Glioma progression in diabesity

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam

Glioma progression in diabesity Sebastián Alarcóna,1, Ignacio Niechia,1, Fernando Toledob,c, Luis Sobreviab,d,e,∗∗, Claudia Quezadaa,∗ a

Molecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia, 5090000, Chile Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, 8330024, Chile c Department of Basic Sciences, Faculty of Sciences, Universidad del Bío-Bío, Chillán, 3780000, Chile d Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville, E-41012, Spain e University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD, 4029, Queensland, Australia b

A R T I C LE I N FO

A B S T R A C T

Keywords: Diabesity Diabetes Obesity Glioma Glioblastoma

Diabetes mellitus, obesity, and cancer are diseases that in recent years have caused a large number of deaths worldwide, so have been in the front line of biomedical research. On the other hand, obesity is a risk factor for several types of cancer and type 2 diabetes mellitus. The metabolic disorder and global inflammatory environment seen in obese patients is also critical for the treatment of both diabetes mellitus and gliomas. Several molecules are increased in patients with obesity and are considered risk factors in the failure of multimodal therapies for diabetes mellitus and gliomas. These molecules include adenosine, insulin, adenosine deaminases, adenosine kinase, lipids, as well as adenosine receptors, adenosine membrane transporters, and the immune response. The role of adenosine will be explained in depth since it is a nucleoside aberrantly increased in patients with these diseases, is one of the main causes of diabetes mellitus progression and the failure of glioma therapies. In addition, the role of type 2 diabetes mellitus/obesity, i.e., diabesity, and its implication in glioma treatment is discussed.

1. Introduction The twin epidemic of obesity and diabetes mellitus is a major crisis globally. Several epidemiologic studies reveal the parallel escalation of these diseases. The term ‘diabesity’ expresses their close relationship to each other, as both these metabolic disorders are characterized by defects of insulin action (Cho et al., 2018). Type 2 diabetes mellitus (T2DM) represents ∼90% of all cases of diabetes, and its frequency is similar to that of obesity (Pereira and Alvarez-Leite, 2014). The increase in the prevalence of T2DM is closely linked to the upsurge in obesity. It is estimated that ∼90% of the diagnose of T2DM is attributable to an excess weight of patients (Verma and Hussain, 2017). Diabetes mellitus is a metabolic disease that seems to increase the risk of most malignant tumours (Giovannucci et al., 2010). It is known that overweight and obesity are increasing worldwide health problems in

terms of prevalence and risk factor for a variety of chronic conditions including diabetes mellitus, cardiovascular disease, arthritis, and certain cancers (Trestini et al., 2018). The progression from obesity to a patient with obesity developing into T2DM (diabesity) is significantly associated with higher risk of major human cancers (Tsilidis et al., 2015; Westley and May 2013). It was recently shown that obesity associated with alterations in the fatty acid metabolism and DNA methylation in the colonic epithelium, preceded a tumour-prone gene-expression profile (Li et al., 2018). Several international organizations recognize obesity as a serious public health problem worldwide (Colditz and Peterson, 2017). Obesity and cancer are two major epidemics of this century (Kaidar-Person et al., 2011). The incidence of cancer is expected to continue increasing, partly due to changes in the prevalence of risk factors such as obesity, diabetes mellitus, and lifestyle factors (Park and Colditz, 2017). Glioma is the

∗ Corresponding author. Molecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Campus Isla Teja, P.O. Box 567, Valdivia, 5090000, Chile. ∗∗ Corresponding author. Cellular & Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, 8330024, Chile. E-mail addresses: [email protected] (L. Sobrevia), [email protected] (C. Quezada). 1 These authors contributed equally to this article.

https://doi.org/10.1016/j.mam.2019.02.002 Received 7 August 2018; Received in revised form 12 February 2019; Accepted 19 February 2019 0098-2997/ © 2019 Published by Elsevier Ltd.

Please cite this article as: Sebastián Alarcón, et al., Molecular Aspects of Medicine, https://doi.org/10.1016/j.mam.2019.02.002

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

most common primary intracranial tumour, accounting for ∼80% of all malignant brain tumours of which glioblastoma. (GBM) is one of the most aggressive cancer types, accounting for more than 60% of malignant brain tumours in adults (Kawamura et al., 2018). GBM is the most common type of glioma and is a highly aggressive brain tumour with a poor outcome in both children and adults (Davis et al., 2016). GBM may manifest at any age, its frequency increases with age with most of the cases detected in between the 6th and 8th decade of life (Disney-Hogg et al., 2018). Few established risk factors for the development of glioma have been robustly identified. There are many studies implicating obesity and diabetes mellitus as risk factors for all of the major common cancers, including breast, colorectal, esophageal, pancreatic, ovarian, and renal cancer (Fukumura et al., 2016; Edlinger et al., 2012; Giovannucci et al., 2010; Kyrgiou et al., 2017; Niedermaier et al., 2015; Sergentanis et al., 2015; Wiedmann et al., 2013). However, paradoxically elevated levels of serum glucose are associated with reduced risk of both prostate cancer and glioma (Schwartzbaum et al., 2017; Van Hemelrijck et al., 2011). Some studies have reported diabetes to be protective against glioma or all types of brain tumours (Dankner et al., 2016; Kitahara et al., 2014; Schwartzbaum et al., 2017; Zhao et al., 2016). People with diabetes may be diagnosed at different times during the course of the disease and this diagnosis is usually followed by treatments that may affect associations with subsequent glioma risk (Schwartzbaum et al., 2017). There are several potential mechanisms accounting for the inverse association between hyperglycaemia and glioma. The commonly prescribed anti-diabetic medication, metformin, inhibits proliferation, migration, invasion and induced apoptosis, autophagy and differentiation in glioma cells (Gritti et al., 2014; Sato et al., 2012; Seliger et al., 2016; Würth et al., 2013; Yu et al., 2015). The survival of patients with GBM that were treated with metformin has been investigated. A survival benefit was seen in diabetic patients with metformin (Adeberg et al., 2015; Seliger et al., 2019; Welch and Grommes, 2013). However, there is a number of statistical, biological, and clinical considerations that may have biased the results in these publications. Therefore, this results regarding metformin and GBM should be considered with extreme caution (Lu, 2019). Nonetheless, recent studies suggest that patients with GBM affected with obesity have a worse prognosis than do patients with normal metabolism (Gong et al., 2016). The long-term metabolic consequences of obesity and its treatments are complex, and several mechanisms have been suggested including increased insulin and insulin-like growth factor signalling, chronic inflammation, and signalling via adipokines (Font-Burgada et al., 2016). In this review, we present updated evidence that links obesity, diabetes mellitus, and GBM in treated patients.

contributing factors such as excessive calories intake, sedentary lifestyle, and a diet high in saturated fat. Diabesity involves two principal components, i.e., a genetic component and an environmental component that includes factors such as diet, sedentary lifestyle, socioeconomic and cultural conditions, and tobacco and alcohol consumption (Jones, 2015). The etiology of diabesity is multifactorial and some authors associated this condition with an imbalance between the oxidative systems and the antioxidant mechanisms of the body, in favour of the oxidative systems, leading to the generation of large amounts of free radicals and compromises the rate of their neutralization (Martínez Leo et al., 2016). On the other hand, there are studies that show a significant contribution of chronic stress to the development of diabesity through the activation of the autonomic, neuroendocrine, inflammatory and immunological systems (Gastaldi and Ruiz, 2009). Three main hypotheses have been proposed to explain the interplay between obesity and pathophysiological mechanisms resulting in diabesity. The first one is an “inflammation hypothesis” proposing causal links between pro-inflammatory cytokines such as interleukins, tumour necrosis factor-α, and monocyte chemotactic protein-1 produced by excess adipose tissues, and increased insulin resistance leading to T2DM. The second hypothesis regards with the “lipid overflow hypothesis” staying that lipid metabolites released from the fatty tissue inhibit insulin signal transduction and induce insulin resistance. The third one, known as the “adipokine hypothesis” implicates different hormonal and chemical substances secreted from the adipose tissue, collectively termed adipokines, that induce inflammatory and metabolic cascades resulting in insulin resistance and T2DM (Chadt et al., 2014: Pappachan and Viswanath, 2017). Epidemiological data attribute a pernicious effect of metabolic disorders, notably obesity and diabetes mellitus, on cancer progression (Dali-Youcef et al., 2016). Recent studies suggest that patients with GBM affected by these metabolic failures have worse prognoses than those with normal metabolism (Gong et al., 2016). 3. Diabesity and glioma The gold standard drug for GBM treatment is temozolomide and, as in the other cancer types, the patient is treated in the same way whether or not they have obesity (Kolb et al., 2016). However, the inflammatory environment found in obese patients affects their response to therapy. The latter is documented in patients with breast, kidney, prostate, and colon cancer (Allott and Hursting, 2015; Kolb et al., 2016), and it is possible that the increase of pro-inflammatory factors such as interleukins will change the therapeutic approach (Yeung et al., 2013). Nonetheless Barami et al. found no evidence of a link between diabetes and glioma survival (Barami et al., 2017). Paradoxically, long-term diabetes mellitus as assessed by elevated glycated haemoglobin A1c (HbA1c) level, is associated with decreased glioma risk (Schwartzbaum et al. 2005, 2017). Diabesity includes an obesity-associated inflammatory environment promoting the expression of interleukins and increasing the frequency of a poor outcome whether the patient already suffers from this type of cancer. Although there is no conclusive evidence linking diabetes mellitus or obesity with the appearance of gliomas, obesity may be associated with a poor prognosis of patients who already have some type of glioma. For example, an obesity-associated inflammatory environment commanded the production and release of interleukins, including interleukin 6 (IL-6) (Mauer et al., 2014). The plasma level of IL-6 increases with the degree of obesity and is also related to insulin resistance (Weiss et al., 2004). In this context, diabesity could have a direct role in the malignancy and development of gliomas (Chen et al., 2016; Li et al., 2010; Liu et al., 2010) since IL-6 level is higher in GBM promoting angiogenesis and cellular invasion. Furthermore, patients with a high IL-6 plasma level show reduced survival (Fig. 1) (Tchirkov et al., 2007). The inflammatory context generated by the increase of interleukins level potentiates the activation of signalling pathways such as c-Jun N-terminal kinases (JNKs),

2. Diabesity Diabesity refers to patients developing T2DM in the context of obesity (Farag and Gaballa, 2011; Iyengar et al., 2016; Kalra, 2013; Ziv and Shafir, 1995). It is a term first coined by Sims and colleagues in 1970's, is used to describe the patho-physiological interlink between T2DM and obesity (Deol et al., 2017: Sims et al., 1973). Of concern is the fact that the worldwide prevalence of obesity nearly tripled between 1975 and 2016 (Friedrich, 2017). Along with this fact, the number of health problems that affect obese people has also increased (Friedrich, 2017; Colditz and Peterson, 2017). In 2016, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 650 million were obese. Most of the world population live in countries where being overweight and obese is associated with higher mortality rates than being underweight (WHO, 2018). Several studies indicate that obesity represents a risk factor for the development of T2DM. The possibility of developing diabetes mellitus is ∼80 times higher in obese than in non-obese patients (Agha and Agha, 2017). Recent advances in the understanding of obesity have identified a genetic component of obesity, along with other 2

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

Fig. 1. Adenosine signalling in glioma poor outcome and diabesity. Schematic representation showing that the inflammatory condition and the high extracellular level of adenosine seen in diabesity triggers A1 (A1AR), A2A (A2AAR), A2B (A2BAR), and A3 (A3AR) adenosine receptors-associated signalling promoting poor prognosis and failure in the treatment of glioma. Adenosine signalling through its receptors promote several signalling pathways but diabesity and glioma mainly share c-Jun N-terminal kinase (JNK) pathway, activating c-jun transcription factor (c-jun) thereby enhancing interleukin 1β (IL1β) and 6 (IL-6) expression. These interleukins activate their corresponding signalling pathways in other cells promoting the inflammatory response, cell viability, chemoresistance, and treatment failure in diabesity and glioma.

diabetic patients could allow or favour proliferation of Mes GSCs, however, there are no studies that evaluate this condition in GSCs. Mes GSCs showed more aggressive phenotypes in vitro and as intracranial xenografts in mice compared with PN GSCs (Mao et al., 2013). Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM) (Davidson and Sloan, 2017). Interestingly, metformin inhibits GSCs viability, with significantly higher efficiency than in differentiated GBM cells or normal stem cells (umbilical cord mesenchymal stem cells, MSCs). Moreover, metformin impairs in vitro GBM GSCs self-renewal as measured by spherogenic activity (Sato et al., 2012; Würth et al., 2013). A therapeutic target for diabetes mellitus, obesity, and GBM is not yet reported. However, increased extracellular blood D-glucose level associates with an increase in plasma adenosine level which enhances the activation of the adenosine receptors (Torres et al., 2016). Adenosine signalling is increased in patients with diabetes mellitus and in obese patients, a phenomenon related to metabolic alterations leading to chronic renal failure (Oyarzún et al., 2017). Likewise, GBM tumours show high level of extracellular adenosine, especially in the hypoxic niches characteristic of this neoplasia (Yang et al., 2012). The increased extracellular concentration of adenosine and adenosine receptor's triggered signalling are not only related to chemotherapy resistance, proliferation, and cellular invasion, but also to the maintenance of the stem and GBM stem-like cell phenotype (Uribe et al., 2017). In this context, adenosine and its associated signalling mechanisms may be a therapeutic target for the treatment of diabesity and GBM. The main molecules involved in diabetes, obesity, and glioma are summarized on Table 1.

specifically JNK1 in diabetes mellitus and JKN3 in GBM (Fig. 1) (Solinas and Becattini, 2017; Yeung et al., 2013). Thus, the use of inhibitors for all isoforms of JNKs in diabesity may reduce inflammation and will likely counteract its pathological effect in GBM (Solinas and Becattini, 2017; Yeung et al., 2013; Zeke et al., 2016). An elevated plasma D-glucose concentration is a common finding in glioma, diabetes mellitus, and obesity (Giovannucci et al., 2010). DGlucose homeostasis is dysregulated in these pathologies and glioma cells are avid of D-glucose leading to higher proliferation and tumorigenesis (Ding et al., 2018; Klil-Drori et al., 2017; Strickland and Stoll, 2017). Tumour cells are highly dependent on glucose even in the presence of oxygen, this concept is called the Warburg effect is a hallmark of cancer (Oppermann et al., 2016). The Warburg effect refers to the incomplete, non-oxidative metabolism of glucose even in the presence of oxygen thought to be characteristic of cancer cells, in comparison to normal cells which readily undergo oxidative phosphorylation (Warburg, 1956). Until now, there is no innovative therapeutic strategy that exploits this potential achilles heel of cancer (Xing et al., 2017). Studies indicate that glioblastoma is composed of populations of heterogeneous tumour cells that include tumour cells with stem cell properties called glioma initiator/propagating cells or glioblastoma stem like cells (GSC) (Singh et al., 2004; Uribe et al., 2017). Diverse groups worldwide have revealed by transcriptome analysis, the presence of two subtypes of high grade GBM: pro-neural (PN) and mesenchymal (Mes), which also have their own clinical profile (Mao et al., 2013; Phillips et al., 2006; Verhaak et al., 2010). It has been described that glycolytic activity is higher in Mes GSCs with respect to PN GSCs (Mao et al., 2013), this suggests that the hyperglycemia present in Table 1 Main molecules and signalling pathways involved in diabesity and glioma. Molecule/pathway

Process

Reference

IL-1β IL-6 IL-8 JNK Insulin/Akt signalling pathway Adenosine signalling D-Glucose homeostasis

Inflammation Inflammation, invasion, proliferation Inflammation Inflammation Cell proliferation Chemoresistance, cell viability Inflammation, glycolysis

Yeung et al. (2012) Mauer et al. (2014) Yeung et al. (2012) Yoon et al. (2012) Alarcón et al. (2017) Alarcón et al. (2017); Torres et al. (2016) Alarcón et al. (2017); Schwartzbaum et al. (2017)

IL-1β, interleukin 1β; IL-6, interleukin 6; IL-8, interleukin 8; JNK, c-Jun N-terminal kinase; Akt, protein kinase B/Akt. 3

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

4. Diabesity, glioma, and adenosine

et al., 2018). For several years, efforts have been made to investigate the different signalling pathways activated in the tumour microenvironment that are important for tumour progression, with extracellular adenosine been a major player in these phenomena (Sepúlveda et al., 2016). Elevated level of extracellular adenosine associate with different pathological conditions such as cancer, epilepsy, ischemia, pain, inflammation, and GDM (Borea et al., 2016; Sáez et al., 2018; San Martin et al., 2009; Sobrevia and Fredholm, 2017). Adenosine favours the initiation and growth of the tumour (Blay et al., 1997; Mandapathil et al., 2009; Sitkovsky et al., 2008; Stagg and Smyth, 2010; Vaupel and Mayer, 2016; Young et al., 2014) by increasing the angiogenesis and matrix remodelling (Bianco et al., 1997; Feoktistov et al., 2009; Linden, 2006; Ryzhov et al., 2008). For example, it has been described in chronic lymphocytic leukemia (CLL) and glioma, the catabolic activity of cluster of differentiation 73 (CD73), an ecto-5′-nucleotidase that degrades AMP to adenosine (Silva et al., 2017), is critical in generating an immunosuppressive and pro-angiogenic adenosine “halo” that contributes to cancer progression (Antonioli et al., 2013; Linden, 2006; Xu et al., 2013). Thus, it is feasible that in CLL the adenosinergic axis may be a good candidate acting at two different levels, i.e. preventing the generation of an adenosine-protecting halo and awaking the immune system against leukemic cells (Vaisitti et al., 2018). Extracellular adenosine also acts as inhibitor of the immune function (Ohta, 2016; Sepúlveda et al., 2016). Studies in solid tumours show a high level of extracellular adenosine in this pathological tissue (Blay et al., 1997; Ohta et al., 2006; Torres et al., 2016). It has been shown that glioma cells have a high resistance to ATP-induced cell death compared to tissue samples from normal subjects (Ledur et al., 2012; Morrone et al., 2005). Interestingly, the purinergic system plays an important role in glioma growth, since ATP induces the proliferation of glioma cells (Ledur et al., 2012). On the other hand, the activity of CD73 is increased in the human glioma cell lines U87, U138, U373, and U251 compared with astrocytes highlighting the importance of the adenosine axis in this disease (Wink et al., 2003).

Insulin resistance induced by obesity accelerates the deterioration of β-pancreatic islets with the consequent manifestation of T2DM (AlGoblan et al., 2014; Kleinert et al., 2018). Several studies address a relationship between overfeeding and hormonal dysregulation triggering type 1 diabetes mellitus (T1DM), a disease where the synthesis of insulin is blunted (Wilkin, 2001). The exact mechanism that links T1DM and obesity is not entirely clear (Al-Goblan et al., 2014). Some studies suggest a role of adenosine in the regulation of D-glucose homeostasis and in the pathophysiology of T1DM and T2DM (Antonioli et al., 2015; Silva et al., 2017). The latter is a possibility supported by findings showing that adenosine signalling is involved in both physiological and pathological processes including diseases such as cancer, diabetes mellitus, obesity, preeclampsia, among others (Pardo et al., 2017; Sáez et al., 2018; Salsoso et al., 2017; Silva et al., 2017; Sobrevia and Fredholm, 2017). In the central nervous system, adenosine plays an important role in the release of neurotransmitters (Sperlagh and Vizi, 2011), synaptic plasticity (Sebastiao and Ribeiro, 2015), and neuroprotection in ischemia, hypoxia, and oxidative stress (Dorotea et al., 2018; Fredholm et al., 2011). At the systemic level, adenosine plays several key functions in various tissues, including the cardiovascular system where promotes vasoconstriction or vasodilation of veins and arteries (Heusch, 2010; Vallon et al., 2006; Westermeier et al., 2016), inhibits lipolysis (Van der Graaf et al., 1999), stimulates bronchoconstriction (Oldenburg and Mustafa, 2005), and associates with foetoplacental vascular dysfunction in gestational diabetes mellitus (GDM), a type of diabetes mellitus that is first recognized or identified in pregnancy (Sáez et al., 2018; San Martín and Sobrevia, 2006; Silva et al., 2017; Subiabre et al., 2017; Villalobos-Labra et al., 2018). The level of adenosine in adipose tissue in obese adults was higher compared to subjects with normal weight (Ranta et al., 1985). Equally, obese children have high plasma level of this nucleoside compared with children with normal weight (Escudero et al., 2012). Furthermore, children with obesity and with high plasma adenosine level also present with increased total cholesterol, triglyceride, and LDL-cholesterol levels compared with children showing undetectable adenosine levels. Noticeable, in the latter study the potential effect of obesity in children is not conclusive since the reported undetectable level of adenosine in children with normal weight may well be due to the methodological approach selected for the study. An undetectable level of adenosine does not necessarily mean lack or lower level of this nucleoside. Another study reported that adenosine participates in the regulation of lipolysis in the adipocyte exerting a potent antilipolytic effect through the activation of A1AR (Fruhbeck et al., 2014).

4.2. Nucleoside membrane transporters Once adenosine is formed or released into the extracellular space it can be deaminated to inosine or may be taken by the cells via concentrative (CNTs) or equilibrative (ENTs) nucleoside membrane transporters (Silva et al., 2017; Whiteside, 2017; Pastor-Anglada and PerézTorras, 2018). ENTs are the most abundant nucleoside transporters in the brain with a large expression in neurons and glia (Parkinson et al., 2011; Arroyo et al., 2013). Interestingly, A1AR and ENT1 but A2AAR and ENT2 are preferentially co-expressed in the cortex and hippocampus and thalamus, respectively, in the human brain (Arroyo et al., 2013). Whether this is a phenomenon to sustain a proper and selective activation of adenosine receptors in the brain is not yet defined. Alterations in the transcript levels have been observed in various animal models of T1DM for both ENTs and CNTs (Pawelczyk et al., 2003; Podgorska et al., 2007). Studies in human umbilical vein endothelial cells (HUVECs) isolated from pregnancies with GDM or from normal pregnancies but exposed to high concentrations of D-glucose (25 mmol/ L, 24 h) show reduced adenosine uptake resulting in a higher extracellular bioavailability of this nucleoside (Vásquez et al., 2004). This phenomenon was due to a NO-dependent reduced expression of SLC29A1 (for hENT1) leading to lower hENT1 protein abundance (Farías et al., 2006; Vásquez et al., 2004). Several studies show that both D-glucose and insulin, molecules that are deregulated in diabesity, modulate the expression and activity of the human ENT isoforms 1 (hENT1) and 2 (hENT2) (Alarcón et al., 2017; Farías et al., 2006; Salomón et al., 2012; Vásquez et al., 2004; Westermeier et al., 2011, 2016). In GDM there is a decrease in the uptake of adenosine by the human fetoplacental macrovascular and microvascular endothelium (Salomón et al., 2012; Vásquez et al., 2004;

4.1. Adenosine receptors Adenosine is a substrate for the synthesis of nucleic acids and acts as precursor for other 5′-phosphate nucleosides such as adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP), which are main sources of cell energy (Cronstein and Sitkovsky, 2016; Dorotea et al., 2018; Silva et al., 2017). This nucleoside regulates several aspects of tissue function by activating at least four G-protein coupled receptors (A1AR, A2AAR, A2BAR, and A3AR) (Fig. 1) (Alarcón et al., 2017; Peleli et al., 2017; Sobrevia and Fredholm, 2017). A1AR and A2AAR show relatively high-affinity for adenosine (with Kd values in the range of nanomolar), whereas A2BAR and A3AR are of relatively low-affinity (with Kd values in the range of micromolar) for this nucleoside (Peleli et al., 2017; San Martín and Sobrevia, 2006; Sheth et al., 2014). Intracellular ATP is an important reservoir for the production of adenosine; however, this nucleoside is mainly formed in the extracellular space as a result of the sequential dephosphorylation of nucleotides from ATP to AMP and AMP into adenosine (Cronstein and Sitkovsky, 2016; Silva et al., 2017; Sousa 4

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

(Vindeirinho et al., 2013). It is reported that after administration of insulin, ADAs activity was lower in skeletal muscle, the heart, and the liver of normoglycemic rats. On the other hand, a profound reduction in the plasma insulin concentration in streptozotocin-induced diabetes results in elevated ADAs activity in these tissues (Fulzele et al., 2015; Rutkiewicz and Gorski, 1990). Also, AK is decreased in the kidney of diabetic rats leading to a local increase in adenosine concentration (Pawelczyk et al., 2000). All together these studies suggest that the local concentration of adenosine may be affected by the plasma concentration of insulin and its biological actions on ADAs and AK activity in target organs and tissues (Fulzele et al., 2015). On the other hand, studies in vitreous of diabetic patients, decreased miR-146b-3p is associated with increased ADA2 activity. Ectopic expression of miR-146b3p suppressed ADA2 expression, activity, and TNF-α release in the AGA-treated human macrophages. These results suggest a regulatory role of miR-146b-3p in diabetes related retinal inflammation by suppressing ADA2 (Fulzele et al., 2015).

Westermeier et al., 2011, 2016), and vascular smooth muscle cells (Aguayo et al., 2001). This phenomenon results in increased extracellular concentration of this nucleoside and its bioavailability leading to activation of adenosine receptors in an autocrine or paracrine manner (Mann et al., 2003; San Martín and Sobrevia, 2006; Vásquez et al., 2004). This phenomenon increases the synthesis of NO and the uptake of L-arginine, the NO synthase substrate, in endothelial cells. Interestingly, this mechanism is keeping a tonic activation of endothelial cells from the fetoplacental vasculature in GDM. Whether this is a phenomenon seen in the vasculature of patients with obesity, T2DM, T1DM, or diabesity is not yet reported (Sáez et al., 2018). 4.3. Insulin Insulin stimulates the transport of adenosine by increasing the expression and activity of hENT1 and hENT2 in human fetoplacental endothelium (Muñoz et al., 2006; Salomón et al., 2012; Westermeier et al., 2011, 2016). GDM-reduced adenosine transport and hENTs expression in HUVECs and human placental microvascular endothelial cells (hPMECs) is restored by insulin (Salomón et al., 2012; Westermeier et al., 2011, 2016). This phenomenon seems to result from redistribution of hENT1 from GDM-associated intracellular clusters to the plasma membrane increasing its maximal transport capacity thus restoring adenosine transport and extracellular adenosine concentration to physiological levels (∼200 nmol/L) (Westermeier et al., 2016). It is also described that insulin modulates the expression of adenosine receptors in HUVECs from GDM (Guzmán-Gutiérrez et al., 2016; Westermeier et al., 2011, 2016), preeclampsia (Salsoso et al., 2015, 2017), as well as in other pathologies (Chiarello et al., 2018; Pardo et al., 2017, 2018; Silva et al., 2017). Insulin required expression and activation of A1AR to reverse the GDM-increased L-arginine transport in HUVECs (Guzmán-Gutiérrez et al., 2016). However, insulin required the activation of A2AAR in HUVECs from preeclampsia to restore the Larginine uptake and synthesis of NO (Salsoso et al., 2015). Other studies show that insulin suppressed the expression of A1AR and A2BAR and had no effect on A2AAR and A3AR expression in rat cardiac fibroblasts (Grden et al., 2006). On the other hand, it was shown that insulin increased the A1AR and A2AAR but decreased the A2BAR protein abundance in rat B lymphocytes (Sakowicz-Burkiewicz et al., 2010). Therefore, it is likely that altered adenosine receptors expression in animal models of diabetes mellitus could result from changes in the plasma concentration of insulin.

4.5. Immune response The relationship between inflammation and insulin-resistant states (obesity and diabetes) is well established. Diabesity, are associated with an increased risk of cardiovascular complications, for example, atherosclerosis, myocardial infarction, and stroke (Esser et al., 2014; Tan et al., 2010). Diabesity has been suggested to be a combination of T2DM and obesity with the link being inflammation and oxidative stress (Schmidt and Duncan, 2003). The role of innate immunity-mediated inflammation in cancer biology is still debated. Moreover, through the expression of certain cytokines, metabolites, and membrane receptors, macrophages and myeloid-derived suppressor cells (MDSCs) can inhibit adaptive anti-tumour responses. Suppression of effector immune responses in the tumour microenvironment is a central mechanism of tumour escape (Fuxe and Karlsson, 2014; Grinberg-Bleyer and Ghosh, 2016). Tumour cells use several routes to evade the anti-tumour immune response. Adenosine also acts as an immunosuppressive metabolite that is commonly elevated in the extracellular tumour microenvironment because cAMP, a second messenger of adenosine signalling, is a potent negative regulator of T cell immune function (Allard et al., 2017). Adenosine accumulates in inflammatory microenvironment, an important diabesity hallmark, and induce suppression of the T cell response (Liu et al., 2016). Neutrophils release AMP during their transmigration through endothelial monolayer, which gets dephosphorylated by CD73 to generate adenosine. This nucleoside binds to A2AAR receptors expressed on neutrophils and decreases tissue damaging activity of neutrophils by inhibiting the generation of free radicals, cytokines release, leukotriene B4 level, and expression of adhesion molecules (Cronstein, 1994; Flamand et al., 2000). Adenosine limits the neutrophil infiltration into tissues and thus prevents neutrophil mediated tissue injury via activation of A2AAR (Thompson et al., 2008). On the other hand, exogenous adenosine prevents the differentiation of monocytes into macrophages and blocks monocytes development to a stage resembling a dendritic cell phenotype (Najar et al., 1990). In hypoxic regions (i.e. cancerous and inflamed tissues) activation of adenosine receptors skews the differentiation of dendritic cells to a totally different cell population (Ryzhov et al., 2008). Indeed, dendritic cells differentiated under the influence of adenosine promoting tumour growth when this nucleoside is injected into Lewis lung carcinoma tumours implanted in mice (Novitskiy et al., 2008). Increased adenosine levels have also been found in hypoxic regions of solid tumours causing interference in tumour cell recognition by cytotoxic immune cells (Blay et al., 1997; Merighi et al., 2003). This phenomenon provides a favourable environment for cancer cells to grow and proliferate. Interestingly, a possible role of adenosine as an endogenous inhibitor of killer T cells activity in the microenvironment of solid tumours was described (Hoskin et al., 1994). Thus, adenosine acts

4.4. Adenosine deaminases and adenosine kinase It has been described that adenosine, an endogenous anti-inflammatory metabolite, is increased in response to inflammation produced by adipose tissue in obesity (Jadhav and Jain, 2012). The extracellular concentration of adenosine is regulated by a fine balance between ENTs activity and the expression and activity of enzymes that metabolize adenosine, including adenosine deaminases (ADAs), adenosine kinase (AK), and CD73 (Borea et al., 2018, Fried et al., 2017; Silva et al., 2017, 2019). The expression and protein abundance of AK is unaltered in rat retinal cultures exposed to high D-glucose and in retinas from diabetic rats after one week of the induction of diabetes (Vindeirinho et al., 2013). Similarly, in retinas from diabetic mice, the AK protein abundance was decreased after eight weeks of the induction of diabetes, an effect reduced by inhibiting AK (Elsherbiny et al., 2013), suggesting an important role on diabesity. It is reported that ADAs activity was significantly increased in serum of obese subjects as compared to non-obese control subjects (Kurtul et al., 2006), A complex relationship seems to exist between ADAs and insulin in obesity. The rise in ADAs activities in obesity may be due to insulin resistance or increased secretion of adenosine (Ogbu et al., 2006). On the other hand, enzymatic assays performed in cultured retinal cell reveal a decrease in ADAs activity under high D-glucose 5

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

as a local immunosuppressant within the solid tumour environment and inhibits the killer activity of cytotoxic T cells.

Antonioli, L., Pacher, P., Vizi, E.S., Haskó, G., 2013. CD39 and CD73 in immunity and inflammation. Trends Mol. Med. 19, 355–367. https://doi.org/10.1016/j.molmed. 2013.03.005. Arroyo, P., Guzmán-Gutiérrez, E., Pardo, F., Salomón, C., Westermeier, F., Salsoso, R., Sáez, T., Leiva, A., Sobrevia, L., 2013. Gestational diabetes mellitus and the role of adenosine in the human placental endothelium and central nervous system. Global J. Pathol. Microbiol. 1, 24–42. https://doi.org/10.14205/2310-8703.2013.01.01.5. Barami, K., Lyon, L., Conell, C., 2017. Type 2 diabetes mellitus and glioblastoma multiforme–assessing risk and survival: results of a large retrospective study and systematic review of the literature. World Neurosurg. 106, 300–307. https://doi.org/10. 1016/j.wneu.2017.06.164. Bianco, C., Tortora, G., Baldassarre, G., Caputo, R., Fontanini, G., Chine, S., Bianco, A.R., Ciardiello, F., 1997. 8-Chloro-cyclic AMP inhibits autocrine and angiogenic growth factor production in human colorectal and breast cancer. Clin. Cancer Res. 3, 439–448. Blay, J., White, T.D., Hoskin, D.W., 1997. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57, 2602–2605. https://doi.org/10.1158/0008-5472.can-11-2104. Borea, P.A., Gessi, S., Merighi, S., Varani, K., 2016. Adenosine as a multi-signalling guardian angel in human diseases: when, where and how does it exert its protective effects? Trends Pharmacol. Sci. 37, 419–434. https://doi.org/10.1016/j.tips.2016. 02.006. Borea, P.A., Gessi, S., Merighi, S., Vincenzi, F., Varani, K., 2018. Pharmacology of adenosine receptors: the state of the art. Physiol. Rev. 98, 1591–1625. https://doi.org/ 10.1152/physrev.00049.2017. Chadt, A., Scherneck, S., Joost, H.-G., Al-Hasani, H., 2014. Molecular Links between Obesity and Diabetes: “Diabesity,” Endotext [Internet]. South Dartmouth (MA). MDText.com, Inc. 2000-.2018 Jan 23. www.ncbi.nlm.nih.gov/books/NBK279051/. Chen, W., Xia, T., Wang, D., Huang, B., Zhao, P., Wang, J., Qu, X., Li, X., 2016. Human astrocytes secrete IL-6 to promote glioma migration and invasion through upregulation of cytomembrane MMP14. Oncotarget 7, 62425–62438. https://doi.org/10. 18632/oncotarget.11515. Chiarello, D.I., Marín, R., Proverbio, F., Coronado, P., Toledo, F., Salsoso, R., Gutiérrez, J., Sobrevia, L., 2018. Mechanisms of the effect of magnesium salts in preeclampsia. Placenta 69, 134–139. https://doi.org/10.1016/j.placenta.2018.04.011. Cho, N.H., Shaw, J.E., Karuranga, S., Huang, Y., da Rocha Fernandes, J.D., Ohlrogge, A.W., Malanda, B., 2018. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 138, 271–281. https:// doi.org/10.1016/j.diabres.2018.02.023. Colditz, G.A., Peterson, L.L., 2017. Obesity and cancer: evidence, impact, and future directions. Clin. Chem. 64, 154–162. https://doi.org/10.1373/clinchem.2017.277376. Cronstein, B.N., 1994. Adenosine, an endogenous anti-inflammatory agent. J. Appl. Physiol. 76, 5–13. https://doi.org/10.1152/jappl.1994.76.1.5. Cronstein, B.N., Sitkovsky, M., 2016. Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat. Rev. Rheumatol. 13, 41–51. https://doi.org/10.1038/nrrheum.2016.178. Dali-Youcef, N., Hnia, K., Blaise, S., Messaddeq, N., Blanc, S., Postic, C., Valet, P., Tomasetto, C., Rio, M.C., 2016. Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch. Sci. Rep. 6, 25140. https://doi.org/10.1038/ srep25140. Dankner, R., Boffetta, P., Balicer, R.D., Boker, L.K., Sadeh, M., Berlin, A., Olmer, L., Goldfracht, M., Freedman, L.S., 2016. Time-dependent risk of cancer after a diabetes diagnosis in a cohort of 2.3 million adults. Am. J. Epidemiol. 183, 1098–1106. https://doi.org/10.1093/aje/kwv290. Davidson, J.A., Sloan, L., 2017. Fixed-dose combination of canagliflozin and metformin for the treatment of type 2 diabetes: an overview. Adv. Ther. 34, 41–59. https://doi. org/10.1007/s12325-016-0434-2. Davis, T., Doyle, H., Tobias, V., Ellison, D.W., Ziegler, D.S., 2016. Case report of spontaneous resolution of a congenital glioblastoma. Pediatrics 137, e20151241. https:// doi.org/10.1542/peds.2015-1241. Deol, H., Lekkakou, L., Viswanath, A.K., Pappachan, J.M., 2017. Combination therapy with GLP-1 analogues and SGLT-2 inhibitors in the management of diabesity: the real world experience. Endocrine 55, 173–178. https://doi.org/10.1007/s12020-0161125-0. Disney-Hogg, L., Sud, A., Law, P.J., Cornish, A.J., Kinnersley, B., Ostrom, Q.T., Labreche, K., Eckel-Passow, J.E., Armstrong, G.N., Claus, E.B., Il'Yasova, D., Schildkraut, J., Barnholtz-Sloan, J.S., Olson, S.H., Bernstein, J.L., Lai, R.K., Swerdlow, A.J., Simon, M., Hoffmann, P., Nöthen, M.M., Jöckel, K.H., Chanock, S., Rajaraman, P., Johansen, C., Jenkins, R.B., Melin, B.S., Wrensch, M.R., Sanson, M., Bondy, M.L., Houlston, R.S., 2018. Influence of obesity-related risk factors in the aetiology of glioma. Br. J. Canc. 118, 1020–1027. https://doi.org/10.1038/s41416-018-0009-x. Ding, C.Z., Guo, X.F., Wang, G.L., Wang, H.T., Xu, G.H., Liu, Y.Y., Wu, Z.J., Chen, Y.H., Wang, J., Wang, W.G., 2018. High glucose contributes to the proliferation and migration of non-small cell lung cancer cells via GAS5-TRIB3 axis. Biosci. Rep. 38, BSR20171014. https://doi.org/10.1042/BSR20171014. Dorotea, D., Cho, A., Lee, G., Kwon, G., Lee, J., Sahu, P.K., Jeong, L.S., Cha, D.R., Ha, H., 2018. Orally active, species-independent novel A3 adenosine receptor antagonist protects against kidney injury in db/db mice. Exp. Mol. Med. 50, 38. https://doi.org/ 10.1038/s12276-018-0053-x. Edlinger, M., Strohmaier, S., Jonsson, H., Bjørge, T., Manjer, J., Borena, Haggstrom, C., Engeland, A., Tretli, S., Concin, H., Nagel, G., Selmer, R., Johansen, D., Stocks, T., Hallmans, G., Stattin, P., Ulmer, H., 2012. Blood pressure and other metabolic syndrome factors and risk of brain tumour in the large population-based Me-Can cohort study. J. Hypertens. 30, 290–296. https://doi.org/10.1097/HJH. 0b013e32834e9176. Elsherbiny, N.M., Ahmad, S., Naime, M., Elsherbini, A.M., Fulzele, S., Al-Gayyar, M.M.,

5. Concluding remarks The mechanistic basis of how diabesity affects an increased GBM risk is poorly understood. Recent studies suggest that GBM patients affected by these metabolic failures have worse prognosis compared with those with normal metabolic conditions. Thus, few established risk factors for the development of glioma have been robustly identified. Adenosine is a molecule that seems to serve as a link between diabesity and GBM. Adenosine is a nucleoside with several functions and its role in cellular homeostasis is key in different types of diseases, including diabetes mellitus and gliomas. The extracellular level of adenosine is aberrantly increased in patients with these diseases, promoting a proinflammatory environment. In several tissues and cell models, adenosine has been described as an anti-inflammatory molecule, but in glioma it is widely accepted that it is a nucleoside that promotes an inflammatory microenvironment that enhances cell proliferation (Uribe et al., 2017). Under these conditions, the level of inflammatory factors such as interleukins increase, especially IL-6 among others. In addition to conclude that adenosine is involved in the development of these diseases, it is clearer that it is also one of the main molecules responsible for the failure of treatments approaches of the patients. In this context, the link is made with patients that are obese in addition to having diabetes mellitus establishing the term “diabesity”, a condition in which there are additive or synergic effects between both diseases, promoting inflammation and increase in adenosine concentration. This is why patients with cancer, such as glioma, suffering with diabesity, have a positive regulation loop of the proinflammatory environment preventing the action of multimodal therapies (Fig. 1). Conflicts of interest The authors confirm that there are no conflicts of interest. Acknowledgements This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (grant numbers 1160777, 1150377, 3170851, 3180621), Chile. Founding sources had no role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. References Adeberg, S., Bernhardt, D., Harrabi, S.B., Bostel, T., Mohr, A., Koelsche, C., Diehl, C., Rieken, S., Debus, J., 2015. Metformin influences progression in diabetic glioblastoma patients. Strahlenther. Onkol. 191, 928–935. https://doi.org/10.1007/ s00066-015-0884-5. Agha, M., Agha, R., 2017. The rising prevalence of obesity: part A: impact on public health. Int. J. Surg. Oncol. 2, e17. https://doi.org/10.1097/IJ9.0000000000000017. Aguayo, C., Flores, C., Parodi, J., Rojas, R., Mann, G.E., Pearson, J.D., Sobrevia, L., 2001. Modulation of adenosine transport by insulin in human umbilical artery smooth muscle cells from normal or gestational diabetic pregnancies. J. Physiol. 534, 243–254. https://doi.org/10.1111/j.1469-7793.2001.00243.x. Alarcón, S., Garrido, W., Cappelli, C., Suárez, R., Oyarzún, C., Quezada, C., San Martín, R., 2017. Deficient insulin-mediated upregulation of the equilibrative nucleoside transporter 2 contributes to chronically increased adenosine in diabetic glomerulopathy. Sci. Rep. 7, 9439. https://doi.org/10.1038/s41598-017-09783-0. Al-Goblan, A.S., Al-Alfi, M.A., Khan, M.Z., 2014. Mechanism linking diabetes mellitus and obesity. Diabetes Metab. Syndr. Obes. 7, 587–591. https://doi.org/10.2147/DMSO. S67400. Allard, D., Turcotte, M., Stagg, J., 2017. Targeting A2 adenosine receptors in cancer. Immunol. Cell Biol. 95, 333–339. https://doi.org/10.1038/icb.2017.8. Allott, E.H., Hursting, S.D., 2015. Obesity and cancer: mechanistic insights from transdisciplinary studies. Endocr. Relat. Cancer 22, R365–R386. https://doi.org/10.1530/ ERC-15-0400. Antonioli, L., Blandizzi, C., Csóka, B., Pacher, P., Haskó, G., 2015. Adenosine signalling in diabetes mellitus-pathophysiology and therapeutic considerations. Nat. Rev. Endocrinol. 11, 228–241. https://doi.org/10.1038/nrendo.2015.10.

6

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

1007/s11695- 011-0490-2. Kalra, S., 2013. Diabesity. J. Pak. Med. Assoc. 63, 532–534. https://jpma.org.pk/ PdfDownload/4131. Kawamura, Y., Takouda, J., Yoshimoto, K., Nakashima, K., 2018. New aspects of glioblastoma multiforme revealed by similarities between neural and glioblastoma stem cells. Cell Biol. Toxicol. 34, 425–440. https://doi.org/10.1007/s10565-017-9420-y. Kitahara, C.M., Linet, M.S., Brenner, A.V., Wang, S.S., Melin, B.S., Wang, Z., Inskip, P.,D., et al., 2014. Personal history of diabetes, genetic susceptibility to diabetes, and risk of brain glioma: a pooled analysis of observational studies. Cancer Epidemiol. Biomark. Prev. 23, 47–54. https://dx.doi.org/10.1158%2F1055-9965.EPI-13-0913. Kleinert, M., Clemmensen, C., Hofmann, S.M., Moore, M.C., Renner, S., Woods, S.C., Huypens, P., Beckers, J., De Angelis, M.H., Schürmann, A., Bakhti, M., Klingenspor, M., Heiman, M., Cherrington, A.D., Ristow, M., Lickert, H., Wolf, E., Havel, P.J., Müller, T.D., Tschöp, M.H., 2018. Animal models of obesity and diabetes mellitus. Nat. Rev. Endocrinol. 14, 140–162. https://doi.org/10.1038/nrendo.2017.161. Klil-Drori, A.J., Azoulay, L., Pollak, M.N., 2017. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat. Rev. Clin. Oncol. 14, 85–99. https://doi.org/ 10.1038/nrclinonc.2016.120. Kolb, R., Sutterwala, F.S., Zhang, W., 2016. Obesity and cancer: inflammation bridges the two. Curr. Opin. Pharmacol. 29, 77–89. https://doi.org/10.1016/j.coph.2016.07. 005. Kurtul, N., Akarsu, E., Aktaran, S., 2006. The relationship between serum total sialic acid levels and adenosine deaminase activity in obesity. Saudi Med. J. 27, 170–173. Kyrgiou, M., Kalliala, I., Markozannes, G., Gunter, M.J., Paraskevaidis, E., Gabra, H., Martin- Hirsch, P., Tsilidis, K.K., 2017. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ 356, j477. https://doi.org/10.1136/bmj. j477. Ledur, P.F., Villodre, E.S., Paulus, R., Cruz, L.A., Flores, D.G., Lenz, G., 2012. Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells. Purinergic Signal. 8, 39–48. https://doi.org/10.1007/s11302-011-9252-9. Li, R., Li, G., Deng, L., Liu, Q., Dai, J., Shen, J., Zhang, J., 2010. IL-6 augments the invasiveness of U87MG human glioblastoma multiforme cells via up-regulation of MMP-2 and fascin- 1. Oncol. Rep. 23, 1553–1559. https://doi.org/10.3892/or00000795. Li, R., Grimm, S.A., Mav, D., Gu, H., Djukovic, D., Shah, R., Merrick, B.A., Raftery, D., Wade, P.A., 2018. Transcriptome and DNA methylome analysis in a mouse model of diet- induced obesity predicts increased risk of colorectal cancer. Cell Rep. 22, 624–637. https://doi.org/10.1016/j.celrep.2017.12.071. Linden, J., 2006. Adenosine metabolism and cancer. Focus on “Adenosine down regulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatases and reducing ERK1/2 activity via a novel pathway.”. Am. J. Physiol. 291, C405–C406. https://doi.org/10.1152/ajpcell.00242.2006. Liu, Q., Li, G., Li, R., Shen, J., He, Q., Deng, L., Zhang, C., Zhang, J., 2010. IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines. J. Neuro Oncol. 100, 165–176. https://doi.org/10.1007/s11060-010-0158-0. Liu, C., Mukienko, Y., Wu, C., Zavialov, A., 2016. Human adenosine deaminases control the immune cell responses to activation signals by reducing extracellular adenosine concentration. J. Immunol. 196, 124–163. http://www.jimmunol.org/content/196/ 1_Supplement/124.63. Lu, V.,M., 2019. Connecting the dots between metformin and high‐grade glioma. Int. J. Cancer 144, 1754–1755. https://doi.org/10.1002/ijc.31987. Mandapathil, M., Szczepanski, M.J., Szajnik, M., Ren, J., Lenzner, D.E., Jackson, E.K., Gorelik, E., Lang, S., Johnson, J.T., Whiteside, T.L., 2009. Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin. Cancer Res. 15, 6348–6357. https://doi.org/10.1158/1078-0432.CCR-09-1143. Mann, G.E., Yudilevich, D.L., Sobrevia, L., 2003. Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol. Rev. 83, 183–252. https://doi.org/10.1152/physrev.00022.2002. Mao, P., Joshi, K., Li, J., Kim, S.H., Li, P., Santana-Santos, L., Luthra, S., Chandran, U.R., Benos, P.V., Smith, L., Wang, M., Hu, B., Cheng, S.Y., Sobol, R.W., Nakano, I., 2013. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc. Natl. Acad. Sci. U.S.A. 110, 8644–8649. https://doi.org/10.1073/pnas.1221478110. Martínez Leo, E.E., Acevedo Fernández, J.J., Segura Campos, M.R., 2016. Biopeptides with antioxidant and anti-inflammatory potential in the prevention and treatment of diabesity disease. Biomed. Pharmacother. 83, 816–826. https://doi.org/10.1016/j. biopha.2016.07.051. Mauer, J., Chaurasia, B., Goldau, J., Vogt, M.C., Ruud, J., Nguyen, K.D., Theurich, S., Hausen, A.C., Schmitz, J., Brönneke, H.S., Estevez, E., Allen, T.L., Mesaros, A., Partridge, L., Febbraio, M.A., Chawla, A., Wunderlich, F.T., Brüning, J.C., 2014. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity- associated resistance to insulin. Nat. Immunol. 15, 423–430. https://doi.org/10.1038/ni.2865. Merighi, S., Mirandola, P., Varani, K., Gessi, S., Leung, E., Baraldi, P.G., Tabrizi, M.A., Borea, P.A., 2003. A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol. Ther. 100, 31–48. https://doi.org/10.1016/S0163-7258(03) 00084-6. Morrone, F.B., Horn, A.P., Stella, J., Spiller, F., Sarkis, J.J.F., Salbego, C.G., Lenz, G., Battastini, A.M.O., 2005. Increased resistance of glioma cell lines to extracellular ATP cytotoxicity. J. Neuro Oncol. 71, 135–140. https://doi.org/10.1007/s11060-0041383-1. Muñoz, G., San Martín, R., Farías, M., Cea, L., Vecchiola, A., Casanello, P., Sobrevia, L., 2006. Insulin restores glucose inhibition of adenosine transport by increasing the expression and activity of the equilibrative nucleoside transporter 2 in human umbilical vein endothelium. J. Cell. Physiol. 209, 826–835. https://doi.org/10.1002/ jcp.20769.

Eissa, L.A., El-Shishtawy, M.M., Liou, G.I., 2013. ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy. Life Sci. 93, 78–88. https:// doi.org/10.1016/j.lfs.2013.05.024. Escudero, A., Carreno, B., Retamal, N., Celis, C., Castro, L., Aguayo, C., Acurio, J., Escudero, C., 2012. Elevated concentrations of plasma adenosine in obese children. Biofactors 38, 422–428. https://doi.org/10.1002/biof.1039. Esser, N., Legrand-Poels, S., Piette, J., Scheen, A.J., Paquot, N., 2014. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract 105, 141–150. https://doi.org/10.1016/j.diabres.2014.04.006. Farag, Y.M.K., Gaballa, M.R., 2011. Diabesity: an overview of a rising epidemic. Nephrol. Dial. Transplant. 26, 28–35. https://doi.org/10.1093/ndt/gfq576. Farías, M., San Martín, R., Puebla, C., Pearson, J.D., Casado, J.F., Pastor-Anglada, M., Casanello, P., Sobrevia, L., 2006. Nitric oxide reduces adenosine transporter ENT1 gene (SLC29A1) promoter activity in human fetal endothelium from gestational diabetes. J. Cell. Physiol. 208, 451–460. https://doi.org/10.1002/jcp.20680. Feoktistov, I., Biaggioni, I., Cronstein, B.N., 2009. Adenosine receptors in wound healing, fibrosis and angiogenesis. Handb. Exp. Pharmacol. 193, 383–397. https://doi.org/10. 1007/978-3-540-89615-9_13. Flamand, N., Boudreault, S., Picard, S., Austin, M., Surette, M.E., Plante, H., Krump, E., Vallée, M.J., Gilbert, C., Naccache, P., Laviolette, M., Borgeat, P., 2000. Adenosine, a potent natural suppressor of arachidonic acid release and leukotriene biosynthesis in human neutrophils. Am. J. Respir. Crit. Care Med. 161, S88–S94. https://doi.org/10. 1164/ajrccm.161.supplement_1.ltta-18. Font-Burgada, J., Sun, B., Karin, M., 2016. Obesity and cancer: the oil that feeds the flame. Cell Metabol. 23, 48–62. https://doi.org/10.1016/j.cmet.2015.12.015. Fredholm, B.B., IJzerman, A.P., Jacobson, K.A., Linden, J., Muller, C.E., 2011. International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol. Rev. 63, 1–34. https:// doi.org/10.1124/pr.110.003285. Fried, N.T., Elliott, M.B., Oshinsky, M.L., 2017. The role of adenosine signaling in headache: a review. Brain Sci. 7, 30. https://doi.org/10.3390/brainsci7030030. Friedrich, M.J., 2017. Global obesity epidemic worsening. J. Am. Med. Assoc. 318, 603. https://doi.org/10.1001/jama.2017.10693. Fulzele, S., El-Sherbini, A., Ahmad, S., Sangani, R., Matragoon, S., El-Remessy, A., Radhakrishnan, R., Liou, G.I., 2015. MicroRNA-146b-3p regulates retinal inflammation by suppressing adenosine deaminase-2 in diabetes. Biomed. Res. 2015, 8. https://doi.org/10.1155/2015/846501. Frühbeck, G., Méndez-Giménez, L., Fernández-Formoso, J.A., Fernández, S., Rodríguez, A., 2014. Regulation of adipocyte lipolysis. Nutr. Res. Rev. 27, 63–99. https://doi. org/10.1017/S095442241400002X. Fukumura, D., Incio, J., Shankaraiah, R., Jain, R., 2016. Obesity and cancer: an angiogenic and inflammatory link. Microcirculation 23, 191–206. https://doi.org/10. 1111/micc.12270. Fuxe, J., Karlsson, M.C.I., 2014. Epithelial-mesenchymal transition: a link between cancer and inflammation. In: Hiraku, Y., Kawanishi, S., Ohshima, H. (Eds.), Cancer and Inflammation Mechanisms: Chemical, Biological, and Clinical Aspects, (Chapter 3). https://doi.org/10.1002/9781118826621.ch3. Gastaldi, G., Ruiz, J., 2009. Metabolic dysfunction and chronic stress: a new sight at “diabesity” pandemic. Rev. Med. Suisse 5, 1273–1277. Giovannucci, E., Harlan, D.M., Archer, M.C., Bergenstal, R.M., Gapstur, S.M., Habel, L.A., Pollak, M., Regensteiner, J.G., Yee, D., 2010. Diabetes and cancer: a consensus report. Diabetes Care 60, 207–221. https://doi.org/10.2337/dc10-0666. Gong, Y., Ma, Y., Sinyuk, M., Loganathan, S., Thompson, R.C., Sarkaria, J.N., Chen, W., Lathia, J.D., Mobley, B.C., Clark, S.W., Wang, J., 2016. Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation. Neuro Oncol. 18, 48–57. https://doi.org/10.1093/neuonc/nov096. Grden, M., Podgorska, M., Kocbuch, K., Szutowicz, A., Pawelczyk, T., 2006. Expression of adenosine receptors in cardiac fibroblasts as a function of insulin and glucose level. Arch. Biochem. Biophys. 455, 10–17. https://doi.org/10.1016/j.abb.2006.08.022. Grinberg-Bleyer, Y., Ghosh, S., 2016. A novel link between inflammation and cancer. Cancer Cell 30, 829–830. https://doi.org/10.1016/j.ccell.2016.11.013. Gritti, M., Würth, R., Angelini, M., Barbieri, F., Peretti, M., Pizzi, E., Pattarozzi, A., Carra, E., Sirito, R., Daga, A., Curmi, P.M., Mazzanti, M., et al., 2014. Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current. Oncotarget 5, 11252–11268. https://doi.org/10.18632/oncotarget.2617. Guzmán-Gutiérrez, E., Armella, A., Toledo, F., Pardo, F., Leiva, A., Sobrevia, L., 2016. Insulin requires A1 adenosine receptors expression to reverse gestational diabetesincreased L- arginine transport in human umbilical vein endothelium. Purinergic Signal. 12, 175–190. https://doi.org/10.1007/s11302-015-9491-2. Heusch, G., 2010. Editorial: adenosine and maximum coronary vasodilation in humans: myth and misconceptions in the assessment of coronary reserve. Basic Res. Cardiol. 105, 1–5. https://doi.org/10.1007/s00395-009-0074-7. Hoskin, D.W., Reynolds, T., Blay, J., 1994. Adenosine as a possible inhibitor of killer Tcell activation in the microenvironment of solid tumours. Int. J. Cancer 59, 854–855. https://doi.org/10.1002/ijc.2910590625. Iyengar, N.M., Gucalp, A., Dannenberg, A.J., Hudis, C.A., 2016. Obesity and cancer mechanisms: tumor microenvironment and inflammation. J. Clin. Oncol. 34, 4270–4276. https://doi.org/10.1200/JCO.2016.67.4283. Jadhav, A., Jain, A., 2012. Elevated adenosine deaminase activity in overweight and obese Indian subjects. Arch. Physiol. Biochem. 118, 1–5. https://doi.org/10.3109/ 13813455.2011.603341. Jones, D., 2015. Chronic disease in the twentieth century: a history. Glob. Public Health 10, 414–415. https://doi.org/10.1080/17441692.2014.996173. Kaidar-Person, O., Bar-Sela, G., Person, B., 2011. The two major epidemics of the twentyfirst century: obesity and cancer. Obes. Surg. 21, 1792–1797. https://doi.org/10.

7

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

Salsoso, R., Farías, M., Gutiérrez, J., Pardo, F., Chiarello, D.I., Toledo, F., Leiva, A., Mate, A., Vázquez, C.M., Sobrevia, L., 2017. Adenosine and preeclampsia. Mol. Aspect. Med. 55, 126–139. https://doi.org/10.1016/j.mam.2016.12.003. Salomón, C., Westermeier, F., Puebla, C., Arroyo, P., Guzmán-Gutiérrez, E., Pardo, F., Leiva, A., Casanello, P., Sobrevia, L., 2012. Gestational diabetes reduces adenosine transport in human placental microvascular endothelium, an effect reversed by insulin. PLoS One 7, e40578. https://doi.org/10.1371/journal.pone.0040578. San Martín, R., Sobrevia, L., 2006. Gestational diabetes and the adenosine/L-arginine/ nitric oxide (ALANO) pathway in human umbilical vein endothelium. Placenta 27, 1–10. https://doi.org/10.1016/j.placenta.2005.01.011. San Martin, R., Valladares, D., Roa, H., Troncoso, E., Sobrevia, L., 2009. Do adenosine receptors offer new therapeutic options for diabetic nephropathy? Curr. Vasc. Pharmacol. 7, 450–459. https://doi.org/10.2174/157016109789043964. Sato, A., Sunayama, J., Okada, M., Watanabe, E., Seino, S., Shibuya, K., Suzuki, K., Narita, Y., Shibui, S., Kayama, T., Kitanaka, C., 2012. Glioma‐initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem cells Transl. Med. 1, 811–824. https://dx.doi.org/10.5966%2Fsctm.2012-0058. Schmidt, M.I., Duncan, B.B., 2003. Diabesity: an inflammatory metabolic condition. Clin. Chem. Lab. Med. 41, 1120–1130. https://doi.org/10.1515/CCLM.2003.174. Schwartzbaum, J., Edlinger, M., Zigmont, V., Stattin, P., Rempala, G.A., Nagel, G., Hammar, N., Ulmer, H., Föger, B., Walldius, G., Manjer, J., Malmström, H., Feychting, M., 2017. Associations between prediagnostic blood glucose levels, diabetes, and glioma. Sci. Rep. 7, 1436. https://doi.org/10.1038/s41598-017-01553-2. Schwartzbaum, J., Jonsson, F., Ahlbom, A., Preston-Martin, S., Malmer, B., Lönn, S., Soderberg, K., Feychting, M., 2005. Prior hospitalization for epilepsy, diabetes, and stroke and subsequent glioma and meningioma risk. Cancer Epidemiol. Biomark. Prev. 14, 643–650. https://doi.org/10.1158/1055-9965.EPI-04-0119. Sebastião, A.M., Ribeiro, J.A., 2015. Neuromodulation and metamodulation by adenosine: impact and subtleties upon synaptic plasticity regulation. Brain Res. 1621, 102–113. https://doi.org/10.1016/j.brainres.2014.11.008. Seliger, C., Luber, C., Gerken, M., Schaertl, J., Proescholdt, M., Riemenschneider, M.J., Meier, C.,R., Bogdahn, U., Leitzmann, M.,F., Klinkhammer-Schalke, M., Hau, P., 2019. Use of metformin and survival of patients with high‐grade glioma. Int. J. Cancer 144, 273–280. https://doi.org/10.1002/ijc.31783. Seliger, C., Ricci, C., Meier, C.R., Bodmer, M., Jick, S.S., Bogdahn, U., Hau, P., Leitzmann, M.F., 2016. Diabetes, use of antidiabetic drugs, and the risk of glioma. Neuro Oncol. 18, 340–349. https://doi.org/10.1093/neuonc/nov100. Sergentanis, T.N., Tsivgoulis, G., Perlepe, C., Ntanasis-Stathopoulos, I., Tzanninis, I.G., Sergentanis, I.N., Psaltopoulou, T., 2015. Obesity and risk for brain/CNS tumors, gliomas and meningiomas: a meta-analysis. PLoS One 10, e0136974. https://doi. org/10.1371/journal.pone.0136974. Sheth, S., Brito, R., Mukherjea, D., Rybak, L.P., Ramkumar, V., 2014. Adenosine receptors: expression, function and regulation. Int. J. Mol. Sci. 15, 2024–2052. https:// doi.org/10.3390/ijms15022024. Sepúlveda, C., Palomo, I., Fuentes, E., 2016. Role of adenosine A2b receptor overexpression in tumor progression. Life Sci. 166, 92–99. https://doi.org/10.1016/j.lfs. 2016.10.008. Silva, L., Subiabre, M., Araos, J., Sáez, T., Salsoso, R., Pardo, F., Leiva, A., San Martín, R., Toledo, F., Sobrevia, L., 2017. Insulin/adenosine axis linked signalling. Mol. Aspect. Med. 55, 45–61. https://doi.org/10.1016/j.mam.2016.11.002. Silva, L., Plösch, T., Toledo, F., Faas, M.M., Sobrevia, L., 2019. Adenosine kinase and cardiovascular fetal programming in gestational diabetes mellitus. Biochim. Biophys. Mol. Basis Dis In Press. https://doi.org/10.1016/j.bbadis.2019.01.023. Sims, E.A., Danforth, E., Horton, E.S., Bray, G.A., Glennon, J.A., Salans, L.B., 1973. Endocrine and metabolic effects of experimental obesity in man. Recent Prog. Horm. Res. 29, 457–496. Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, M., Cusimano, M.,D., Dirks, P.B., 2004. Identification of human brain tumour initiating cells. Nature 432, 396–401. https://doi.org/10.1038/nature03128. Sitkovsky, M.V., Kjaergaard, J., Lukashev, D., Ohta, A., 2008. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin. Cancer Res. 14, 5947–5952. https://doi.org/10.1158/1078-0432.CCR08-0229. Sobrevia, L., Fredholm, B.B., 2017. Adenosine – from molecular mechanisms to pathophysiology. Mol. Aspect. Med. 55, 1–3. https://doi.org/10.1016/j.mam.2017.06.003. Solinas, G., Becattini, B., 2017. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Mol. Metab. 6, 174–184. https://doi.org/10.1016/j.molmet.2016.12. 001. Sperlágh, B., Vizi, E.S., 2011. The role of extracellular adenosine in chemical neurotransmission in the hippocampus and basal ganglia: pharmacological and clinical aspects. Curr. Top. Med. Chem. 11, 1034–1046. https://doi.org/10.2174/ 156802611795347564. Stagg, J., Smyth, M.J., 2010. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29, 5346–5348. https://doi.org/10.1038/onc.2010.292. Sousa, J.B., Fresco, P., Diniz, C., Gonçalves, J., 2018. Adenosine receptor ligands on cancer therapy: a review of patent literature. Recent Pat. Anti-Cancer Drug Discov. 13, 40–69. https://doi.org/10.2174/1574892812666171108115959. Strickland, M., Stoll, E.A., 2017. Metabolic reprogramming in glioma. Front. Cell Dev. Biol. 5, 43. https://doi.org/10.3389/fcell.2017.00043. Subiabre, M., Silva, L., Villalobos-Labra, R., Toledo, F., Paublo, M., López, M.A., Salsoso, R., Pardo, F., Leiva, A., Sobrevia, L., 2017. Maternal insulin therapy does not restore foetoplacental endothelial dysfunction in gestational diabetes mellitus. Biochim. Biophys. Acta (BBA) - Mol. Basis Dis. 1863, 2987–2998. https://doi.org/10.1016/j. bbadis.2017.07.022. Tan, B.K., Adya, R., Randeva, H.S., 2010. Omentin: a novel link between inflammation, diabesity, and cardiovascular disease. Trends Cardiovasc. Med. 20, 143–148. https://

Najar, H.M., Ruhl, S., Bru-Capdeville, A.C., Peters, J.H., 1990. Adenosine and its derivatives control human monocyte differentiation into highly accessory cells versus macrophages. J. Leukoc. Biol. 47, 429–439. https://doi.org/10.1002/jlb.47.5.429. Niedermaier, T., Behrens, G., Schmid, D., Schlecht, I., Fischer, B., Leitzmann, M.F., 2015. Body mass index, physical activity, and risk of adult meningioma and glioma: a metaanalysis. Neurology 85, 1342–1350. https://doi.org/10.1212/WNL. 0000000000002020. Novitskiy, S.V., Ryzhov, S., Zaynagetdinov, R., Goldstein, A.E., Huang, Y., Tikhomirov, O.Y., Blackburn, M.R., Biaggioni, I., Carbone, D.P., Feoktistov, I., Dikov, M.M., 2008. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112, 1822–1831. https://doi.org/10.1182/blood-2008-02-136325. Ogbu, I.S.I., Nebo, N.C., Onyeanusi, J.C., 2006. Adenosine deaminase activities and fasting blood glucose in obesity. J. Med. 11, 115–119. Ohta, A., 2016. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front. Immunol. 7, 109. https://doi.org/10.3389/fimmu.2016.00109. Ohta, A., Gorelik, E., Prasad, S.J., Ronchese, F., Lukashev, D., Wong, M.K.K., Huang, X., Caldwell, S., Liu, K., Smith, P., Chen, J.-F., Jackson, E.K., Apasov, S., Abrams, S., Sitkovsky, M., 2006. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl. Acad. Sci. U. S. A 103, 13132–13137. https://doi.org/10.1073/pnas. 0605251103. Oldenburg, P.J., Mustafa, S.J., 2005. Involvement of mast cells in adenosine-mediated bronchoconstriction and inflammation in an allergic mouse model. J. Pharmacol. Exp. Therapeut. 313, 319–324. https://doi.org/10.1124/jpet.104.071720. Oppermann, H., Ding, Y., Sharma, J., Paetz, M.B., Meixensberger, J., Gaunitz, F., Birkemeyer, C., 2016. Metabolic response of glioblastoma cells associated with glucose withdrawal and pyruvate substitution as revealed by GC-MS. Nutr. Metab. 13, 70. https://doi.org/10.1186/s12986-016-0131-9. Oyarzún, C., Garrido, W., Alarcón, S., Yáñez, A., Sobrevia, L., Quezada, C., San Martín, R., 2017. Adenosine contribution to normal renal physiology and chronic kidney disease. Mol. Aspect. Med. 55, 75–89. https://doi.org/10.1016/j.mam.2017.01.004. Pappachan, J.M., Viswanath, A.K., 2017. Medical management of diabesity: do we have realistic targets? Curr. Diabetes Rep. 17, 4. https://doi.org/10.1007/s11892-0170828-9. Pardo, F., Villalobos-Labra, R., Chiarello, D.I., Salsoso, R., Toledo, F., Gutierrez, J., Leiva, A., Sobrevia, L., 2017. Molecular implications of adenosine in obesity. Mol. Aspect. Med. 55, 90–101. https://doi.org/10.1016/j.mam.2017.01.003. Pardo, F., Villalobos-Labra, R., Sobrevia, B., Toledo, F., Sobrevia, L., 2018. Extracellular vesicles in obesity and diabetes mellitus. Mol. Aspect. Med. 60, 81–91. https://doi. org/10.1016/j.mam.2017.11.010. Park, Y., Colditz, G.A., 2017. Diabetes and adiposity: a heavy load for cancer. Lancet Diabetes Endocrinol. 6, 82–83. https://doi.org/10.1016/S2213-8587(17)30396-0. Parkinson, F., L. Damaraju, V., Graham, K., Y.M. Yao, S., A. Baldwin, S., E. Cass, C., D. Young, J., 2011. Molecular biology of nucleoside transporters and their distributions and functions in the brain. Curr. Top. Med. Chem. 11, 948–972. https://doi.org/10. 2174/156802611795347582. Pastor-Anglada, M., Pérez-Torras, S., 2018. Emerging roles of nucleoside transporters. Front. Pharmacol. 9, 606. https://doi.org/10.3389/fphar.2018.00606. Pawelczyk, T., Sakowicz, M., Szczepanska-Konkel, M., Angielski, S., 2000. Decreased expression of adenosine kinase in streptozotocin-induced diabetes mellitus rats. Arch. Biochem. Biophys. 375, 1–6. https://doi.org/10.1006/abbi.1999.1548. Pawelczyk, T., Podgorska, M., Sakowicz, M., 2003. The effect of insulin on expression level of nucleoside transporters in diabetic rats. Mol. Pharmacol. 63, 81–88. https:// doi.org/10.1124/MOL.63.1.81. Peleli, M., Fredholm, B., Sobrevia, L., Carlström, M., 2017. Pharmacological targeting of adenosine receptor signalling. Mol. Aspect. Med. 55, 4–8. https://doi.org/10.1016/j. mam.2016.12.002. Pereira, S.S., Alvarez-Leite, J.I., 2014. Low-grade inflammation, obesity, and diabetes. Curr. Obes. Rep. 3, 422–431. https://doi.org/10.1007/s13679-014-0124-9. Phillips, H.S., Kharbanda, S., Chen, R., Forrest, W.F., Soriano, R.H., Wu, T.D., Misra, A., Nigro, J.M., Colman, H., Soroceanu, L., Williams, P.M., Modrusan, Z., Feuerstein, B.G., Aldape, K., 2006. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157–173. https://doi.org/10.1016/j.ccr.2006.02.019. Podgorska, M., Kocbuch, K., Grden, M., Szulc, A., Szutowicz, A., Pawelczyk, T., 2007. Different signaling pathways utilized by insulin to regulate the expression of ENT2, CNT1, CNT2 nucleoside transporters in rat cardiac fibroblasts. Arch. Biochem. Biophys. 464, 344–349. https://doi.org/10.1016/j.abb.2007.04.025. Ranta, S., Kiviluoto, T., Newby, A.C., Ohisalo, J., 1985. Assay of adenosine in human adipose tissue. Acta Endocrinol (Copenh). 110, 429–432. Rutkiewicz, J., Górski, J., 1990. On the role of insulin in regulation of adenosine deaminase activity in rat tissues. FEBS Lett. 271, 79–80. Ryzhov, S., Novitskiy, S.V., Zaynagetdinov, R., Goldstein, A.E., Biaggioni, I., Carbone, D.P., Dikov, M.M., 2008. Adenosine A2B receptors in regulation of dendritic cell differentiation and function. Blood 112, 1822–1831. https://doi.org/10.1182/blood2008- 02-136325. Sáez, T., de Vos, P., Sobrevia, L., Faas, M.M., 2018. Is there a role for exosomes in foetoplacental endothelial dysfunction in gestational diabetes mellitus? Placenta 61, 48–54. https://doi.org/10.1016/j.placenta.2017.11.007. Sakowicz-Burkiewicz, M., Kocbuch, K., Grden, M., Szutowicz, A., Pawelczyk, T., 2010. Regulation of adenosine receptors expression in rat B lymphocytes by insulin. J. Cell. Biochem. 109, 396–405. https://doi.org/10.1002/jcb.22417. Salsoso, R., Guzmán-Gutiérrez, E., Sáez, T., Bugueño, K., Ramírez, M.A., Farías, M., Pardo, F., Leiva, A., Sanhueza, C., Mate, A., Vázquez, C., Sobrevia, L., 2015. Insulin restores l- arginine transport requiring adenosine receptors activation in umbilical vein endothelium from late-onset preeclampsia. Placenta 36, 287–296. https://doi.org/10. 1016/j.placenta.2014.12.007.

8

Molecular Aspects of Medicine xxx (xxxx) xxx–xxx

S. Alarcón, et al.

14737140.2017.1316197. Wiedmann, M., Brunborg, C., Lindemann, K., Johannesen, T.B., Vatten, L., Helseth, E., Zwart, J.A., 2013. Body mass index and the risk of meningioma, glioma and schwannoma in a large prospective cohort study (The HUNT Study). Br. J. Canc. 109, 289–294. https://dx.doi.org/10.1038%2Fbjc.2013.304. Wilkin, T.J., 2001. The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia 44, 914–922. https://doi.org/10.1007/ s001250100548. Wink, M.R., Lenz, G., Braganhol, E., Tamajusuku, A.S.K., Schwartsmann, G., Sarkis, J.J.F., Battastini, A.M.O., 2003. Altered extracellular ATP, ADP and AMP catabolism in glioma cell lines. Cancer Lett. 198, 211–218. https://doi.org/10.1016/S03043835(03)00308-2. World Health Organization (WHO), 2018. Obesity and Overweight. Fact Sheet 311. World Health Organization, Geneva, Switzerland. http://www.who.int/news-room/factsheets/detail/obesity-and-overweight. Würth, R., Pattarozzi, A., Gatti, M., Bajetto, A., Corsaro, A., Parodi, A., Sirito, R., Massollo, M., Marini, C., Zona, G., Fenoglio, D., Sambuceti, G., Filaci, G., Daga, A., Barbiere, F., Florio, T., 2013. Metformin selectively affects human glioblastoma tumor-initiating cell viability: a role for metformin-induced inhibition of Akt. Cell Cycle 12, 145–156. https://dx.doi.org/10.4161%2Fcc.23050. Xing, F., Luan, Y., Cai, J., Wu, S., Mai, J., Gu, J., Liang, J., 2017. The anti-warburg effect elicited by the cAMP-PGC1α pathway drives differentiation of glioblastoma cells into astrocytes. Cell Rep. 18, 468–481. https://doi.org/10.1016/j.celrep.2016.12.037. Xu, S., Shao, Q.Q., Sun, J.T., Yang, N., Xie, Q., Wang, D.H., Huang, B., Wang, X.Y., Li, X.G., Qu, X., 2013. Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro Oncol. 15, 1160–1172. https://doi.org/10.1093/neuonc/not067. Yang, L., Lin, C., Wang, L., Guo, H., Wang, X., 2012. Hypoxia and hypoxia-inducible factors in glioblastoma multiforme progression and therapeutic implications. Exp. Cell Res. 318, 2417–2426. https://doi.org/10.1016/j.yexcr.2012.07.017. Yeung, Y.T., Bryce, N.S., Adams, S., Braidy, N., Konayagi, M., McDonald, K.L., Munoz, L., 2012. p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells. J. Neuro Oncol. 109, 35–44. https:// doi.org/10.1007/s11060-012-0875-7. Yeung, Y.T., McDonald, K.L., Grewal, T., Munoz, L., 2013. Interleukins in glioblastoma pathophysiology: implications for therapy. Br. J. Pharmacol. 168, 591–606. https:// doi.org/10.1111/bph.12008. Yoon, C.H., Kim, M.J., Kim, R.K., Lim, E.J., Choi, K.S., An, S., Hwang, S.G., Kang, S.G., Suh, Y., Park, M.J., Lee, S.J., 2012. c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. Oncogene 31, 4655. https://doi.org/10.1007/s11060-012-0875-7. Young, A., Mittal, D., Stagg, J., Smyth, M.J., 2014. Targeting Cancer-Derived Adenosine: New Therapeutic Approaches. Yu, Z., Zhao, G., Xie, G., Zhao, L., Chen, Y., Yu, H., Zhang, Z., Li, C., Li, Y., 2015. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. Oncotarget 6, 32930–32943. https://doi.org/ 10.18632/oncotarget.5405. Zhao, L., Zheng, Z., Huang, P., 2016. Diabetes mellitus and the risk of glioma: a metaanalysis. Oncotarget 7, 4483–4489. https://doi.org/10.18632/oncotarget.6605. Zeke, A., Misheva, M., Reményi, A., Bogoyevitch, M.A., 2016. JNK Signaling: regulation and functions based on complex protein-protein partnerships. Microbiol. Mol. Biol. Rev. 80, 793–835. https://doi.org/10.1128/MMBR.00043-14. Ziv, E., Shafir, E., 1995. Psammomys obesus (sand rat): nutritionally induced NIDDM-like syndrome on a thrifty gene background. In: In: Shafir, E. (Ed.), Lessons from Animal Diabetes, vol 5. Smith-Gordon, London, pp. 285–300.

doi.org/10.1016/j.tcm.2010.12.002. Tchirkov, A., Khalil, T., Chautard, E., Mokhtari, K., Véronèse, L., Irthum, B., Vago, P., Kémény, J.L., Verrelle, P., 2007. Interleukin-6 gene amplification and shortened survival in glioblastoma patients. Br. J. Canc. 96, 474–476. https://doi.org/10.1038/ sj.bjc.6603586. Thompson, L.F., Takedachi, M., Ebisuno, Y., Tanaka, T., Miyasaka, M., Mills, J.H., Bynoe, M.S., 2008. Regulation of leukocyte migration across endothelial barriers by ecto-5′nucleotidase-generated adenosine. Nucleos Nucleot. Nucleic Acids 27, 755–760. https://doi.org/10.1080/15257770802145678. Torres, A., Vargas, Y., Uribe, D., Jaramillo, C., Gleisner, A., Salazar-Onfray, F., López, M.N., Melo, R., Oyarzún, C., San Martín, R., Quezada, C., 2016. Adenosine A3 receptor elicits chemoresistance mediated by multiple resistance-associated protein-1 in human glioblastoma stem-like cells. Oncotarget 7, 67373–67386. https://doi.org/ 10.18632/oncotarget.12033. Trestini, I., Carbognin, L., Bonaiuto, C., Tortora, G., Bria, E., 2018. The obesity paradox in cancer: clinical insights and perspectives. Eat. Weight Disord. 23, 185–193. https:// doi.org/10.1007/s40519-018-0489-y. Tsilidis, K.K., Kasimis, J.C., Lopez, D.S., Ntzani, E.E., Ioannidis, J.P., 2015. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350, g7607. https://doi.org/10.1136/bmj.g7607. Uribe, D., Torres, Á., Rocha, J.D., Niechi, I., Oyarzún, C., Sobrevia, L., San Martín, R., Quezada, C., 2017. Multidrug resistance in glioblastoma stem-like cells: role of the hypoxic microenvironment and adenosine signaling. Mol. Aspect. Med. 55, 140–151. https://doi.org/10.1016/j.mam.2017.01.009. Vaisitti, T., Arruga, F., Deaglio, S., 2018. Targeting the adenosinergic axis in chronic lymphocytic leukemia: a way to disrupt the tumor niche? Int. J. Mol. Sci. 19, 1167. https://doi.org/10.3390/ijms19041167. Vallon, V., Mühlbauer, B., Osswald, H., 2006. Adenosine and kidney function. Physiol. Rev. 86, 901–940. https://doi.org/10.1152/physrev.00031.2005. Van der Graaf, P.H., Van Schaick, E.A., Visser, S.A.G., De Greef, H.J.M.M., Ijzerman, A.P., Danhof, M., 1999. Mechanism-based pharmacokinetic-pharmacodynamic modeling of antilipolytic effects of adenosine A1 receptor agonists in rats: prediction of tissuedependent efficacy in vivo. J. Pharmacol. Exp. Therapeut. 290, 702–709. Van Hemelrijck, M., Garmo, H., Holmberg, L., Walldius, G., Jungner, I., Hammar, N., Lambe, M., 2011. Prostate cancer risk in the Swedish AMORIS study: the interplay among triglycerides, total cholesterol, and glucose. Cancer 117, 2086–2095. https:// doi.org/10.1002/cncr.25758. Vásquez, G., Sanhueza, F., Vásquez, R., González, M., San Martín, R., Casanello, P., Sobrevia, L., 2004. Role of adenosine transport in gestational diabetes-induced Larginine transport and nitric oxide synthesis in human umbilical vein endothelium. J. Physiol. 560, 111–122. https://doi.org/10.1113/jphysiol.2004.068288. Vaupel, P., Mayer, A., 2016. Hypoxia-driven adenosine accumulation: a crucial microenvironmental factor promoting tumor progression. Adv. Exp. Med. Biol. 876, 177–183. https://doi.org/10.1007/978-1-4939-3023-4_22. Verhaak, R.G.W., Hoadley, K.A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M.D., Miller, C.R., Ding, L., Golub, T., Mesirov, J.P., Alexe, G., Lawrence, M., O'Kelly, M., Tamayo, P., Weir, B.A., Stacey, Gabrie, Winckler, W., Gupta, S., Jakkula, L., Feiler, H.J., Hodgson, G., James, C.D., Sarkaria, J.N., Brennan, C., Kahn, A., Spellman, P.T., Wilson, R.K., Speed, T.P., Gray, J.W., Meyerson, M., Getz, G., Perou, C.M., Hayes, D.N., 2010. The cancer genome atlas research network. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell 17, 98–110. https://doi. org/10.1016/j.ccr.2009.12.020. Verma, S., Hussain, M.E., 2017. Obesity and diabetes: an update. Diabetes Metab. Syndr. 11, 73–79. https://doi.org/10.1016/j.dsx.2016.06.017. Vindeirinho, J., Costa, G.N., Correia, M.B., Cavadas, C., Santos, P.F., 2013. Effect of diabetes/hyperglycemia on the rat retinal adenosinergic system. PLoS One 8, e67499. https://doi.org/10.1371/journal.pone.0067499. Villalobos-Labra, R., Sáez, P.J., Subiabre, M., Silva, L., Toledo, F., Westermeier, F., Pardo, F., Farías, M., Sobrevia, L., 2018. Pre-pregnancy maternal obesity associates with endoplasmic reticulum stress in human umbilical vein endothelium. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 3195–3210. https://doi.org/10.1016/j.bbadis. 2018.07.007. Warburg, O., 1956. On respiratory impairment in cancer cells. Science 124, 269–270. Weiss, R., Dziura, J., Burgert, T.S., Tamborlane, W.V., Taksali, S.E., Yeckel, C.W., Allen, K., Lopes, M., Savoye, M., Morrison, J., Sherwin, R.S., Caprio, S., 2004. Obesity and the metabolic syndrome in children and adolescents. N. Engl. J. Med. 350, 2362–2374. https://doi.org/10.1056/NEJMoa031049. Welch, M.R., Grommes, C., 2013. Retrospective analysis of the effects of steroid therapy and antidiabetic medication on survival in diabetic glioblastoma patients. CNS Oncol. 2, 237–246. https://doi.org/10.2217/cns.13.12. Westermeier, F., Salomón, C., González, M., Puebla, C., Guzmán-Gutiérrez, E., Cifuentes, F., Leiva, A., Casanello, P., Sobrevia, L., 2011. Insulin restores gestational diabetes mellitus- reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium. Diabetes 60, 1677–1687. https://doi.org/10.2337/db11-0155. Westermeier, F., Saez, T., Arroyo, P., Toledo, F., Gutierrez, J., Sanhueza, C., Pardo, F., Leiva, A., Sobrevia, L., 2016. Insulin receptor isoforms: an integrated view focused on gestational diabetes mellitus. Diabetes Metab. Res. Rev. 32, 350–365. https://doi. org/10.1002/dmrr.2729. Westley, R.L., May, F.E.B., 2013. A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. Internet J. Endocrinol. 2013, 632461. https://doi.org/10.1155/2013/632461. Whiteside, T.L., 2017. Targeting adenosine in cancer immunotherapy: a review of recent progress. Expert Rev. Anticancer Ther. 17, 527–535. https://doi.org/10.1080/

Sebastian Alarcon is a biochemist and holds a PhD in science mention of cellular and molecular biology of the Universidad Austral de Chile. His primary research line is related to the study of nucleoside transporters in glioblastoma. Likewise, their interest has focused on determining how the metabolism of adenosine nucleosides works in different glioblastoma stem-like cells population. Ignacio Niechi is an engineer in molecular biotechnology holding a PhD in Biochemistry from the University of Chile. His research line regards with cancer progression, chemoresistance and cell invasion. His projects relate to glioblastoma recurrence through adenosine signalling. Fernando Toledo is a mathematician dedicated to statistics analysis and modelling of biological phenomena. Luis Sobrevia is a BSc in biological sciences holding a MSc in Physiological Sciences from the Universidad de Concepción (Chile) and a PhD in Physiology and Medical Sciences and postdoctoral training in vascular physiology from the King's College London from University of London (UK). His research line regards with human vascular endothelial dysfunction in diseases of pregnancy involving cell signalling through adenosine receptors and insulin receptors, and the role of membrane transport systems in this phenomenon. Claudia Quezada is a biochemist from the Universidad Austral de Chile and holds a PhD in Molecular Biosciences from Universidad Andrés Bello, Chile. Her primary research line is related to the study of multiple drug resistance in glioblastoma. Likewise, their interest has been focused on determining the role of the glioblastoma stem-like cells within a tumour, since they would represent the main therapeutic target.

9