Friend or foe: Multiple roles of adipose tissue in cancer formation and progression

Obesity is well-known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity-related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity-related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy.     

Stromal Cells Derived from Visceral and Obese Adipose Tissue Promote Growth of Ovarian Cancers

Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.     

Adipokines and the cardiovascular system: mechanisms mediating health and disease

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.     

Human adipose tissue macrophages display activation of cancer-related pathways

Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.     

Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth

Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.     

Adipose tissue. Pathophysiology, distribution, sex differences and the role in inflammation and cancerogenesis

The role of adipose tissue is energy storage, but there is increasing evidence that adipocytes and adipokines are involved in metabolic and inflammatory processes. This paper reviews the pathophysiology of different adipose tissue depots. Interrelationships between sex hormones, adipose tissue and risk factors are also discussed. Present study focuses on the effects of adipokines on immune system and on the mechanisms relating adiposity to cancer risk.     

Identification and validation of novel adipokines released from primary human adipocytes

Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, termed adipokines, via which adipose tissue communicates with other organs. Expansion of adipose tissue in obesity alters adipokine secretion, which may contribute to the development of metabolic diseases. Although recent profiling studies have identified numerous adipokines, the amount of overlap from these studies indicates that the adipokinome is still incompletely characterized. Therefore, we conducted a complementary protein profiling on concentrated conditioned medium derived from primary human adipocytes. SDS-PAGE/liquid chromatography-electrospray ionization tandem MS and two-dimensional SDS-PAGE/matrix-assisted laser desorption ionization/time of flight MS identified 347 proteins, 263 of which were predicted to be secreted. Fourty-four proteins were identified as novel adipokines. Furthermore, we validated the regulation and release of selected adipokines in primary human adipocytes and in serum and adipose tissue biopsies from morbidly obese patients and normal-weight controls. Validation experiments conducted for complement factor H, αB-crystallin, cartilage intermediate-layer protein, and heme oxygenase-1 show that the release and expression of these factors in adipocytes is regulated by differentiation and stimuli, which affect insulin sensitivity, as well as by obesity. Heme oxygenase-1 especially reveals to be a novel adipokine of interest. In vivo, circulating levels and adipose tissue expression of heme oxygenase-1 are significantly increased in obese subjects compared with lean controls. Collectively, our profiling study of the human adipokinome expands the list of adipokines and further highlights the pivotal role of adipokines in the regulation of multiple biological processes within adipose tissue and their potential dysregulation in obesity.     

Relationship between obesity, inflammation and insulin resistance: new concepts

White adipose tissue is the main site of energy storage, but it is now recognized as an active participant in regulating physiologic and pathologic processes including immunity and inflammation. It has an endocrine function by secreting at least two main hormones, leptin and adiponectin. It can secrete other products, named adipokines, including cytokines and chemokines, involved in inflammation process. The release of adipokines by either adipocytes or adipose tissue infiltrated macrophages lead to a chronic sub-inflammatory state that could play a central role in cardiovascular complications linked to obesity and insulin resistance, a risk factor to develop type-2 diabetes.     

肿瘤微环境中脂肪细胞分泌因子对肿瘤细胞的作用

肿瘤微环境是由肿瘤局部浸润的巨噬细胞、成纤维细胞、脂肪细胞以及其所分泌的活性因子等与肿瘤细胞共同构成的局部内环境。肿瘤的发生和转移与肿瘤细胞所处的微环境密切相关。近年研究发现,脂肪组织是一个代谢活跃的分泌器官,可分泌多种与肿瘤相关脂肪因子。在多种类型肿瘤的恶化过程中,肿瘤微环境中的脂肪细胞代谢和分泌作用受到广泛的重视。随着对脂肪细胞病理学研究的深入,肿瘤微环境中的脂肪细胞对肿瘤恶化所起的重要作用已逐渐凸现出来,本文着重阐述了脂肪组织病理学变化所引发的体内相关代谢紊乱,以及其所导致的脂肪细胞分泌因子的变化对肥胖相关癌症发生发展的影响,深入探讨了脂肪细胞功能障碍所诱发的代谢紊乱对肿瘤生物学的影响。     

Secreted proteins from adipose tissue and skeletal muscle - adipokines, myokines and adipose/muscle cross-talk

White adipose tissue and skeletal muscle are the largest organs in the body and both are composed of distinct cell types. The signature cell of adipose tissue is the adipocyte while myocytes are the defining cell of skeletal muscle. White adipocytes are major secretory cells and this is increasingly apparent also for myocytes. Both cells secrete a range of bioactive proteins, generally termed adipokines in the case of adipocytes and myokines for muscle cells. There has, however, been some confusion over nomenclature and we suggest that the name myokine is restricted to a protein that is secreted from myocytes, while the term adipokine should be used to describe all proteins secreted from any type of adipocyte (white, brown or brite). These definitions specifically exclude proteins secreted from other cells within adipose tissue and muscle, including macrophages. There is some commonality between the myokines and adipokines in that both groups include inflammation-related proteins - for example, IL-6, Il-8 and MCP-1. Adipokines and myokines appear to be involved in local autocrine/paracrine interactions within adipose tissue and muscle, respectively. They are also involved in an endocrine cross-talk with other tissues, including between adipose tissue and skeletal muscle, and this may be bi-directional. For example, IL-6, secreted from myocytes may stimulate lipolysis in adipose tissue, while adipocyte-derived IL-6 may induce insulin resistance in muscle.     

Adipokines in inflammation and metabolic disease

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.     

Adipose tissue-derived progenitor cells and cancer

Recruitment of stem cells and partially differentiated progenitor cells is a process which accompanies and facilitates the progression of cancer. One of the factors complicating the clinical course of cancer is obesity, a progressively widespread medical condition resulting from overgrowth of white adipose tissue (WAT), commonly known as white fat. The mechanisms by which obesity influences cancer risk and progression are not completely understood. Cells of WAT secret soluble molecules (adipokines) that could stimulate tumor growth, although there is no consensus on which cell populations and which adipokines are important. Recent reports suggest that WAT-derived mesenchymal stem (stromal) cells, termed adipose stem cells (ASC), may represent a cell population linking obesity and cancer. Studies in animal models demonstrate that adipokines secreted by ASC can promote tumor growth by assisting in formation of new blood vessels, a process necessary for expansion of tumor mass. Importantly, migration of ASC from WAT to tumors has been demonstrated, indicating that the tumor microenvironment in cancer may be modulated by ASC-derived trophic factors in a paracrine rather than in an endocrine manner. Here, we review possible positive and adverse implications of progenitor cell recruitment into the diseased sites with a particular emphasis on the role in cancer progression of progenitors that are expanded in obesity.     

Uric Acid Secretion from Adipose Tissue and Its Increase in Obesity

Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity.     

Adipokines oversecreted by omental adipose tissue in human obesity

Central-omental obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines are involved in the pathogenesis of this syndrome. However, adipokines secreted by omental adipose tissue (OAT) are still poorly characterized in human obesity. Therefore, we searched for novel adipokines abnormally secreted by OAT in obesity and examined their relationships with some features of metabolic syndrome and the respective contribution of adipocytes vs. stromal-vascular cells. OAT from obese and nonobese men was fractionated into adipocytes and SV cells, which were then cultured. Medium was screened by medium-scale protein arrays and ELISAs. Adipokine mRNA levels were measured by real-time RT-qPCR. We detected 16 cytokines secreted by each cellular fraction of lean and obese subjects. Of the 16 cytokines, six adipokines were newly identified as secretory products of OAT, which were dysregulated in obesity: three chemokines (growth-related oncogen factor, RANTES, macrophage inflammatory protein-1beta), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1), and one growth factor (thrombopoietin). Their secretion and expression were enhanced in obesity, with a relatively similar contribution of the two fractions. The higher proportion of macrophages and endothelial cells in obesity may contribute to this enhanced production as well as changes in intrinsic properties of hypertrophied adipocytes. Accordingly, mRNA concentrations of most of these adipokines increased during adipocyte differentiation. Eventually, expression of the investigated adipokines did correlate with several features of the metabolic syndrome. In conclusion, six adipokines were newly identified as oversecreted by OAT in obesity. These adipokines may link obesity to its cardiovascular or metabolic comorbidities.     

Adipose tissue secretory function: implication in metabolic and cardiovascular complications of obesity

The adipose tissue exerts a double function that is crucial for energy homeostasis. On the one hand, it is the only organ suited to stock triglycerides in highly specialized cells, the adipocytes. On the other hand, the adipose tissue produces biologically active molecules, collectively named "adipokines", which have been implicated in energy balance and glucose and lipid metabolism. Both adipocytes and cells of the stromal fraction participate in this function of secretion. The adipokines acts locally, in an autocrine or paracrine manner, and distantly (endocrine), on various targets, including muscles, the liver and the hypothalamus. Some adipokines, as TNFalpha and IL6, promote insulin resistance and inflammation, whereas others, as leptin and adiponectin, are required for energy and glucose homeostasis. In obesity, adipose cell hypertrophy and the recruitment of macrophages alter the secretory function and induce an inflammatory profile in the adipose tissue. Analyses of gene expression suggest that hypoxia is one of the factors favoring the attraction of the macrophages. The local and systemic consequences of interactions between macrophages and adipocytes are currently actively studied, to understand their potential implication in the metabolic and cardiovascular complications associated with obesity.     

Do novel adipokines play a causative or only modulating role in the pathogenesis of obesity and metabolic disorders?

Adipose tissue is an endocrine and paracrine organ that releases a large number of bioactive mediators. Approximately 100 adipokines have been identified including cytokines, chemokines, growth factors and enzymes. The use of adipoproteomic analyses resulted in new findings and, in consequence, the number of new adipokines is rising rapidly. Novel adipokines such as visfatin, vaspin and omentin were discovered about five years ago. Visfatin and vaspin production and secretion take place in adipocytes, but omentin comes from the stromal cells of adipose tissue. Several differences are noticeable between these adipokines especially in correlation with obesity as visfatin and vaspin serum levels increase in obese subjects while omentin serum levels decrease. It has been suggested that these adipokines act as insulin-sensitizers/insulin-mimetics. Increasing number of publications reporting the role of new adipokines does not allow to assess clearly the influence of those adipokines on the pathogenesis of obesity.     

Adipocytokine Orosomucoid Integrates Inflammatory and Metabolic Signals to Preserve Energy Homeostasis by Resolving Immoderate Inflammation

Orosomucoid (ORM), also called α-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections. In this study, we reveal that Orm is induced selectively in the adipose tissue of obese mice to suppress excess inflammation that otherwise disturbs energy homeostasis. Adipose Orm levels were elevated by metabolic signals, including insulin, high glucose, and free fatty acid, as well as by the proinflammatory cytokine tumor necrosis factor-α, which is found in increased levels in the adipose tissue of morbid obese subjects. In both adipocytes and macrophages, ORM suppressed proinflammatory gene expression and pathways such as NF-κB and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-α-mediated lipolysis in adipocytes. Accordingly, ORM improved glucose and insulin tolerance in obese and diabetic db/db mice. Taken together, our results suggest that ORM integrates inflammatory and metabolic signals to modulate immune responses to protect adipose tissue from excessive inflammation and thereby from metabolic dysfunction.     

URB is abundantly expressed in adipose tissue and dysregulated in obesity

Dysregulated production of adipocytokines in obesity is involved in the development of metabolic syndrome. URB/DRO1 contains N-terminal signal sequence and is thought to play a role in apoptosis of tumor cells. In the present study, we investigated the expression pattern of URB mRNA in adipose tissue and secretion from cultured adipocytes. In human and mouse, URB mRNA was predominantly expressed in adipose tissue and was downregulated in obese mouse models, such as ob/ob, KKAy, and diet-induced obese mice. In 3T3L1 adipocytes, insulin, TNF-α, H₂O₂ and hypoxia decreased URB mRNA level. This regulation was similar to that for adiponectin and opposite to MCP-1. URB protein was secreted in media of URB cDNA-stably transfected cells and endogenous URB was detected in media of cultured human adipocytes. In conclusion, the expression pattern of URB suggests its role in obesity and the results suggest that URB is secreted, at least in part, from adipocytes.