Maria Dalamaga

The Role of Adiponectin in Cancer: A Review of Current Evidence

Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD) but also with various types of malignancies. Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties. Circulating adiponectin levels, which are determined predominantly by genetic factors, diet, physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies.

Leptin's Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals

Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptins contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.

Leptin at the Intersection of Neuroendocrinology and Metabolism: Current Evidence and Therapeutic Perspectives

Since its discovery as an adipocyte-secreted hormone, leptin has been found to impact food intake, energy homeostasis, and metabolism through its effects on the central nervous system and peripheral organs. Recent research indicates that leptin may also be involved in cognition, immune function, and bone metabolism. These findings place leptin at the intersection of neuroendocrinology and metabolism, and possibly immune function, and render it an appealing therapeutic target for several niche areas of unmet clinical need. Current evidence regarding classic and emerging roles of leptin as well as the pros and cons of its potential clinical use are summarized herein.

Serum resistin: a biomarker of breast cancer in postmenopausal women? Association with clinicopathological characteristics, tumor markers, inflammatory and metabolic parameters.

OBJECTIVE Previous few studies have shown that resistin is significantly elevated in breast cancer (BC) patients. Therefore, we investigated whether serum resistin could be used as a potential diagnostic and prognostic tool for postmenopausal BC (PBC), taking into account clinicopathological features, serum tumor markers, anthropometric, metabolic, and, for the first time, inflammatory parameters. METHODS Serum resistin, tumor markers (CA 15-3 and CEA), metabolic, anthropometric and inflammatory parameters (TNF-α, IL-6, hsCRP) were determined in 103 postmenopausal women with incident, pathologically confirmed, invasive BC, 103 controls matched on age and time of diagnosis, and 51 patients with benign breast lesions (BBL). RESULTS Mean serum resistin was significantly higher in cases than in controls and patients with BBL (p<0.001). In patients, resistin was significantly associated with tumor and inflammatory markers, cancer stage, tumor size, grade and lymph node invasion but not with anthropometric, metabolic parameters and hormone receptor status. Multivariable regression analysis revealed that serum IL-6 (p=0.02) and cancer stage (p=0.048) were the strongest determinants of serum resistin in cases adjusting for demographic, metabolic and clinicopathological features. Although resistins diagnostic performance was low based on ROC curve analysis [0.72, 95% CI: 0.64-0.79], it could, however, represent a BC biomarker reflecting advanced disease stage and inflammatory state. CONCLUSION Further prospective and longitudinal studies are needed to evaluate whether serum resistin could be used as a prognostic tool in BC monitoring and management. More research is essential to elucidate resistins ontological role in the association between obesity, representing a chronic low-grade subclinical inflammation, and PBC.

Could serum visfatin be a potential biomarker for postmenopausal breast cancer

OBJECTIVE Previous studies have shown that visfatin is significantly elevated in patients with gastric carcinoma and postmenopausal breast cancer (PBC). We thus explored whether serum visfatin could be used as a potential diagnostic and prognostic tool for PBC, taking into account clinicopathological features, serum tumor markers, anthropometric and metabolic parameters. METHODS Serum visfatin, tumor marker CA 15-3, carcinoembryonic antigen, metabolic and anthropometric parameters were determined in 103 postmenopausal women with pathologically confirmed, incident invasive breast cancer, 103 controls matched on age and time of diagnosis, and 51 patients with benign breast lesions (BBL). RESULTS Mean serum visfatin was significantly higher in cases than in controls and patients with BBL (p<0.001). In cases, visfatin was significantly associated with CA 15-3 (p=0.03), hormone-receptor status (p<0.001), lymph node invasion (p=0.06) but not with metabolic and anthropometric variables (p>0.05). Multivariable regression analysis revealed that absence of estrogen and progesterone receptors (ER-PR-) was the strongest significant determinant of serum visfatin (p<0.001) in cases adjusting for demographic, metabolic and clinicopathological features. Based upon receiver operator characteristic analysis, serum visfatin outperformed CA 15-3 only in discriminating between PBC cases with early cancer stage than those with late stage, and in differentiating particularly patients with ER-PR- breast tumors. CONCLUSION Further prospective and longitudinal studies are needed to determine whether serum visfatin could be used as a prognostic tool in the armamentarium of PBC monitoring and management in conjunction with other biomarkers.

Evidence on the infectious etiology of childhood leukemia: the role of low herd immunity (Greece)

AbstractObjective: Acute lymphoblastic leukemia (ALL) among children may be a rare outcome of a delayed non-specific infection in situations of overall low herd immunity. We evaluated the hypothesis as to whether newly diagnosed ALL cases, compared to their controls, are characterized by lower herd immunity, as reflected in a more seronegative spectrum to several agents, with the exception of a strongly positive response to a single infectious agent, assumed to trigger ALL. Methods: The study included 94 incident cases of ALL, from all pediatric hematology–oncology units of Greece, and 94, matched for age and gender, controls hospitalized with minor non-infectious conditions. The past exposure to common infections was assessed using 10 serological markers. Results: There was little evidence for an association of ALL with the serology of any of the studied infectious agents among the very young children. In contrast, among children aged 5 years or older, leukemia was inversely associated with seropositivity to Epstein–Barr virus, human herpes virus-6, Mycoplasma pneumoniae and parvovirus B19. Conclusions: Among children aged 5 years or older the risk of leukemia may be higher when the low herd immunity for several agents is challenged by late infection from an agent that, as a rule, would attack children at a younger age.

Serum adiponectin and leptin in relation to risk for preeclampsia: results from a large case-control study.

Conditions resulting in insulin resistance, as well as metabolic, immune, and angiogenic perturbations, have been associated with an increased risk of preeclampsia (PE). Our purpose was to assess whether the adipose tissue-secreted hormones adiponectin, which has immune-modulating, metabolic, and angiogenic properties, and leptin, which reflects overall fat mass, are associated with PE risk. We performed a case-control design study within a hospital-based cohort of 368 pregnant women (106 with PE and 262 controls; mean age, 26.6 ± 6.8 years; mean gestational age at admission, 38.2 ± 2.8 weeks) between March 2005 and August 2007 at the Hospital of Pennsylvania University. Serum adiponectin and leptin were measured by radioimmunoassay. Statistical analysis of data was performed using simple and multiple regression analyses. No significant differences in adiponectin or leptin levels between preeclamptic and control pregnant women emerged in univariate analyses (P = .57 and P = .15, respectively). Among preeclamptic women, there were also no differences in adipokines between those with mild and severe disease. Serum adiponectin and leptin were not associated with higher risk of PE before and after adjustment for maternal age, race, primigravida, smoking status, body mass index at screening, gestational age at admission, history of PE, chronic hypertension, and gestational diabetes (odds ratio, 0.93; 95% confidence interval, 0.83-1.04 and odds ratio, 1; 95% confidence interval, 0.97-1.03, respectively). Maternal serum adiponectin and leptin levels, drawn at the time of PE diagnosis, were not associated with PE.

Adiponectin and resistin are associated with risk for myelodysplastic syndrome, independently from the insulin-like growth factor-I (IGF-I) system

AIM Obesity has been implicated in the aetiology of myelogenous leukaemia and myelodysplasia (MDS). We hypothesised that altered secretion of adiponectin and resistin may underlie this association. We thus investigated the role of both total and high molecular weight (HMW) adiponectin and resistin in MDS. METHODS In a case-control study, we studied 101 cases with incident, histologically confirmed primary MDS and 101 controls matched on gender and age between 2004 and 2007. Total and HMW adiponectin, resistin, insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein (IGFBP-3) were determined. RESULTS Lower serum total or HMW adiponectin and/or resistin levels were independently associated with higher risk of MDS controlling for age, gender, BMI and serum levels of leptin, IGF-I and IGFBP-3 (p<0.002). Although total and HMW adiponectin were both significantly inversely associated with MDS when modelled either in quartiles or continuously, HMW did not offer any substantial additional predictive value over total adiponectin (Odds ratio (OR)=0.91 versus 0.93 for a 1 microg/ml change, respectively). IGF-I was positively associated with MDS by bivariate analysis and both IGF-I and IGFBP-3 were higher in advanced MDS and higher risk stages, but were not significantly and independently associated with MDS. CONCLUSION Total and HMW adiponectin may have a protective role in MDS, whereas resistin levels may be decreased via a compensatory mechanism.

Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets

Worldwide, breast cancer (BC) represents the most common type of non-skin human malignancy and the second leading cause of cancer-related deaths amid women in Western countries. Obesity and its metabolic complications have rapidly become major global health issues and are associated with increased risk for cancer, especially BC in postmenopausal women. Adipose tissue is considered as a genuine endocrine organ secreting a variety of bioactive adipokines, such as leptin, adiponectin, resistin and nicotinamide phosphoribosyl-transferase/visfatin. Recent evidence has indicated that the constellation of obesity, insulin resistance and adipokines is associated with the risk and prognosis of postmenopausal BC. Direct evidence is growing rapidly supporting the stimulating and/or inhibiting role of adipokines in the process of development and progression of BC. Adipokines could exert their effects on the normal and neoplastic mammary tissue by endocrine, paracrine and autocrine mechanisms. Recent studies support a role of adipokines as novel risk factors and potential diagnostic and prognostic biomarkers in BC. This editorial aims at providing important insights into the potential pathophysiological mechanisms linking adipokines to the etiopathogenesis of BC in the context of a dysfunctional adipose tissue and insulin resistance in obesity. A better understanding of these mechanisms may be important for the development of attractive preventive and therapeutic strategies against obesity-related breast malignancy.

Nicotinamide phosphoribosyl-transferase/visfatin: A missing link between overweight/obesity and postmenopausal breast cancer? Potential preventive and therapeutic perspectives and challenges

Worldwide breast cancer (BC) constitutes a significant public health concern. Excess body weight is associated with postmenopausal BC (PBC) risk. Recent studies have shown that the constellation of obesity, insulin resistance and serum adipokine levels are associated with the risk and prognosis of PBC. Nicotinamide phosphoribosyl-transferase (Nampt), also known as visfatin and pre-B-cell-colony-enhancing factor, found in the visceral fat, represents a novel pleiotropic adipokine acting as a cytokine, a growth factor and an enzyme. It plays an important role in a variety of metabolic and stress responses as well as in the cellular energy metabolism, particularly NAD biosynthesis. Nampt exhibits proliferative, anti-apoptotic, pro-inflammatory and pro-angiogenic properties. Nampts insulin-mimetic function remains a controversial issue. Circulating Nampt levels are increased in obese women. Also, Nampt levels are significantly elevated in women suffering from PBC than in healthy controls independently from known risk factors of BC, anthropometric and metabolic parameters as well as serum concentrations of well known adipokines. High expression of Nampt in BC tissues was reported to be associated with more malignant cancer behavior as well as adverse prognosis. Taking into account the mitogenicity of Nampt as well as its proliferative, anti-apoptotic and pro-angiogenic properties, a novel hypothesis is proposed whereas Nampt may be involved in the etiopathogenesis of PBC and may represent a missing link between overweight/obesity and PBC. Nampt could exert its effects on the normal and neoplastic mammary tissue by endocrine and paracrine mechanisms; Nampt could also be secreted by tumor epithelial cells in an autocrine manner. It could stimulate mammary epithelial cell proliferation, invasion, metastasis, and angiogenesis, which is essential for BC development and progression. Serum Nampt might be a novel risk factor as well as a potential diagnostic and prognostic biomarker in PBC. In addition, pharmacologic agents that neutralize biochemically Nampt or medications that decrease Nampt levels or downregulate signaling pathways downstream of Nampt may prove to be useful anti-cancer agents. The potential harmful effect on PBC risk due to vitamin B3 (nicotinic acid, a natural NAD precursor in the biosynthetic route leading to NAD) intake is speculated for the first time. In this hypothesis, the role of Nampt in BC carcinogenesis and progression is explored as well as the pathophysiological mechanisms that underlie the association between Nampt and PBC in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against PBC.