate cancer.
The importance of testosterone/androgens in prostate growth is well accepted; however, androgens demonstrate a complex interaction with obesity. There is a well-documented age-related decline in serum testosterone, with obesity itself also resulting in decreased free testosterone in men [7]. Data from retrospective studies suggest that testosterone may exert a differentiating effect on prostate cancer; decreased serum testosterone levels have also been associated with more advanced and poorly differentiated tumours at presentation [8], [9]. Thus, obesity may compound physiologic age-related hypoandrogenaemia in men and consequently provide an environment whereby aggressive, partially androgen-insensitive prostate cancers can thrive [10]. Additionally, increased peripheral aromatisation of androgens to oestrogen in adipose tissue, which is related to the degree of adiposity, also contributes to a decline in serum androgen levels. Conversely, hyperinsulinaemia, which is a feature of the metabolic syndrome and obesity, has been shown to up-regulate testosterone production [7]. This same study also demonstrated a reduction in hepatic sex hormone-binding globulin (SHBG) production, which would result in higher levels of free bioactive androgen [7].
One of the most marked characteristics of the Western diet is a high calorie and saturated fat intake. Although there are no conclusive studies showing an association between total dietary fat intake and prostate cancer risk, specific types of dietary fat (eg, animal fat) appear to be more significant in increasing prostate cancer risk [11], [12]. The most abundantly consumed fatty acid in the Western diet is linoleic acid (omega-6 polyunsaturated fatty acid), which has recently been shown to promote prostate cancer migration in vitro [13]. In vitro studies have also shown that high levels of saturated fat act as a growth factor in a variety of prostate cancer cell lines, whereas a low-fat diet results in slower androgen-sensitive prostate cancer growth and can delay progression [14], [15]. Furthermore, results from a recent large prospective study found that use of cholesterol-lowering statin drugs was associated with a reduced risk of advanced (especially metastatic or fatal) prostate cancer [16].
The molecular mechanisms underlying the association between obesity and prostate cancer are numerous and occur at many levels. As well as altering circulating androgen levels, obesity also affects other hormones such as insulin-like growth factors (IGFs), which are known to have mitogenic properties. Oestrogen levels are also elevated due to their conversion from androgens in adipose tissue. It is therefore not surprising that obesity has also been associated as a risk factor for many cancers, in particular, hormone-dependent cancers such as breast, endometrial, and prostate cancer. It has also been shown that prostate cancer cells cultured in the presence of fat cells (adipocytes) demonstrate altered proliferation, differentiation growth, and cytokine expression, suggesting that adipocyte-derived factors may modulate the biologic behaviour of prostate cancer cells [17].
Obesity results from an accumulation of white adipose tissue (WAT), which is a metabolically active endocrine organ, as opposed to a mere repository for excess energy [4]. Adipocytes secrete a variety of hormones, bioactive peptides, and cytokines, termed adipokines, such as leptin, adiponectin, and vascular endothelial growth factor (VEGF). Moreover, many of the aforementioned adipokines have been shown to differentially modulate cellular differentiation, apoptosis, proliferation, and angiogenesis. In addition to adipocytes, adipose tissue also consists of connective tissue matrix, nerve tissue, vascular cells, and immune cells, which also secrete adipokines such as VEGF and tumour necrosis factor α (TNF-α). Adipokines may exert their biologic effects either at a local level via autocrine/paracrine pathways or in an endocrine fashion by entering the circulation and activating receptors on target cells. Paracrine effects of adipokines are important in cases of prostate cancer progression where extracapsular extension and invasion of the retropubic fat pad occurs. This could result in the exposure of malignant cells to high concentrations of potentially proangiogenic and proliferative factors, which may enhance further their capacity for further growth and metastasis [18].
Clearly, numerous mechanisms could contribute to the molecular association between obesity and prostate cancer, as summarised in Fig. 1. This review article provides an overview of the current evidence that supports a role for adipose tissue-derived adipokines in the association between obesity and prostate cancer. It is not within the scope of this article to provide details on molecular mechanisms or to summarise epidemiologic evidence on this subject. We have focused our review on four of the major adipokines (leptin, interleukin 6 [IL-6], VEGF, and adiponectin) and have aimed to keep this review specific to their role as molecular mediators of obesity and prostate cancer, rather than carcinogenesis in general.
Section snippets
Materials and methods
We performed a PubMed literature search for articles from 1990 to 2006, with the search limited to articles in the English language. The search terms used included “adipokines,” “leptin,” “interleukin 6,” “vascular endothelial growth factor,” and “adiponectin,” linked with “and prostate cancer.” Articles were reviewed and those deemed relevant to this discussion were considered for this review. Articles were also identified from references cited in relevant articles, where appropriate.
Leptin
Leptin, first described by Zhang et al in 1994 [19], is a 16-kD adipokine produced predominantly by adipocytes in WAT. Circulating leptin concentrations exhibit a positive correlation with total body fat, so that serum leptin is elevated in obese individuals compared to lean individuals [20]. Besides playing roles in the regulation of energy homeostasis, neuroendocrine physiology, and immune function, it is also speculated to be important in the development and maintenance of reproductive
Discussion
Obesity is a complex disease state, resulting in a multitude of metabolic and endocrine disturbances and this may account for the inconsistencies seen in epidemiologic studies investigating the association between obesity and prostate cancer to date. Much evidence suggests that the presence of obesity may promote the progression of established prostate cancer rather than being a risk factor for the development of prostate cancer per se. The identification of adipose tissue as a metabolically
Conclusions
Evidence suggests an association between obesity and prostate cancer progression that may occur at many levels. Adipokines may provide a molecular basis for this association, and future studies are required to investigate the complex interaction between these adipose tissue-derived factors with obesity, prostate cancer, and other hormones. A greater understanding of the pathogenesis of prostate cancer and adiposity could allow the development of new therapeutic markers, prognostic indicators,
Conflicts of interest
None of the authors have any direct or indirect commercial financial incentive associated with publishing this article.
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T. Mistry is a Clinical Research Fellow supported by the Ipsen Fund. Ipsen played no role in the in the writing of this review article. The authors have no financial interest in Ipsen.