Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi


CiteScore 2017: 2.48

SCImago Journal Rank (SJR) 2017: 1.021
Source Normalized Impact per Paper (SNIP) 2017: 0.830

Online
ISSN
1868-1891
See all formats and pricing
More options …
Volume 21, Issue 1

Issues

Adipose tissue, obesity and adipokines: role in cancer promotion

Andrea Booth
  • Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Aaron Magnuson
  • Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Josephine Fouts
  • Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Michelle Foster
  • Corresponding author
  • Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-03-06 | DOI: https://doi.org/10.1515/hmbci-2014-0037

Abstract

Adipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release several adipocytokines that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Adipocyte hypertrophy and excessive adipose tissue accumulation, as occurs during obesity, dysregulates the microenvironment within adipose depots and systemically alters peripheral tissue metabolism. The term “adiposopathy” is used to describe this promotion of pathogenic adipocytes and associated adipose – elated disorders. Numerous epidemiological studies confirm an association between obesity and various cancer forms. Proposed mechanisms that link obesity/adiposity to high cancer risk and mortality include, but are not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk. The aim of this review is to define the function, in normal weight and obesity states, of well-characterized and novel adipokines including leptin, adiponectin, apelin, visfatin, resistin, chemerin, omentin, nesfatin and vaspin and summarize the data that relates their dysfunction, whether associated or direct effects, to specific cancer outcomes. Overall research suggests most adipokines promote cancer cell progression via enhancement of cell proliferation and migration, inflammation and anti-apoptosis pathways, which subsequently can prompt cancer metastasis. Further research and longitudinal studies are needed to define the specific independent and additive roles of adipokines in cancer progression and reoccurrence.

Keywords: adipocytokines; adiposity; cancer progression; cancer reoccurence; cell lines; human; rodent

Introduction

Adipose tissue was formerly characterized to have limited physiological roles mainly pertaining to energy storage following nutrient excess and insulation to protect from cold temperatures. Currently it is recognized that adipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release over 20 hormones and signaling molecules termed “adipokines” or “adipocytokines” that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Under normal conditions, adipocytokines function to regulate numerous physiological processes that play an overall role in appetite and energy balance such as, but not limited to, lipid metabolism, glucose homeostasis, insulin sensitivity, angiogenesis, blood pressure and inflammatory processes. In obesity, however, adipocyte hypertrophy and excessive adipose tissue accumulation, termed “hyperplasia”, dysregulate the sensitive microenvironment within adipose depots, which consequently alters their physiological processes. This action causes “adiposopathy”, which is the promotion of pathogenic adipocytes and adipose tissue related disorders.

Obesity-associated diseases are a rapidly growing concern of national and international public health. In particular, obesity is highly associated with heightened risk of several chronic illnesses including cancer development, reoccurrence and death. It has been estimated that roughly 20% of all cancers are caused by excess weight gain, however this percent is proposed to be an underestimation [1, 2]. In addition, cancer survivors with higher body mass index (BMI) have a greater cancer reoccurrence risk [3]. Epidemiological observation also supports that Americans with a high BMI have a significant increase in risk of dying from cancer than those with average BMI [1, 4]. Common cancers that run a greater risk of occurrence/prevalence with increased adiposity include, but are not limited to prostate, colon, breast, ovarian, endometrial and pancreatic. Prostate cancer in obese men is demonstrated to be more aggressive when compared with normal weight individuals [5]; consequently, obesity increases the risk of prostate cancer mortality [6]. A reduction in body mass, however, is proposed to reduce the risk of prostate cancer [5]. Although colon cancer readily occurs in both men and women, the associated obesity risk with this cancer is greater in men than women, hence studies suggest that obesity increases the risk of colon cancer death in men only [7, 8]. In women, obesity-associated cancer risks are commonly attributed to weight accumulation that occurs post-menopause. Postmenopausal obesity is a predictor of fatal breast cancer [9] and increased risk for endometrial cancer [10] and ovarian cancer [11]. Much like the other cancers, obesity also increases pancreatic cancer risk [12, 13]. Other studies indicate, however, that weight loss – in particular that accompanying with gastric bypass – is associated with reduced cancer risk when compared to those without surgery [14]. This data supports recommendations of weight loss to reduce cancer risk.

There are several proposed mechanisms that link obesity/adiposity to high cancer risk and mortality such as, but not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk; these studies will be discussed below. In general, diseases including cancer are proposed to be more prevalent during obesity because adipose tissue dysregulation that occurs with excessive lipid accumulation induces chronic systemic low grade inflammation. During obesity, the paracrine loop between adipocytes and immune cells becomes dysregulated because most adipokines significantly increase and consequently alter immune cell cytokine secretion. Overall, adipose tissue is a highly involved mediator of the inflammatory immune system response. Enhanced secretion of adipose-derived hormones, growth factors and pro-inflammatory cytokines are major factors in the pathogenesis of tumor growth, increased cell migration and subsequently cancer metastasis.

Leptin

The human leptin gene LEP, also known as the ob gene, encodes a protein that is 16 kDa in weight and 167 amino acids long [15]. It was isolated in 1994 by Jeffrey Friedman [15] and has since been dubbed “the hunger gene” because of its primary action to regulate food intake and energy expenditure. The peptide hormone is secreted from adipose tissue in proportion to an individual’s fat mass and exerts its effects via blood circulation with targets such as the central nervous system, muscle, liver and adipose tissue [16]. The discovery of leptin was seminal in redefining adipose tissue as an endocrine organ, which discredited traditional views suggesting it was just an inert lipid storing tissue.

Leptin binds to leptin receptors encoded by LEPR, also called the db gene, which has six isoforms (ObRa-ObRf) belonging to the family of cytokine receptors. The long form ObRb is a single transmembrane protein that is expressed throughout the central nervous system (CNS), but its function is most relevant in the hypothalamus [17]. Of the short forms identified, ObRa and ObRc are active in most tissues throughout the body [17]. Leptin and its long form receptor act in the fed state on appetite and metabolism through stimulation of proopiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART) or suppression of neuropeptide Y/AgRP [18], these alterations ultimately result in an increase of α-melanocyte-stimulating hormone. The fasted state induces decreases in leptin concentration that subsequently reverse the above actions in the CNS [18]. As leptin binds to its receptors in either the CNS or periphery, it induces Janus kinase 2 (JAK2) to phosphorylate tyrosine resides on the cytosolic domain. Once JAK2 is activated, multiple downstream pathways are stimulated, including the signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K) pathways [19], which regulate gene expression, cell growth, and inflammation.

Resistance to leptin is one of the hallmarks of obesity and is proposed to contribute to the many co-morbidities of the metabolic syndrome. Circulating levels in a normal lean individual are 5–15 ng/mL, whereas with obesity these levels can reach 100 ng/mL and exceed 250 ng/mL in the morbidly obese [20]. High circulating leptin concentrations, known as “hyperleptinemia”, interfere with intracellular signaling by increasing the transcription of SOCS3 (suppressor of cytokine signaling) [21], which ultimately thwarts further signaling cascades. It is also proposed that obesity causes a reduction in blood-brain barrier transport, which reduces accessibility of leptin to the hypothalamus [21]. Overall, leptin resistance leads to dysregulated cytokine signaling, reduced appetite suppression and energy expenditure, which perpetuates inflammation and subsequently further increases adiposity and its associated co-morbidities [22].

It is well-established that obesity is a highly associated risk factor for cancer, hence as BMI increases so does the relative risk of many types of cancer [1]. Epidemiological studies indicate increased circulating levels of leptin, as occurs during obesity, and are associated with cancers such as breast [23] and colorectal [23, 24]. Leptin has also been studied in vitro on cancer cells and is implicated in proliferation of breast, colon, prostate, pancreatic, ovarian, and lung cancers [25]. Indeed, research suggests that leptin plays a role in the progression of mammary tissue tumorigenesis via its function as a growth hormone [26]. Upon binding and activation of JAK2, STAT3 is phosphorylated and dimerizes, causing the transcription factor to translocate to the nucleus where it upregulates genes involved in cell cycle, anti-apoptosis (cell survival), cell invasion/migration, angiogenesis, and inflammation [27]. The general effects of leptin in cancer research include proliferation, cell survival, angiogenesis, and subsequent cancer progression. For the most part, proliferation of cancer cells occurs through activation of the STAT3, ERK, and PI3K signaling pathways that stimulate growth and cell cycle genes [25]. The mechanisms of cell survival are related to an inhibition of apoptosis mediated by upregulation of Bcl anti-apoptotic genes [28]. Angiogenesis occurs through vascular endothelial growth factor (VEGF), which is stimulated by HIF-1α and NFκB, as shown in 4T1 mouse mammary cells [29]. Leptin and its receptor are overexpressed in cancer cells, particularly epithelial cells lining certain tissues. This pathway is responsible for cross-talk between leptin and oncogenes to facilitate in tumor growth and impaired cell death. Specifically, the VEGF gene is induced by leptin and stimulates angiogenesis to support tissue expansion by allowing oxygen to reach proliferating cells [30]. Another downstream effect of JAK2 activation is the MAPK or ERK – extracellular signal regulated kinase (ERK) pathway [31]. The ERK phosphorylation cascade results in activation of transcription factors that interact and bind to serum response elements in the promoter region of the c-fos gene required for cell division [32]. Also, following JAK2 activation is initiation of PI3K [31] and Akt phosphorylation, which stimulates glucose utilization, cell growth via mTOR, cell proliferation and differential apoptosis [33]. Once carcinogenesis occurs, tissue cells release signaling molecules, including leptin, in a paracrine and autocrine manner [34]. To summarize the effects of leptin, its properties include anti-apoptotic, pro-angiogenic, mitogenic, and pro-inflammatory, all supporting tumor growth and cancer progression.

Leptin is shown to be overexpressed in ductal breast tumors, contributing to a proliferative effect, while it is unexpressed in healthy breast tissue not in the vicinity of tumor growth [35]. The role of leptin in tumor growth is demonstrated via mice cancer models. More specifically, MMTV-Wnt-1 mice, a model of mammary tumor growth, that are obese but leptin deficient, have suppressed mammary tumor growth and decreased tumor cell survival compared with those that are leptin sufficient [36]. Leptin acts as a growth hormone in the MCF-7 breast cancer cell line through an increase in aromatase via ERK and STAT pathways [37], as well as enhanced DNA binding of the AP-1 transcription factor [37]. Indeed, increases in aromatase activity were demonstrated in cultured breast cancer cells following leptin incubation, however this did not occur if cells were treated with an aromatase inhibitor [37]. Recent findings on the strong relationship of adipocyte-derived leptin with breast cancer has lent itself to being a target of treatment.

Research also proposes that obesity-induced increases in circulating insulin can enhance the effect of adipose-derived leptin on breast cancer progression. Obesity is characterized by both hyperinsulinemia and increases in circulating leptin. In breast cancer cells, insulin has been demonstrated to stimulate leptin receptor expression, thus increases in insulin along with adipocyte-derived leptin act accumulatively to induce cancer progression [38]. In breast cancer cells, the leptin activity is enhanced following treatment with insulin, which acts via the ERK and PI3K pathways [38]. Transcription factors required for the insulin-mediated increase in leptin expression include Sp1, involved in cell growth and HIF-1α, a response to hypoxia [38].

Breast cancer patients with high circulating levels of leptin are also more susceptive to further cancer cell progression. Leptin is proposed to act initially on breast epithelial cells, transforming them into malignant forms that affect surrounding cells in a paracrine fashion to mediate further cancer cell proliferation [39]. Moreover, addition of leptin to MCF-7 breast cancer cells decreases the expression of the cancer suppression protein p53, exploiting cancer cell survival property [40]. In a female transgenic mouse model susceptible to mammary tumor growth, deficiency of either the leptin gene (ob/ob) [41] or its receptor (db/db) resulted in no development of mammary tumors, whereas tumors were detected in over half of the controls [42].

Leptin has been identified as a biomarker for gastro-oesophageal patients who fail to respond to therapy. Treatment effectiveness is extremely variable in these individuals and greatly affects prognosis and survival [43]. Patients with higher levels of leptin mRNA expression are less responsive to treatment, while those with low levels were more likely to survive [43]. Therefore, leptin levels can be used as an indicator of tumor responsiveness and help guide treatment options to improve a patient’s outcome.

Leptin is expressed in colorectal tumors with a greater expression in more aggressive tumors (more histologically differentiated tumors) [44]. The contribution of leptin to colorectal cancer growth has not been established at this point, however leptin gene expression is regulated by HIF-1α induced by hypoxia [44].

Liver cancer cells HepG2 have been demonstrated to be sensitive to leptin treatment where leptin promotes cell growth and prevents cell death through its unfolded protein response [45]. Both proliferation and survival are aided by inhibition of ER stress signals, which is a regulatory pathway for apoptosis [45]. Both PERK and caspase 12 are implicated in inadvertent cell survival and enhanced proliferation [45]. In the inflammatory condition of hepatitis C virus, human hepatocellular carcinomas (HCC) arise and LEPR has been identified as the most mutated gene in the affected tissue resulting in reduced phosphorylation of STAT3 [46]. Impairment in STAT3 is demonstrated to contribute to enhanced tumorigenesis [46]. Furthermore, patients with hepatitis B virus who have specific single nucleotide polymorphisms Lys109Arg or Gln223Arg in the leptin receptor gene were shown to have differential risk of HCC [47].

There are clear association between obesity, leptin and cancer in various tissues. Though the mechanisms are not fully understood, increased circulating levels of leptin and the downstream effects of its receptor contribute to tumor growth and progression. Figure 1 includes a general model of the best characterized pathways of leptin and its relation to cancer progression.

Leptin is increased with obesity. Leptin binds to its receptor and initiates phosphorylation of JAK2 on its cytosolic domain. Ras/Raf signaling is activated and induces mitogen-activated protein kinase activity, including cell cycle inducers and inactivation of tumor suppressor protein p53. STAT3 binds to phosphor-tyrosines on receptor and translocates to the nucleus to activate transcription of cell proliferative genes. Activation of phosphoinositide 3-kinase (PI3K) leads to AKT/mTOR stimulation promoting cell growth and survival.
Figure 1:

Leptin is increased with obesity.

Leptin binds to its receptor and initiates phosphorylation of JAK2 on its cytosolic domain. Ras/Raf signaling is activated and induces mitogen-activated protein kinase activity, including cell cycle inducers and inactivation of tumor suppressor protein p53. STAT3 binds to phosphor-tyrosines on receptor and translocates to the nucleus to activate transcription of cell proliferative genes. Activation of phosphoinositide 3-kinase (PI3K) leads to AKT/mTOR stimulation promoting cell growth and survival.

Adiponectin

The hormone adiponectin is secreted exclusively from adipose tissue and is the only adipokine with an inverse relationship to fat mass. It is encoded by the gene AdipoQ, makes a protein 244 amino acids in length that is 30 kDa in weight [48]. Adiponectin is involved in glucose and lipid homeostasis and is therefore implicated in the pathogenesis of insulin resistance [49] and diabetes [50]. Adiponectin was discovered in the mid-1990s as a requirement for adipocyte differentiation of 3T3-L1 cells and its secretion is correlated with insulin sensitivity [48]. Plasma concentrations of this hormone range from 2 to 20 μg/mL [51].

Adiponectin acts through its receptors, AdipoR1 and AdipoR2 [52], which are transmembrane receptors that activate a signaling cascade upon ligand binding [53]. AdipoR1 is found mostly in skeletal muscle, but also appears in the hypothalamus, liver, and other tissue [54]. It stimulates the AMP-activated kinase pathway both directly and through an influx of extracellular calcium leading to factors that affect lipid and glucose metabolism [54]. AdipoR2 is commonly found in liver tissue and appears also within white adipose tissue and the vasculature [54]. This isoform affects PPARα activity, which regulates lipid metabolism through gene transcription and increased expression of its ligands [54]. Adiponectin receptors also have ceramidase stimulatory activity, which lowers intracellular ceramide, increases sphingosine 1-phosphate levels, and protects against apoptosis [55].

Obesity is associated with lower plasma adiponectin levels [56] as well as decreased expression of its receptors AdipoR1 and AdipoR2 [57]. Blood plasma levels are not only reduced in obese individuals, but also in non-obese individuals with related conditions such as type 2-diabetes and cardiovascular disease [58]. Adiponectin has been recognized as an insulin-sensitizing hormone that works by decreasing liver and muscle triglyceride content through increased AMPK activity and expression of energy expenditure molecules [59]. Hence this hormone has similar properties of exercise in that it increases glucose uptake in muscle and suppresses glucose production in liver.

Adiponectin is one of the only adipocyte-secreted protein with beneficial effects on health and disease due to its role in lipid metabolism and glucose homeostasis. When adiponectin is decreased with obesity, known as hypoadiponectinemia, as the result of increased secretion of other cytokines like TNFα, its anti-disease properties are also dampened [60]. As the most prolific protein secreted by adipocytes, adiponectin is anti-inflammatory, pro-apoptotic, and anti-proliferative under normal circumstances [60]. There are two ways the hormone can effect cancer retardation: either directly on the tumor cells as several cancer lines express adiponectin receptors or through its insulin-sensitizing effects [61]. Either way, decreases in adiponectin have been associated with breast, endometrial, colon, esophageal, and liver cancer among many others [61].

Actions of adiponectin in breast cancer lines that express AdipoR1/R2 include reduce cancer invasion and migration to other cells [62]. Research demonstrates adiponectin is anti-carcinogenic in breast cancer cell lines, including MCF-7, MDA-MB-231 and T47D through its anti-proliferative properties [63]. In all three cancer cell lines mentioned above, adiponectin increases activation of cell apoptosis and inhibits the cell regulatory cycle [64–66]. Others also demonstrate adiponectin pre-treatment significantly attenuates mammary tumor growth and tumor weight in mice injected with the human breast cancer cells MDA-MB-231 [67]. In a human breast cancer cell study, in vitro exposure of MCF-7 cells to adiponectin-induced phosphorylation of AMPK, which subsequently hindered cell cycle progression through decreased expression of cyclin D1 and c-myc mRNA expression, and stimulated apoptotic responses through increased expression of p53 and Bax [64]. Adiponectin also reduces the bioavailability of certain growth factors, such as platelet-derived growth factor BB (PDGF-BB), basic fibroblast growth factor (FGF), and heparin-binding epidermal growth factor-like growth factor (HB EGF) [68]. Therapeutic targets of breast cancer include therapies that activate the signaling or mimic the actions of adiponectin such as Metformin, PPARγ agonists and activators of AMPK signaling pathway [62].

Decreased adiponectin receptor expression is associated with a histological higher grade of endometrial cancer [69]. Henece, adiponectin receptor expression decrese is a proposed contributor to cancer progression and currently is a proposed target of treatment for endometrioid adenocarcinomas [69]. In one study, KLE and RL95–2 human endometrial cancer cell lines had a decrease in proliferation when incubated with adiponectin [70]. If adiponectin receptors, however, were repressed in the same cancer lines, the protective effects of adiponectin were reduced [70]. These results suggest a reliance on receptors adipoR1 and adipoR2 in the inhibitory effects of adiponetin on endometrial tumor cell progression [70]. LKB1 was identified as a tumor suppressor gene required for adiponectin-mediated AMPK activation in KLE and RL95–2 endometrial cancer cell lines [70]. Consistent with this, a cohort of 60 patients with endometrial cancer had significantly lower serum adiponectin levels than controls [71]. Taken together, decreased expression of the protective adiponectin hormone is a risk factor for endometrial cancer in postmenopausal women.

Adiponectin and plasminogen activator inhibitor-1 (Pai-1) are known mediators of colorectal cancer progression. The two proteins are inversely regulated in both the early and late stages of adipocyte differentiation [72]. During early stages of 3T3-L1 cell differentiation, activation of PPARγ or reduction of Pai-1 causes an increase in adiponectin and AMPK activity [72]. This shows that treatment with adiponectin may modulate the poor prognosis of colorectal cancer patients associated with increased Pai-1 levels [72]. Aside from treatment possibilities, adiponectin is a good biomarker for colorectal adenoma patients due to its significant inverse correlation with the number of adenomas [73]. Additionally, low adiponectin levels are associated with insulin resistance as well as stage of colorectal cancer, indicating that low adiponectin is connected to poor prognosis and possibly carcinogenesis [74]. Furthermore, in both human and mouse colon cancer cell lines adiponectin and Metformin combined reversed the effect of IL-1β, an inducer of cancer carcinogenesis via tumor suppressor protein p53 [75].

Taken together, high adiponectin levels have attenuating effects on cancer expression and progression. Its inverse relationship with fat mass supports adiponectin’s role in cancer as it relates to obesity and weight status. Figure 2 includes a general model of the best characterized pathways of adiponectin and its relation to cancer progression.

Adiponectin is decreased with obesity. Translation of protein synthesis S6K/eIF4E and cell cycle genes as well as angiogenesis via mTOR pathway is blocked by activation of the AMP-activated protein kinase (AMPK). Cell growth and proliferation factors initiated by the insulin-induced PI3K pathway is also blocked via AMPK. Anti-apoptotic and migratory proteins induced by p65/p50 of the NFkB pathway is inhibited by peroxisome proliferator-activated receptor-alpha. Adiponectin receptors exhibit ceramidase enzymatic activity to reduce detrimental effects of intracellular ceramide accumulation.
Figure 2:

Adiponectin is decreased with obesity.

Translation of protein synthesis S6K/eIF4E and cell cycle genes as well as angiogenesis via mTOR pathway is blocked by activation of the AMP-activated protein kinase (AMPK). Cell growth and proliferation factors initiated by the insulin-induced PI3K pathway is also blocked via AMPK. Anti-apoptotic and migratory proteins induced by p65/p50 of the NFkB pathway is inhibited by peroxisome proliferator-activated receptor-alpha. Adiponectin receptors exhibit ceramidase enzymatic activity to reduce detrimental effects of intracellular ceramide accumulation.

Apelin

Apelin is a peptide hormone discovered in 1998 that functions as a ligand for the G-protein coupled receptor APJ [76]. It is expressed in many tissues throughout the body and ranges between 13 and 36 amino acids with intended target receptors that include the CNS [76]. Apelin produced and secreted by adipocytes has been demonstrated to have effects ranging from fluid homeostasis, insulin secretion, epithelial proliferation, and cytokine regulation [77, 78]. This hormone is proposed to be anti-obesigenic in normal weight individuals and behaves similar to that of insulin, however levels are found to be increased in obese individuals as well as those with type 2-diabetes [79]. The true role of apelin, however, is unclear as it exhibits opposing effects on energy metabolism with respect to peripheral vs. central tissue [79]. Due to the ability of apelin to increase glucose uptake and decrease insulin resistance and adiposity in the periphery [79], it is an attractive target for control of body weight and metabolic disorders.

In regards to cancer, apelin had been demonstrated to play a role in lymph node metastasis and lymphangiogenesis via binding to its receptor in lymphatic endothelial cells that activates ERK and PI3K pathways, leading to cell proliferation, migration, and cell survival [80]. In addition, in a study of females with endometrial cancer, apelin levels were significantly higher in the obese group than non-obese controls and was positively correlated with fasting insulin levels, suggesting that high circulating levels of apelin associated with obesity is a risk factor for endometrial cancer [81].

Visfatin

Visfatin a small molecule of 52 kDa was originally identified as Pre-B-cell Colony enhancing factor (PBEF) by Samal et al. [82]. Nampt, discovered even earlier by Preiss et al. in 1957 [83], was similar to PBEF and visfatin, but was not well characterized at the time of discovery. The connection that PBEF and Nampt were the same molecule was later made by Rongvaux et al. [84]. Nampt would later be renamed visfatin, which is essentially the same molecule as PBEF. This molecule plays several biologically significant roles, including immune cell signaling, insulin mimetic effects, and regulation of the NAD biosynthetic pathway. Nampt is the enzymatic form, capable of catalyzing biosynthetic reactions, of the molecule that plays an important part in the biosynthesis of NAD as it is the rate-limiting enzyme [84, 85]. This enzyme is important both in regulation of cellular energetics and the control of other enzymes dependent upon NAD for their functions [86]. PBEF is another recognized form of the visfatin molecule that functions as a cytokine produced and secreted by cells of the immune system, leukocytes, which stimulate the expression of a number of pro-inflammatory cytokines including TNF-alpha, IL-1B, and IL-6 and promote the differentiation of B-cells [82, 86]. The final form, visfatin, was discovered to be secreted from mainly visceral adipose tissue cells and has the ability to function similarly to insulin [87]. Recent studies, however, demonstrate that visfatin may be more heavily expressed in macrophages that infiltrate adipose tissue [88]. Therefore the macrophages are proposed to release visfatin in response to inflammatory signals rather than the adipocytes excreting it themselves [88].

It has been somewhat controversial as to the role that visfatin may actually be playing in obesity. However, mounting evidence suggests that there is indeed an association between obesity and increased visfatin levels in the body. In a recent meta-analysis by Chang et al. [89], they observed a positive correlation between visfatin and insulin resistance as well as elevated visfatin levels association with obesity, adiposity, metabolic syndrome, type 2 diabetes and cardiovascular disease. Another recent analysis by Jurdana et al. [90] also showed higher baseline levels of visfatin after fasting in overweight and obese subjects than those in controls. The association of visfatin and obesity is of importance to consider as it has been demonstrated that obesity is a significant risk factor for cancer development [1, 91–93]. Based on all of the actions of visfatin it has become of increasing interest to define the role that it may play in cancer pathophysiology, especially in relation to obesity.

Current studies propose that visfatin is involved in the development and pathophysiology of a number of different cancers. The relation of visfatin to colorectal cancer (CRC) is among the best characterized to date [94–96], but data supporting its role in breast cancer or postmenopausal breast cancer (BC/PBC) is increasing [97]. Research also demonstrates a role of visfatin in ovarian cancers [98]. The role of visfatin in the development of the previously mentioned cancers has been attributed to several possible mechanisms. First, visfatin can directly induce the production of inflammatory cytokines, such as Il-6, however the receptor that mediates this particular pathway is currently unknown [99]. In addition, increases in visfatin are directly associated with increases in TNF via Sirt6 [100]. Sirt6 is an NAD-dependent enzyme that acts post-transcriptionally in the upregulation of TNF [100]. This links Nampt and levels of NAD to the inflammatory response that can affect promotion of carcinogenesis [98, 100]. The control of TNF and Sirt6 by NAD levels provides a potential link to carcinogenesis by Nampt via a metabolic mechanism. A second mechanism that links visfatin to increased cancer risk is its role in enhancing cancer cell survival. Specifically, CRC cells express chemokine receptors, CXCR4 and CXCR7, both of which can bind SDF-1 that promotes survival and migration of the cancerous cells [101, 102]. Wen-Shih Huang et al. [96] demonstrated that increased production of visfatin leads to increased expression of SDF-1. This is mediated by the B1 integrin and involves signaling through the ERK and p38 MAPK pathways [96]. ERK and p38 MAPK signaling lead to an increase in NF-KB and AP-1, leading to the increased expression of SDF-1 and increased CRC cell survival and migration [96]. Inhibitors of NF-kB and AP-1 effectively decreased the expression of SDF-1 [96]. A third pathway recently identified involves redox pathways and the reduction of reactive oxygen metabolites by visfatin through increased activity of antioxidative enzymes superoxide dismutase (SOD), catalse (CAT), and glutathione peroxidase (GSHPx). Hence, this visfatin pathway induces cancer cell protection from cytotoxic damage of reactive oxygen species [103]. This was demonstrated in cultured human melanoma cells (Me45) where visfatin treatment increased activity of the antioxidative enzymes [103]. Therefore, in an apoptotic state increases in visfatin induce antioxidative activity, which results in increased viability of the cancer cells. This suggests that increased levels of visfatin are protective against oxidative damage in both normal cells and existing cancer cells, thus protecting them from apoptosis and allowing for survival and proliferation [103].

The last mechanism involves the enzymatic activity of Nampt and the generation of NAD. NAD synthesis is required for many cellular functions but mechanisms specifically applicable to cancer progression include those involved in cell growth and survival, DNA repair, and angiogenesis [98]. Among the best characterized cancer-inducing cellular functions regulated by Nampt is the regulation of gene transcripts. An increase in Nampt expression leads to an increase in cell survival and Sirt1 activity, increasing angiogenesis [98]. Based on this outcome, Shackelford et al. [98] tested Nampt expression in ovarian serous adenocarcinomas (OSAs) that exhibit a high level of Stat3expression, which leads to an increase in Nampt levels. The upregulation of Stat3 was demonstrated to be through Il-6 signaling [104]. In this manner it may actually be possible for visfatin to trigger the release of Il-6 that is responsible for the upregulation of Stat3 [104] that in turn increases endogenous Nampt levels [98]. It was also demonstrated that the Nampt levels were indeed significantly increased in the OSAs compared to controls [98]. Figure 3 depicts the best characterized cancer progression pathways induced by visfatin also known as Nampt and PBEF.

Visfatin is increased with obesity. Shown are three distinct mechanisms in which visfatin exerts effects on cancer. First it was shown that visfatin can stimulate monocytes to release the inflammatory cytokine IL-6. IL-6 then signals in an intracellular fashion to increase the expression levels of STAT3 which upregulates the active enzymatic form of visfatin, Nampt. Nampt can then cause increased cell survival through Sirt-1, and Sirt-6 stimulates the release of TNF-α, an inflammatory cytokine that has been linked to carcinogenesis in states of chronic low grade inflammation such as obesity. In the second pathway, visfatin signals through the cell surface receptor, Beta-1 integrin. This binding of ligand signals the upregulation and activation of MAPKs p38 and ERK. The MAPK cascades increase the expression of Ap1 and NFkB transcription factors that then upregulate SDF-1, leading to increased survival and migration in a cancer cell model. The third pathway was demonstrated through the action of visfatin on Me45 cancer cells. Treatment caused an increase in the antioxidative enzymes SOD, CAT, and GSH-PX via an unknown receptor. The increase in the enzymes was speculated to lead to a decrease in cell death by ROS and thus a protective effect on cancerous cells.
Figure 3:

Visfatin is increased with obesity.

Shown are three distinct mechanisms in which visfatin exerts effects on cancer. First it was shown that visfatin can stimulate monocytes to release the inflammatory cytokine IL-6. IL-6 then signals in an intracellular fashion to increase the expression levels of STAT3 which upregulates the active enzymatic form of visfatin, Nampt. Nampt can then cause increased cell survival through Sirt-1, and Sirt-6 stimulates the release of TNF-α, an inflammatory cytokine that has been linked to carcinogenesis in states of chronic low grade inflammation such as obesity. In the second pathway, visfatin signals through the cell surface receptor, Beta-1 integrin. This binding of ligand signals the upregulation and activation of MAPKs p38 and ERK. The MAPK cascades increase the expression of Ap1 and NFkB transcription factors that then upregulate SDF-1, leading to increased survival and migration in a cancer cell model. The third pathway was demonstrated through the action of visfatin on Me45 cancer cells. Treatment caused an increase in the antioxidative enzymes SOD, CAT, and GSH-PX via an unknown receptor. The increase in the enzymes was speculated to lead to a decrease in cell death by ROS and thus a protective effect on cancerous cells.

Resistin

The human gene RETN is responsible for the coding and production of resistin, a small molecule adipokine of roughly 12.5 kDa [105]. Resistin was discovered by Steppan et al. [105] and subsequently named in a paper published in 2001. As an adipokine it was initially considered to mainly be a link between obesity and insulin resistance and was thought to be more heavily secreted by adipocytes as was demonstrated in rodents [105]. As discovered in the mouse model, it was shown that resistin circulates in the serum and is increased in both genetic and diet induced obesity [105]. It was also demonstrated that neutralization of resistin, by way of antibody binding, improves blood glucose levels and insulin sensitivity [105]. Recent studies in humans have indicated that unlike rodents, resistin is heavily expressed in peripheral mononuclear cells, but minimally expressed in adipocytes and preadipocytes [106]. Based on resistin being more highly expressed in immune cells that infiltrate the adipose tissue, Lerkhe et al. [107] demonstrated that the levels of resistin were more likely related to the inflammatory status of the individual. For this reason it has been hypothesized that resistin may be one of the adipocytokines that heavily influences the development of cancers. It has been demonstrated that resistin may represent the link between obesity and an increased inflammatory state and the influence that inflammation then exerts on the development of tumors [108].

Restin has been investigated in a number of cancers including colorectal [73, 95], breast [109], and prostate cancers [110], and HCC [111]. Specific cascades that link resistin to cancer include signaling through TLR4 and the induction of the PI3K signaling cascade, and stimulation of NF-kB [112, 113]. Activation of these pathways can cause a spiraling cascade of cytokines that continually upregulate inflammatory responses and perpetuate an increased inflammatory state that can lead to a carcinogenic state [112, 113]. The downstream pro-inflammatory cytokines produced activate specific pathways that lead to proliferation, differentiation and metastasis of the cancerous cells as seen by the activation of JAK/STAT and MAPK pathways via IL-6 that is upregulated by NF-kB [114]. PI3K and AKT phosphorylation are also induced by resistin and lead to the proliferation of cancer cells as demonstrated in several cancer cell lines [110].

Another mechanism of action for resistin in relation to gastric cancer was discovered to be similar to that previously discussed with visfatin. Gastric cancer cells treated with resistin have increased expression of SDF-1 [115]. Binding of resistin to the TLR-4 receptor induces signaling via the p38 MAPK and NF-kB pathways, which subsequently leads to the upregulation of SDF-1 [115]. The major difference between the visfatin and resistin pathways is the receptor that mediates the signaling cascades responsible for the upregulation of SDF-1. Specifically, visfatin binds to B1 integrin whereas resistin binds to TLR-4. Another signaling pathway for resistin recently defined is related to promotion of cell survival through activation of PI3K/AKT signaling pathways [110], which promotes cell survival by inactivating pro-apoptotic proteins via phosporylation [110]. A major aspect and critical step of tumor metastasis is enhanced cell adhesion to the endothelium [116, 117]. Two important molecules that are involved in this process are the intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) [118]. It was recently demonstrated that resistin mediates expression of these molecules on Sk-Hep1 cancer cells, thus tumor cell adhesion to the endothelium is regulated by resistin [111]. It was also demonstrated that blocking the generation of NF-kB effectively blocked the upregulation of the two adhesion molecules [111].

A number of mechanisms have been indicated for the involvement of resistin in the pathogenesis of cancer. As discussed, many of these mechanisms are triggered through an intracellular signaling cascade and many flow through NF-kB. Downstream effects are seen in increases in the inflammatory profile and immune cell recruitment, changes in expression of adhesion molecules and production of cellular products that help to increase survival, differentiation and metastasis of the cancer cells themselves. A summary of the best characterized pathways of the role of resistin in cancer progression are depicted in Figure 4.

Resistin is increased with obesity. Adipose tissue expansion, especially in an obesogenic state, causes an increase in the release of resistin. Resistin is released from both the adipocytes and the resident immune cells that are increased as the result of local inflammation. Resistin is recognized by the TLR4 receptor on the surface and cells and binding of resistin as a ligand triggers downstream signaling. Two distinct signaling pathways are triggered. The first is through PI3K upregulation followed by AKT and NFkB. The second is through the MAPK pathway, notably p38 among others, followed by upregulation of NFkB. NFkB can then itself trigger three distinct pathways. The first is an upregulation of inflammatory cytokines leading to increased immune cell recruitment followed by an increase in the generation of reactive oxygen species and cellular damage. The second is through the upregulation of the adhesion molecules ICAM-1 and VCAM-1. These two molecules lead to increased adhesion of cancer cells to the endothelium. The third pathway is by upregulation of SDF-1 that promotes tumor development and metastasis.
Figure 4:

Resistin is increased with obesity.

Adipose tissue expansion, especially in an obesogenic state, causes an increase in the release of resistin. Resistin is released from both the adipocytes and the resident immune cells that are increased as the result of local inflammation. Resistin is recognized by the TLR4 receptor on the surface and cells and binding of resistin as a ligand triggers downstream signaling. Two distinct signaling pathways are triggered. The first is through PI3K upregulation followed by AKT and NFkB. The second is through the MAPK pathway, notably p38 among others, followed by upregulation of NFkB. NFkB can then itself trigger three distinct pathways. The first is an upregulation of inflammatory cytokines leading to increased immune cell recruitment followed by an increase in the generation of reactive oxygen species and cellular damage. The second is through the upregulation of the adhesion molecules ICAM-1 and VCAM-1. These two molecules lead to increased adhesion of cancer cells to the endothelium. The third pathway is by upregulation of SDF-1 that promotes tumor development and metastasis.

Chemerin

Expression of the mature/active form of chemerin, a 16-kDA protein, was originally characterized in human tissues such as the spleen, lymph nodes and lung [119]. Within these tissues, chemerin is proposed to be a mediator of antitumor immunity and immune surveillance by functioning as a chemoattractant for immune cells, including natural killer, macrophages and dendritic cells [119–121]. In 2007 it was discovered that chemerin and its associated receptor, CMKLR1, were also highly expressed in isolated human and mouse adipocytes [122] suggesting that adipose tissue is a source and target for chemerin signaling. Adipocytes have been demonstrated to secrete physiological amounts of chemerin in early adipocyte differentiation and as the cells mature this adipokine is increasingly secreted [122]. Adipose-tissue-derived chemerin acts in both an autocrine and paracrine manner. Under normal physiological circumstances the autocrine chemerin pathway in adipocytes regulates elements critical in the early events of adipogenesis, hence knockdown of chemerin or CMKLR1 in preadipocytes greatly inhibits subsequent differentiation to mature adipocytes [122]. In mature adipose tissue the autocrine response of chemerin is linked to modulating metabolic pathways of lipolysis, glucose uptake and lipostatic signaling [122]. The paracrine response of adipocyte release chemerin is described to be predominately active during an inflammatory process such as chronic low grade inflammation associated with obesity. Specifically, excessive lipid accumulation induces adipose tissue hypoxia and increases free fatty acid release, adipokine secretion and metabolic dysregulation [123]; these alterations consequently activate an inflammatory response. Like many adipokines, increases in plasma chemerin concentration are highly associated with increases in BMI and metabolic syndrome [124]. The contribution of adipose tissue secreted chemerin to the progression of pathophysiology of obesity and metabolic dysregulation is proposed to stem from its role in local pro-inflammatory response. Indeed, CMKLR1 is significantly expressed in immune cells such as neutrophils, activated macrophages and dendritic cells [119]. It is suggested that increases in adipocyte-derived chemerin, as occurs in obesity, induce local paracrine inflammatory response by enhancing the recruitment of CMKLR1 expressing immune cells [125].

In addition to enhancing the inflammatory response within adipose tissue, chemerin also enhances the inflammatory response of macrophages within tumors [126]. Limited evidence exists demonstrating increases in circulating chemerin concentration are associated with progression of cancers. Thus far the association between serum chemerin and gastric cell cancer is best characterized. Compared with healthy non-cancer subjects, stage 1 gastric cancer patients have higher serum concentration of chemerin [127]. In advanced stages of gastric cancer, high grade/aggressive cancer, serum chemerin concentration is higher than levels demonstrate in stage 1 [127]. In support of this others demonstrate that an elevation in preoperative chemerin concentration is associated with poor post-operative prognosis and survival gastric cancer [128]. Chemerin promotes the progression of gastric cancer by increasing its invasiveness, the spread of cancer outside of the tissue the cancer has originated, but not proliferation [127]. Mechanisms for these increases in invasiveness include chemerin-induced increases in pro-invasive genes such as VEGF, MMP-7 and IL-6 and activation of MAPK signaling such as ERK1/2 and p38.

Omentin

Omentin was originally founded under the name “intelectin”. Under its first identity, this protein was isolated from small intestine paneth cells and classified as a soluble galactofuranose-binding lectin with a role in gut immunity against pathogenic bacteria [129]. In 2006, omentin-1, a 34 k-Da protein, was determined to be secreted from adipose tissue in a depot-specific manner with higher expression and release from central (visceral) depots [130]. In humans, omentin is primarily expressed in adipose tissue stromal vascular cells and, as a secretory factor, acts as an endocrine factor to modulate systemic metabolism, but also acts locally in an autocrine and paracrine fashion [130]. The paracrine and endocrine effects of omentin in normal weight individuals function to enhance insulin sensitivity and glucose metabolism [130]. Omentin is also demonstrated to play a role in inflammatory responses and cell differentiation by AMPK/eNOS signaling pathway, which suppresses activation of JNK to suppress inflammation responses and increase cell differentiation [131]. Circulating omentin-1 levels in a healthy individual are reported to be roughly 0.37 μg/mL, but are significantly reduced in obese individuals to 0.31 μg/mL [132]. As stated previously, omentin levels are inversely correlated to obesity, but lower levels of omentin-1 are also found in patients with impaired glucose tolerance, type 2 diabetes, increased waist circumference, and elevated blood pressure [133]. Therefore, omentin-1 is considered to be predictive of metabolic abnormalities. In vitro studies have shown that omentin-1 treatment reverses these metabolic dysfunctions by stimulating glucose uptake via Akt activation [134]. Recently clinical research shows that cancers such as prostate [135], colon [136], liver [137], and colorectal [94] are associated with increases in omentin serum levels independent of various factors such as BMI, glucose, lipid parameters, disease differentiation [134, 136]. As demonstrated in HCC cells, omentin is considered anti-cancerous because it promotes apoptosis of cancer cells [137]. According to Zhang and Zhou, omentin-1 inhibits HCC proliferation via upregulating p21 protein in human HCC cells, which in turn increases p53 protein, a tumor suppressor gene [137]. Omentin-1 also promotes HCC apoptosis by increasing the bax-to-bacl-2 ratio and inducing capases-3 activation [137]. To the best of our knowledge, there are no additional studies directly associating the anti-inflammatory and tumor-suppressing effects of omentin on other cancers; therefore, this would be the most profitable step in the upcoming research of omentin.

Nesfatin

Derived from the protein nucleobindin 2, nesfatin-1 discovered in 2006, also known as NUCB2, is identified as an anorexigenic peptide that regulates appetite and body weight [138]. Originally, nesfatin-1/NUCB2 was discovered in hypothalamic nuclei but is now characterized to be expressed in numerous tissues such as the arcuate nuclei, lateral hypothamus, paraventicular nuclei, supraoptic nuclei, stomach tissues, pancreatic islets, testis and adipose tissues [138, 139]. Nesfatin-1 secretion from adipose tissue, in particular subcutaneous adipose depots, is increased in obesity and by other factors such as pro-inflammatory cytokines such as TNF-αa and IL-6 as well as insulin and dexamethasone [94, 138]. In obesity nesfatin-1 is suggested to play a role in the enhancement of lipid accumulation pathways [138].

To the best of our knowledge, there is currently only one prospective study that reports a connection between circulating nesfatin-1 concentration and cancer. In this study, nesfatin-1 levels are decreased in lung cancer patients with, but not without, cachexia; hence, nesfatin-1 levels are decreased with decrease adiposity [139]. Additional studies in cell lines, however, have further elucidated the effect of nesfatin-1 on cancer cell regulation. According to Xu et al. [140], nesfatin-1 treatment to the ovarian epithelial carcinoma cell line HO-8910 inhibits cancer cell proliferation by altering elements of the cell cycle, leading to a decrease in the number of cells that reach maturation. Nesfatin-1 treatment in this study is also reported to promote apoptosis of the HO-9010 cells via the mammalian target of rapamycin (mTOR) signaling pathway [140]. mTOR, a central cell growth regulator that controls cell proliferation, had a significant decrease in activation with nesfatin-1 treatment, as did its downstream target, the S6 ribosomal protein [140]. In addition, the activity of caspase-3, a well-known apoptosis marker in mammalian cells, was increased, which further adds to the apoptosis effect [140]. Finally, in this study, RhoA/ROCK pathway ratios were measured to further solidify the findings that nesfatin-1 both promotes apoptosis of cancerous cells and inhibits their proliferation [13]. Many cellular processes, including apoptosis, are dependent on RhoA, a small GTPase, and its downstream effector, Rho-associated coiled coil-containing protein kinase (ROCK) [141]. Nesfatin-1 significantly increased RhoA activity levels, also increasing the activity of ROCK, thus inducing apoptosis and further inhibiting the proliferation of HO-9010 cells [140]. Ideally, further research on the benefits of nesfatin-1 treatment is in order on a number of various other cancers and after then, rodent specific studies to identify direct correlation.

Vaspin

Vaspin, a visceral adipose tissue-derived serine protease inhibitor known mainly for its insulin-sensitizing effects and modulatory role on glucose tolerance [134]. This 50 k-Da adipokine was first discovered when identifying genes that were differentially expressed between during the development of obesity and type 2 diabetes in a rat model study; vaspin was identified to be increased in obesity [134]. Thereafter, increased vaspin levels have been reported to be linked to diabetes, metabolic syndrome, obesity, coronary artery disease and impaired insulin sensitivity [142].

There is only one recent study that has used a rodent model to directly correlate the effects of vaspin with obesity. According to Nakatuska and colleges, vaspin transgenic (Tg) mice fed a high fat-high sucrose (HFHS) diet were protected from increased adiposity, glucose intolerance, hepatic steatosis and obesity-induced inflammation [143]. Vaspin knockout mice, however, had opposite results with glucose intolerance, being highly associated with the upregulation of liver ER stress markers (marker of liver dysregulation) [143]. The effect of liver ER stress on insulin resistance/glucose intolerance in this model involved down regulation of ER chaperone proteins, such as 78 k-Da glucose-regulated protein (GRP78) [16]. Hence, increased expression of GRP78 in the liver is proposed to be metabolically beneficial. Indeed, in lean rodents vaspin interacts with GRP78 to induce intracellular signaling that activates Akt and AMPK, which improves glucose and lipid metabolism and relieves metabolic dysfunction and inflammatory responses in obesity [144].

To the best of our knowledge, there are only two recent prospective studies relating the link between vaspin and specific cancers: one on colorectal [94] and another on endometrial [71]. Neither study has successfully identified the mechanism of vaspin to the respective cancer. Furthermore, the results from one study contradicts the other. There are reports of lower levels of vaspin in endometrial cancer results while there are reports of higher levels in colorectal [10, 18]. Clearly there is much more need research on the benefits and effects of vaspin on all levels from molecular to demographic.

Cytokines

Cytokines are another class of molecule that have been heavily indicated in the induction and pathogenesis of cancer. Cytokines are primarily linked to the development of cancers by way of their influence on inflammation, mainly chronic low grade inflammation associated with many diseases such as obesity, hence inflammation is one of the major factors that links obesity to the development of its associated co-morbidities [145]. One of the proposed major connections between cytokines and cancer is through the molecule NF-kB. NF-kB is a transcription factor that is activated in response to a number of stimuli, including inflammatory molecules (Il-6, TNF-alpha, and Il-1B), growth factors, viruses and bacteria. NF-kB in turn is linked to cell proliferation, apoptosis, angiogenesis and metastasis [146].

One of the major cytokines regulated through NF-kB and that has been heavily studied in its relationship to cancer is Il-6 [147]. Cytokines within the IL-6 family include, but are not limited to, IL-11, IL-27 and IL-31 [145]. This cytokine family has been investigated in relation to several cancers including colon and prostate [148]. It was demonstrated that in prostate cancers, Il-6 functionally changes from a growth inhibitor to a growth promoter with the ability to potentiate cancer cell growth [148]. It was also demonstrated that in colon cancers Il-6 promotes tumor development and growth via Stat3 signaling especially in the early stages of development in relation to colitis [149].

The important aspect of cytokines in cancer development has been narrowed down to the role that they play in inflammation. Much of the inflammatory response has been demonstrated to flow through the transcription factor NF-kB that is activated by many of the inflammatory molecules and machinery [150]. One of the most important aspects that has been demonstrated for NF-kB is its ability to activate anti-apoptotic gene expression that blocks the apoptotic process that is induced by many of the inflammatory cytokines such as TNF-alpha [151]. Combining upregulation of inflammatory cytokines through tissue injury as well as increased adipocytokine secretion by adipose tissue and immune molecules, especially in a state of obesity, and the ability of many of these to induce NF-kB, overall promotes a protumorigenic environment.

Conclusion

Dissecting mechanisms underlying adipokine involvement in obesity-driven cancer is of high importance because of risk reduction and treatment to prevent recurrence. Current suggestions to decrease obesity-associated cancer risk include lifestyle interventions such as losing weight, physical activity and dietary modifications. The epidemiological, pathophysiology and mechanistic studies provided to date signify the important role adipocytokines play in cancer progression and reoccurrence. The previous studies clearly demonstrate that adipose tissue dysregulation is not localized to the adipose depot, rather in obesity it becomes a systemic issue. Studies should further characterize not only the independent role these adipokines play in cancer production, but also the combined effects that may occur since all are dysregulated with obesity.

References

  • 1.

    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–38.Google Scholar

  • 2.

    Wolin KY, Carson K, Colditz GA. Obesity and cancer. Oncologist 2010;15:556–65.CrossrefGoogle Scholar

  • 3.

    Jones DH, Nestore M, Henophy S, Cousin J, Comtois AS. Increased cardiovascular risk factors in breast cancer survivors identified by routine measurements of body composition, resting heart rate and arterial blood pressure. SpringerPlus 2014;3:150.CrossrefGoogle Scholar

  • 4.

    Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 1999;341:1097–105.Google Scholar

  • 5.

    Rodriguez C, Freedland SJ, Deka A, Jacobs EJ, McCullough ML, Patel AV, Thun MJ, Calle EE. Body mass index, weight change, and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2007;16:63–9.CrossrefGoogle Scholar

  • 6.

    Rodriguez C, Patel AV, Calle EE, Jacobs EJ, Chao A, Thun MJ. Body mass index, height, and prostate cancer mortality in two large cohorts of adult men in the United States. Cancer Epidemiol Biomarkers Prev 2001;10:345–53.Google Scholar

  • 7.

    Murphy TK, Calle EE, Rodriguez C, Kahn HS, Thun MJ. Body mass index and colon cancer mortality in a large prospective study. Am J Epidemiol 2000;152:847–54.Google Scholar

  • 8.

    Wang Y, Jacobs EJ, Patel AV, Rodriguez C, McCullough ML, Thun MJ, Calle EE. A prospective study of waist circumference and body mass index in relation to colorectal cancer incidence. Cancer Causes Control 2008;19:783–92.CrossrefGoogle Scholar

  • 9.

    Petrelli JM, Calle EE, Rodriguez C, Thun MJ. Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women. Cancer Causes Control 2002;13:325–32.CrossrefGoogle Scholar

  • 10.

    McCullough ML, Patel AV, Patel R, Rodriguez C, Feigelson HS, Bandera EV, Gansler T, Thun MJ, Calle EE. Body mass and endometrial cancer risk by hormone replacement therapy and cancer subtype. Cancer Epidemiol Biomarkers Prev 2008;17:73–9.CrossrefGoogle Scholar

  • 11.

    Rodriguez C, Calle EE, Fakhrabadi-Shokoohi D, Jacobs EJ, Thun MJ. Body mass index, height, and the risk of ovarian cancer mortality in a prospective cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev 2002;11:822–8.Google Scholar

  • 12.

    Genkinger JM, Spiegelman D, Anderson KE, Bernstein L, van den Brandt PA, Calle EE, English DR, Folsom AR, Freudenheim JL, Fuchs CS, Giles GG, Giovannucci E, Horn-Ross PL, Larsson SC, Leitzmann M, Mannisto S, Marshall JR, Miller AB, Patel AV, Rohan TE, Stolzenberg-Solomon RZ, Verhage BA, Virtamo J, Willcox BJ, Wolk A, Ziegler RG, Smith-Warner SA. A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk. Int J Cancer 2011;129:1708–17.CrossrefGoogle Scholar

  • 13.

    Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer Epidemiol Biomarkers Prev 2005;14:459–66.CrossrefGoogle Scholar

  • 14.

    Adams TD, Stroup AM, Gress RE, Adams KF, Calle EE, Smith SC, Halverson RC, Simper SC, Hopkins PN, Hunt SC. Cancer incidence and mortality after gastric bypass surgery. Obesity (Silver Spring) 2009;17:796–802.CrossrefGoogle Scholar

  • 15.

    Friedman J. 20 Years of leptin: leptin at 20: an overview. J Endocrinol 2014;223:T1–8.Google Scholar

  • 16.

    Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 2002;26:1407–33.CrossrefGoogle Scholar

  • 17.

    Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011;301:E567–84.Google Scholar

  • 18.

    Harwood HJ Jr. The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology 2012;63:57–75.CrossrefGoogle Scholar

  • 19.

    Zhou Y, Rui L. Leptin signaling and leptin resistance. Front Med 2013;7:207–22.CrossrefGoogle Scholar

  • 20.

    Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest 1996;98:1277–82.CrossrefGoogle Scholar

  • 21.

    Jequier E. Leptin signaling, adiposity, and energy balance. Ann NY Acad Sci 2002;967:379–88.Google Scholar

  • 22.

    Yang R, Barouch LA. Leptin signaling and obesity: cardiovascular consequences. Circ Res 2007;101:545–59.CrossrefGoogle Scholar

  • 23.

    Tessitore L, Vizio B, Jenkins O, De Stefano I, Ritossa C, Argiles JM, Benedetto C, Mussa A. Leptin expression in colorectal and breast cancer patients. Int J Mol Med 2000;5:421–6.Google Scholar

  • 24.

    Stattin P, Lukanova A, Biessy C, Soderberg S, Palmqvist R, Kaaks R, Olsson T, Jellum E. Obesity and colon cancer: does leptin provide a link? Int J Cancer 2004;109:149–52.CrossrefGoogle Scholar

  • 25.

    Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol 2006;207:12–22.Google Scholar

  • 26.

    Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Ann Rev Med 2010;61:301–16.CrossrefGoogle Scholar

  • 27.

    Dauer DJ, Ferraro B, Song L, Yu B, Mora L, Buettner R, Enkemann S, Jove R, Haura EB. Stat3 regulates genes common to both wound healing and cancer. Oncogene 2005;24:3397–408.CrossrefGoogle Scholar

  • 28.

    Koda M, Sulkowska M, Kanczuga-Koda L, Jarzabek K, Sulkowski S. Expression of leptin and its receptor in female breast cancer in relation with selected apoptotic markers. Folia Histochem Cytobiol 2007;45:Suppl 1:S187–91.Google Scholar

  • 29.

    Garcia-Robles MJ, Segura-Ortega JE, Fafutis-Morris M. The biology of leptin and its implications in breast cancer: a general view. J Interferon Cytokine Res 2013;33:717–27.CrossrefGoogle Scholar

  • 30.

    Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci USA 2001;98:6390–5.CrossrefGoogle Scholar

  • 31.

    Frankenberry KA, Skinner H, Somasundar P, McFadden DW, Vona-Davis LC. Leptin receptor expression and cell signaling in breast cancer. Int J Oncol 2006;28:985–93.Google Scholar

  • 32.

    Wang Y, Prywes R. Activation of the c-fos enhancer by the erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites. Oncogene 2000;19:1379–85.CrossrefGoogle Scholar

  • 33.

    Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005;24:7455–64.CrossrefGoogle Scholar

  • 34.

    Vona-Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 2007;14:189–206.CrossrefGoogle Scholar

  • 35.

    Caldefie-Chezet F, Damez M, de Latour M, Konska G, Mishellani F, Fusillier C, Guerry M, Penault-Llorca F, Guillot J, Vasson MP. Leptin: a proliferative factor for breast cancer? Study on human ductal carcinoma. Biochem Biophys Res Commun 2005;334:737–41.Google Scholar

  • 36.

    Zheng Q, Dunlap SM, Zhu J, Downs-Kelly E, Rich J, Hursting SD, Berger NA, Reizes O. Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival. Endocr Relat Cancer 2011;18:491–503.Google Scholar

  • 37.

    Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, Ando S. Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 2003;278:28668–76.Google Scholar

  • 38.

    Bartella V, Cascio S, Fiorio E, Auriemma A, Russo A, Surmacz E. Insulin-dependent leptin expression in breast cancer cells. Cancer Res 2008;68:4919–27.CrossrefGoogle Scholar

  • 39.

    Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N. Leptin signaling in breast cancer: an overview. J Cell Biochem 2008;105:956–64.CrossrefGoogle Scholar

  • 40.

    Jarde T, Perrier S, Vasson MP, Caldefie-Chezet F. Molecular mechanisms of leptin and adiponectin in breast cancer. Eur J Cancer 2011;47:33–43.CrossrefGoogle Scholar

  • 41.

    Cleary MP, Phillips FC, Getzin SC, Jacobson TL, Jacobson MK, Christensen TA, Juneja SC, Grande JP, Maihle NJ. Genetically obese MMTV-TGF-alpha/Lep(ob)Lep(ob) female mice do not develop mammary tumors. Breast Cancer Res Treat 2003;77:205–15.CrossrefGoogle Scholar

  • 42.

    Cleary MP, Juneja SC, Phillips FC, Hu X, Grande JP, Maihle NJ. Leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors. Exp Biol Med (Maywood) 2004;229:182–93.Google Scholar

  • 43.

    Bain GH, Collie-Duguid E, Murray GI, Gilbert FJ, Denison A, McKiddie F, Ahearn T, Fleming I, Leeds J, Phull P, Park K, Nanthakumaran S, Grabsch HI, Tan P, Welch A, Schweiger L, Dahle-Smith A, Urquhart G, Finegan M, Petty RD. Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. Brit J Cancer 2014;110:1525–34.CrossrefGoogle Scholar

  • 44.

    Koda M, Sulkowska M, Kanczuga-Koda L, Surmacz E, Sulkowski S. Overexpression of the obesity hormone leptin in human colorectal cancer. J Clin Pathol 2007;60:902–6.Google Scholar

  • 45.

    Xiong Y, Zhang J, Liu M, An M, Lei L, Guo W. Human leptin protein activates the growth of HepG2 cells by inhibiting PERKmediated ER stress and apoptosis. Mol Med Rep 2014;10:1649–55.Google Scholar

  • 46.

    Ikeda A, Shimizu T, Matsumoto Y, Fujii Y, Eso Y, Inuzuka T, Mizuguchi A, Shimizu K, Hatano E, Uemoto S, Chiba T, Marusawa H. Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma. Gastroenterology 2014;146:222–32, e235.CrossrefGoogle Scholar

  • 47.

    Li Z, Yuan W, Ning S, Li J, Zhai W, Zhang S. Role of leptin receptor (LEPR) gene polymorphisms and haplotypes in susceptibility to hepatocellular carcinoma in subjects with chronic hepatitis B virus infection. Mol Diagn Ther 2012;16:383–8.CrossrefGoogle Scholar

  • 48.

    Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995;270:26746–9.Google Scholar

  • 49.

    Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 2001;50:1126–33.CrossrefGoogle Scholar

  • 50.

    Duncan BB, Schmidt MI, Pankow JS, Bang H, Couper D, Ballantyne CM, Hoogeveen RC, Heiss G. Adiponectin and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 2004;53:2473–8.CrossrefGoogle Scholar

  • 51.

    Fonseca-Alaniz MH, Takada J, Alonso-Vale MI, Lima FB. Adipose tissue as an endocrine organ: from theory to practice. J Pediatr 2007;83:S192–203.Google Scholar

  • 52.

    Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007;13:332–9.CrossrefGoogle Scholar

  • 53.

    Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T. Adiponectin receptors: a review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab 2014;28:15–23.CrossrefGoogle Scholar

  • 54.

    Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762–9.Google Scholar

  • 55.

    Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM, Wade MR, Tenorio VM, Kuo MS, Brozinick JT, Zhang BB, Birnbaum MJ, Summers SA, Scherer PE. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 2011;17:55–63.CrossrefGoogle Scholar

  • 56.

    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79–83.Google Scholar

  • 57.

    Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005;26:439–51.CrossrefGoogle Scholar

  • 58.

    Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003;148:293–300.CrossrefGoogle Scholar

  • 59.

    Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941–6.CrossrefGoogle Scholar

  • 60.

    Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev 2012;33:547–94.CrossrefGoogle Scholar

  • 61.

    Barb D, Williams CJ, Neuwirth AK, Mantzoros CS. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am J Clin Nutr 2007;86:s858–66.Google Scholar

  • 62.

    Surmacz E. Leptin and adiponectin: emerging therapeutic targets in breast cancer. J Mammary Gland Biol Neoplasia 2013;18:321–32.CrossrefGoogle Scholar

  • 63.

    Grossmann ME, Nkhata KJ, Mizuno NK, Ray A, Cleary MP. Effects of adiponectin on breast cancer cell growth and signaling. Brit J Cancer 2008;98:370–9.CrossrefGoogle Scholar

  • 64.

    Dieudonne MN, Bussiere M, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R. Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 2006;345:271–9.Google Scholar

  • 65.

    Nakayama S, Miyoshi Y, Ishihara H, Noguchi S. Growth-inhibitory effect of adiponectin via adiponectin receptor 1 on human breast cancer cells through inhibition of S-phase entry without inducing apoptosis. Breast cancer research and treatment 2008;112:405–10.Google Scholar

  • 66.

    Dos Santos E, Benaitreau D, Dieudonne MN, Leneveu MC, Serazin V, Giudicelli Y, Pecquery R. Adiponectin mediates an antiproliferative response in human MDA-MB 231 breast cancer cells. Oncology Rep 2008;20:971–7.Google Scholar

  • 67.

    Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ, Xu A. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 2006;66:11462–70.Google Scholar

  • 68.

    Wang Y, Lam KS, Xu JY, Lu G, Xu LY, Cooper GJ, Xu A. Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J Biol Chem 2005;280:18341–7.Google Scholar

  • 69.

    Yamauchi N, Takazawa Y, Maeda D, Hibiya T, Tanaka M, Iwabu M, Okada-Iwabu M, Yamauchi T, Kadowaki T, Fukayama M. Expression levels of adiponectin receptors are decreased in human endometrial adenocarcinoma tissues. Int J Gynecol Pathol 2012;31:352–7.CrossrefGoogle Scholar

  • 70.

    Moon HS, Chamberland JP, Aronis K, Tseleni-Balafouta S, Mantzoros CS. Direct role of adiponectin and adiponectin receptors in endometrial cancer: in vitro and ex vivo studies in humans. Mol Cancer Ther 2011;10:2234–43.CrossrefGoogle Scholar

  • 71.

    Erdogan S, Sezer S, Baser E, Gun-Eryilmaz O, Gungor T, Uysal S, Yilmaz FM. Evaluating vaspin and adiponectin in postmenopausal women with endometrial cancer. Endocr Relat Cancer 2013;20:669–75.CrossrefGoogle Scholar

  • 72.

    Komiya M, Fujii G, Takahashi M, Shimura M, Noma N, Shimizu S, Onuma W, Mutoh M. Bi-directional regulation between adiponectin and plasminogen activator-inhibitor-1 in 3T3-L1 cells. In Vivo 2014;28:13–9.Google Scholar

  • 73.

    Nakajima TE, Yamada Y, Hamano T, Furuta K, Matsuda T, Fujita S, Kato K, Hamaguchi T, Shimada Y. Adipocytokines as new promising markers of colorectal tumors: adiponectin for colorectal adenoma, and resistin and visfatin for colorectal cancer. Cancer Sci 2010;101:1286–91.CrossrefGoogle Scholar

  • 74.

    Gonullu G, Kahraman H, Bedir A, Bektas A, Yucel I. Association between adiponectin, resistin, insulin resistance, and colorectal tumors. Int J Colorectal Dis 2010;25:205–12.CrossrefGoogle Scholar

  • 75.

    Moon HS, Mantzoros CS. Adiponectin and metformin additively attenuate IL1beta-induced malignant potential of colon cancer. Endocr Relat Cancer 2013;20:849–59.Google Scholar

  • 76.

    Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998;251:471–6.Google Scholar

  • 77.

    Carpene C, Dray C, Attane C, Valet P, Portillo MP, Churruca I, Milagro FI, Castan-Laurell I. Expanding role for the apelin/APJ system in physiopathology. J Physiol Biochem 2007;63:359–73.Google Scholar

  • 78.

    Yue P, Jin H, Aillaud M, Deng AC, Azuma J, Asagami T, Kundu RK, Reaven GM, Quertermous T, Tsao PS. Apelin is necessary for the maintenance of insulin sensitivity. Am J Physiol Endocrinol Metab 2010;298:E59–67.Google Scholar

  • 79.

    Castan-Laurell I, Dray C, Attane C, Duparc T, Knauf C, Valet P. Apelin, diabetes, and obesity. Endocrine 2011;40:1–9.CrossrefGoogle Scholar

  • 80.

    Berta J, Hoda MA, Laszlo V, Rozsas A, Garay T, Torok S, Grusch M, Berger W, Paku S, Renyi-Vamos F, Masri B, Tovari J, Groger M, Klepetko W, Hegedus B, Dome B. Apelin promotes lymphangiogenesis and lymph node metastasis. Oncotarget 2014;5:4426–37.CrossrefGoogle Scholar

  • 81.

    Altinkaya SO, Nergiz S, Kucuk M, Yuksel H. Apelin levels are higher in obese patients with endometrial cancer. J Obstet Gynaecol Res 2015;41:294–300.CrossrefGoogle Scholar

  • 82.

    Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I. Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol 1994;14:1431–7.CrossrefGoogle Scholar

  • 83.

    Preiss J, Handler P. Enzymatic synthesis of nicotinamide mononucleotide. J Biol Chem 1957;225:759–70.Google Scholar

  • 84.

    Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F. Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur J Immunol 2002;32:3225–34.CrossrefGoogle Scholar

  • 85.

    Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 2004;279: 50754–63.CrossrefGoogle Scholar

  • 86.

    Luk T, Malam Z, Marshall JC. Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity. J Leukocyte Biol 2008;83:804–16.CrossrefGoogle Scholar

  • 87.

    Chen MP, Chung FM, Chang DM, Tsai JCR, Huang HF, Shin SJ, Lee YJ. Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus. J Clin Endocr Metab 2006;91:295–9.CrossrefGoogle Scholar

  • 88.

    Curat CA, Wegner V, Sengenes C, Miranville A, Tonus C, Busse R, Bouloumie A. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 2006;49:744–7.CrossrefGoogle Scholar

  • 89.

    Chang YH, Chang DM, Lin KC, Shin SJ, Lee YJ. Visfatin in overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases: a meta-analysis and systemic review. Diabetes Metab Res Rev 2011;27:515–27.CrossrefGoogle Scholar

  • 90.

    Jurdana M, Petelin A, Černelič Bizjak M, Bizjak M, Biolo G, Jenko-Pražnikar Z. Increased serum visfatin levels in obesity and its association with anthropometric/biochemical parameters, physical inactivity and nutrition. e-SPEN Journal 2013;8:e59–67.CrossrefGoogle Scholar

  • 91.

    Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569–78.Google Scholar

  • 92.

    Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. Brit Med J 2007;335:1134.Google Scholar

  • 93.

    Kitahara CM, Platz EA, Freeman LE, Hsing AW, Linet MS, Park Y, Schairer C, Schatzkin A, Shikany JM, Berrington de Gonzalez A. Obesity and thyroid cancer risk among U.S. men and women: a pooled analysis of five prospective studies. Cancer Epidemiol Biomarkers Prev 2011;20:464–72.CrossrefGoogle Scholar

  • 94.

    Fazeli MS, Dashti H, Akbarzadeh S, Assadi M, Aminian A, Keramati MR, Nabipour I. Circulating levels of novel adipocytokines in patients with colorectal cancer. Cytokine 2013; 62:81–5.CrossrefGoogle Scholar

  • 95.

    Ghaemmaghami S, Mohaddes SM, Hedayati M, Gorgian Mohammadi M, Dehbashi G. Resistin and Visfatin Expression in HCT-116 Colorectal Cancer Cell Line. Int J Mol Cell Med 2013;2:143–50.Google Scholar

  • 96.

    Huang WS, Chen CN, Sze CI, Teng CC. Visfatin induces stromal cell-derived factor-1 expression by beta1 integrin signaling in colorectal cancer cells. J Cell Physiol 2013;228:1017–24.Google Scholar

  • 97.

    Dalamaga M. Nicotinamide phosphoribosyl-transferase/visfatin: a missing link between overweight/obesity and postmenopausal breast cancer? Potential preventive and therapeutic perspectives and challenges. Med Hypoth 2012;79:617–21.CrossrefGoogle Scholar

  • 98.

    Shackelford RE, Bui MM, Coppola D, Hakam A. Over-expression of nicotinamide phosphoribosyltransferase in ovarian cancers. Int J Clin Exp Patho 2010;3:522–7.Google Scholar

  • 99.

    Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, Tilg H. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Imunol 2007;178:1748–58.Google Scholar

  • 100.

    Van Gool F, Galli M, Gueydan C, Kruys V, Prevot PP, Bedalov A, Mostoslavsky R, Alt FW, De Smedt T, Leo O. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 2009;15:206–10.CrossrefGoogle Scholar

  • 101.

    Kollmar O, Rupertus K, Scheuer C, Junker B, Tilton B, Schilling MK, Menger MD. stromal cell-derived factor-1 promotes cell migration, tumor growth of colorectal metastasis. Neoplasia 2007;9:862–70.Google Scholar

  • 102.

    Yoshitake N, Fukui H, Yamagishi H, Sekikawa A, Fujii S, Tomita S, Ichikawa K, Imura J, Hiraishi H, Fujimori T. Expression of SDF-1[alpha] and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Brit J Cancer 2008;98:1682–9.CrossrefGoogle Scholar

  • 103.

    Buldak RJ, Buldak L, Polaniak R, Kukla M, Birkner E, Kubina R, Kabala-Dzik A, Dulawa-Buldak A, Zwirska-Korczala K. Visfatin affects redox adaptative responses and proliferation in Me45 human malignant melanoma cells: an in vitro study. Oncol Rep 2013;29:771–8.Google Scholar

  • 104.

    Nowell MA, Richards PJ, Fielding CA, Ognjanovic S, Topley N, Williams AS, Bryant-Greenwood G, Jones SA. Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling – implications in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 2006;54:2084–95.CrossrefGoogle Scholar

  • 105.

    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001;409:307–12.Google Scholar

  • 106.

    Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator–activated receptor-γ action in humans. Diabetes 2001;50:2199–202.CrossrefGoogle Scholar

  • 107.

    Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA. An inflammatory cascade leading to hyperresistinemia in humans. PLos Med 2004;1:161–8.Google Scholar

  • 108.

    Danese E, Montagnana M, Minicozzi AM, Bonafini S, Ruzzenente O, Gelati M, De Manzoni G, Lippi G, Guidi GC. The role of resistin in colorectal cancer. Clinica Chimica Acta 2012;413:760–4.Google Scholar

  • 109.

    Sun CA, Wu MH, Chu CH, Chou YC, Hsu GC, Yang T, Chou WY, Yu CP, Yu JC. Adipocytokine resistin and breast cancer risk. Breast Cancer Res Treat 2010;123:869–76.CrossrefGoogle Scholar

  • 110.

    Kim HJ, Lee YS, Won EH, Chang IH, Kim TH, Park ES, Kim MK, Kim W, Myung SC. Expression of resistin in the prostate and its stimulatory effect on prostate cancer cell proliferation. BJU Int 2011;108:E77–83.CrossrefGoogle Scholar

  • 111.

    Yang CC, Chang SF, Chao JK, Lai YL, Chang WE, Hsu WH, Kuo WH. Activation of AMP-activated protein kinase attenuates hepatocellular carcinoma cell adhesion stimulated by adipokine resistin. BMC Cancer 2014;14:112.Google Scholar

  • 112.

    Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 2003;309:286–90.Google Scholar

  • 113.

    Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun 2005;334:1092–101.Google Scholar

  • 114.

    Yadav A, Kumar B, Datta J, Teknos TN, Kumar P. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 2011;9:1658–67.CrossrefGoogle Scholar

  • 115.

    Hsieh Y-Y, Shen C-H, Huang W-S, Chin C-C, Kuo Y-H, Hsieh M, Yu H-R, Chang T-S, Lin T-H, Chiu Y-W, Chen C-N, Kuo H-C, Tung S-Y. Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFkappaB signaling pathway in gastric cancer cells. J Biomed Sci 2014;21:59.Google Scholar

  • 116.

    Wai Wong C, Dye DE, Coombe DR. The role of immunoglobulin superfamily cell adhesion molecules in cancer metastasis. International journal of cell biology 2012;2012:340296.Google Scholar

  • 117.

    Johnson JP. Cell adhesion molecules in the development and progression of malignant melanoma. Cancer Metastasis Rev 1999;18:345–57.CrossrefGoogle Scholar

  • 118.

    Yoong KF, McNab G, Hubscher SG, Adams DH. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J Immunol 1998;160: 3978–88.Google Scholar

  • 119.

    Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brezillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 2003;198:977–85.CrossrefGoogle Scholar

  • 120.

    Zabel BA, Silverio AM, Butcher EC. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J Immunol 2005;174:244–51.Google Scholar

  • 121.

    Zabel BA, Allen SJ, Kulig P, Allen JA, Cichy J, Handel TM, Butcher EC. Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J Biol Chem 2005;280:34661–6.CrossrefGoogle Scholar

  • 122.

    Goralski KB, McCarthy TC, Hanniman EA, Zabel BA, Butcher EC, Parlee SD, Muruganandan S, Sinal CJ. Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem 2007;282:28175–88.Google Scholar

  • 123.

    Bluher M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Pract Res Clin Endocrinol Metab 2013;27:163–77.CrossrefGoogle Scholar

  • 124.

    Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, Walder K, Segal D. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 2007;148:4687–94.CrossrefGoogle Scholar

  • 125.

    Zabel BA, Ohyama T, Zuniga L, Kim JY, Johnston B, Allen SJ, Guido DG, Handel TM, Butcher EC. Chemokine-like receptor 1 expression by macrophages in vivo: regulation by TGF-beta and TLR ligands. Exp Hematol 2006;34:1106–14.Google Scholar

  • 126.

    Rama D, Esendagli G, Guc D. Expression of chemokine-like receptor 1 (CMKLR1) on J744A.1 macrophages co-cultured with fibroblast and/or tumor cells: modeling the influence of microenvironment. Cell Immunol 2011;271:134–40.Google Scholar

  • 127.

    Wang C, Wu WK, Liu X, To KF, Chen GG, Yu J, Ng EK. Increased serum chemerin level promotes cellular invasiveness in gastric cancer: a clinical and experimental study. Peptides 2014;51:131–8.CrossrefGoogle Scholar

  • 128.

    Zhang J, Jin HC, Zhu AK, Ying RC, Wei W, Zhang FJ. Prognostic significance of plasma chemerin levels in patients with gastric cancer. Peptides 2014;61C:7–11.CrossrefGoogle Scholar

  • 129.

    Komiya T, Tanigawa Y, Hirohashi S. Cloning of the novel gene intelectin, which is expressed in intestinal paneth cells in mice. Biochem Biophys Res Commun 1998;251:759–62.Google Scholar

  • 130.

    Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC, Shuldiner AR, Fried SK, McLenithan JC, Gong DW. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab 2006;290:E1253–61.Google Scholar

  • 131.

    Ohashi K, Shibata R, Murohara T, Ouchi N. Role of anti-inflammatory adipokines in obesity-related diseases. Trends Endocrinol Metab 2014;25:348–55.CrossrefGoogle Scholar

  • 132.

    de Souza Batista CM, Yang RZ, Lee MJ, Glynn NM, Yu DZ, Pray J, Ndubuizu K, Patil S, Schwartz A, Kligman M, Fried SK, Gong DW, Shuldiner AR, Pollin TI, McLenithan JC. Omentin plasma levels and gene expression are decreased in obesity. Diabetes 2007;56:1655–61.CrossrefGoogle Scholar

  • 133.

    Shibata R, Ouchi N, Takahashi R, Terakura Y, Ohashi K, Ikeda N, Higuchi A, Terasaki H, Kihara S, Murohara T. Omentin as a novel biomarker of metabolic risk factors. Diabet Metab Synd 2012;4:37.Google Scholar

  • 134.

    Wada J. Vaspin: a novel serpin with insulin-sensitizing effects. Expert Opin Investig Drugs 2008;17:327–33.CrossrefGoogle Scholar

  • 135.

    Uyeturk U, Sarici H, Kin Tekce B, Eroglu M, Kemahli E, Uyeturk U, Gucuk A. Serum omentin level in patients with prostate cancer. Med Oncol 2014;31:923.CrossrefGoogle Scholar

  • 136.

    Uyeturk U, Alcelik A, Aktas G, Tekce BK. Post-treatment plasma omentin levels in patients with stage III colon carcinoma. J BUON 2014;19:681–5.Google Scholar

  • 137.

    Zhang YY, Zhou LM. Omentin-1, a new adipokine, promotes apoptosis through regulating Sirt1-dependent p53 deacetylation in hepatocellular carcinoma cells. Eur J Pharmacol 2013;698:137–44.Google Scholar

  • 138.

    Ramanjaneya M, Chen J, Brown JE, Tripathi G, Hallschmid M, Patel S, Kern W, Hillhouse EW, Lehnert H, Tan BK, Randeva HS. Identification of nesfatin-1 in human and murine adipose tissue: a novel depot-specific adipokine with increased levels in obesity. Endocrinology 2010;151:3169–80.Google Scholar

  • 139.

    Cetinkaya H, Karagoz B, Bilgi O, Ozgun A, Tuncel T, Emirzeoglu L, Top C, Kandemir EG. Nesfatin-1 in advanced lung cancer patients with weight loss. Regul Pept 2013;181:1–3.CrossrefGoogle Scholar

  • 140.

    Xu Y, Pang X, Dong M, Wen F, Zhang Y. Nesfatin-1 inhibits ovarian epithelial carcinoma cell proliferation in vitro. Biochem Biophys Res Commun 2013;440:467–72.Google Scholar

  • 141.

    Wang L, Ellis MJ, Gomez JA, Eisner W, Fennell W, Howell DN, Ruiz P, Fields TA, Spurney RF. Mechanisms of the proteinuria induced by Rho GTPases. Kidney Int 2012;81:1075–85.CrossrefGoogle Scholar

  • 142.

    Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS. Visceral adipose tissue- derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci USA 2005;102:10610–5.CrossrefGoogle Scholar

  • 143.

    Nakatsuka A, Wada J, Iseda I, Teshigawara S, Higashio K, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Hida K, Eguchi J, Horiguchi CS, Ogawa D, Matsuki Y, Hiramatsu R, Yagita H, Kakuta S, Iwakura Y, Makino H. Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex. Diabetes 2012;61:2823–32.Google Scholar

  • 144.

    Ye R, Jung DY, Jun JY, Li J, Luo S, Ko HJ, Kim JK, Lee AS. Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance. Diabetes 2010;59:6–16.CrossrefGoogle Scholar

  • 145.

    Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 2014;26:54–74.Google Scholar

  • 146.

    Harvey AE, Lashinger LM, Hursting SD. The growing challenge of obesity and cancer: an inflammatory issue. Ann NY Acad Sci 2011;1229:45–52.Google Scholar

  • 147.

    Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118:285–96.CrossrefGoogle Scholar

  • 148.

    Chung TDK, Yu JQJ, Spiotto MT, Bartkowski M, Simons JW. Characterization of the role of IL-6 in the progression of prostate cancer. Prostate 1999;38:199–207.Google Scholar

  • 149.

    Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L, Karin M. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009;15:103–13.Google Scholar

  • 150.

    Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006;441:431–6.CrossrefGoogle Scholar

  • 151.

    Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996;274:782–4.Google Scholar

About the article

Corresponding author: Michelle Foster, Department of Food Science and Human Nutrition, Colorado State University, Gifford 207, Fort Collins, CO 80523–1571, USA, E-mail:


Received: 2014-11-05

Accepted: 2015-01-07

Published Online: 2015-03-06

Published in Print: 2015-01-01


Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 21, Issue 1, Pages 57–74, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2014-0037.

Export Citation

©2015 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Gisela Helfer and Qing-Feng Wu
Journal of Endocrinology, 2018, Volume 238, Number 2, Page R79
[2]
Miriam Nuncia-Cantarero, Sandra Martinez-Canales, Fernando Andrés-Pretel, Gabriel Santpere, Alberto Ocaña, and Eva Maria Galan-Moya
Breast Cancer Research and Treatment, 2018
[3]
Aneta Cymbaluk-Płoska, Anita Chudecka-Głaz, Ewa Pius-Sadowska, Agnieszka Sompolska-Rzechuła, Bogusław Machaliński, and Janusz Menkiszak
BioMed Research International, 2018, Volume 2018, Page 1
[4]
Peter E. Feist, Elizabeth A. Loughran, M. Sharon Stack, and Amanda B. Hummon
Analytical and Bioanalytical Chemistry, 2017
[5]
Benedicte F. Jordan, Florian Gourgue, and Patrice D. Cani
Current Pathobiology Reports, 2017
[6]
Sharon M. Fruh
Journal of the American Association of Nurse Practitioners, 2017, Volume 29, Number S1, Page S3
[7]
Daniel Azamar-Llamas, Gabriela Hernández-Molina, Bárbara Ramos-Ávalos, and Janette Furuzawa-Carballeda
Mediators of Inflammation, 2017, Volume 2017, Page 1
[9]
Rodolfo Camargo, Daniela Riccardi, Henrique Ribeiro, Luiz Carnevali, Emidio de Matos-Neto, Lucas Enjiu, Rodrigo Neves, Joanna Lima, Raquel Figuerêdo, Paulo de Alcântara, Linda Maximiano, José Otoch, Miguel Batista, Gerhard Püschel, and Marilia Seelaender
Nutrients, 2015, Volume 7, Number 6, Page 4465

Comments (0)

Please log in or register to comment.
Log in