• Liver metastasis
• Nomogram model:Risk prediction:BMI (body mass index)
• Non-functional gastroenteropancreatic neuroendocrine neoplasms

• biomarker
• chemotherapy
• head and neck cancer
• proteomics
• radiotherapy

• Humans
• Biomarkers, Tumor/blood
• Head and Neck Neoplasms/therapy
• Head and Neck Neoplasms/blood
• Head and Neck Neoplasms/metabolism
• Proteomics/methods
• Male
• Female
• Middle Aged
• Aged
• Adult
• Chemoradiotherapy
• Treatment Outcome
• Proteome/metabolism

• TC project ETH/6023 International Atomic Energy Agency

• Choroid
• Epidemiology
• Neoplasia
• Pathology

• Humans
• Melanoma/pathology
• Leptin
• Body Mass Index
• Obesity Paradox
• Receptors, Leptin/genetics
• Tumor Suppressor Proteins
• Uveal Neoplasms/pathology
• Prognosis
• Obesity/complications
• RNA

• The Swedish Cancer Society
• Region Stockholm
• The Swedish Eye Foundation

• pancreatic cancer
• survival
• obesity
• adiponectin
• leptin

• Male
• Humans
• Female
• Leptin/genetics
• Adiponectin/genetics
• Adipokines
• Receptors, Adiponectin/genetics
• Pancreatic Neoplasms/genetics
• Polymorphism, Single Nucleotide
• Receptors, Leptin/genetics

• P01 CA087969 NCI NIH HHS
• HHSN268201600018C NHLBI NIH HHS
• R01 HL034595 NHLBI NIH HHS
• HHSN268201600003C NHLBI NIH HHS
• UM1 CA186107 NCI NIH HHS
• R01 HL026490 NHLBI NIH HHS
• R01 HL080467 NHLBI NIH HHS
• R01 CA097193 NCI NIH HHS
• R01 CA034944 NCI NIH HHS
• U01 CA210171 NCI NIH HHS
• HHSN268201600002C NHLBI NIH HHS
• K07 CA222159 NCI NIH HHS
• R01 HL043851 NHLBI NIH HHS
• HHSN268201600004C NHLBI NIH HHS
• UM1 CA182913 NCI NIH HHS
• R01 CA047988 NCI NIH HHS
• HHSN268201600001C NHLBI NIH HHS
• R01 CA049449 NCI NIH HHS
• R01 CA040360 NCI NIH HHS
• P50 CA127003 NCI NIH HHS
• RC1 HL099355 NHLBI NIH HHS

• adiponectin
• leptin
• leptin–adiponectin ratio
• pancreatic neuroendocrine neoplasm

• number PCN-2-072/N/2/K Medical University of Silesia

• adipocyte dysfunction
• adipokines
• fat loss
• pancreatic cancer
• trans-differentiation
• tumor microenvironment

• Humans
• Adipocytes/metabolism
• Adipose Tissue/metabolism
• Pancreatic Neoplasms/pathology
• Adipokines
• Lipids
• Tumor Microenvironment

• National Natural Science Foundation of China
• Jiangsu Provincial Key Research and Development Program
• Natural Science Foundation of Jiangsu Province

• Drug delivery
• Gold nanoparticles
• Nanomedicine
• Obesity
• Tumor microenvironment

Obesity is recognized as a chronic progressive disease and risk factor for many human diseases. The high and increasing number of obese people may underlie the expected increase in pancreatic cancer cases in the United States. There are several pathways discussed that link obesity with pancreatic cancer. Adipose tissue and adipose tissue-released factors may thereby play an important role. This review discusses selected mechanisms that may accelerate pancreatic cancer development in obesity.

The prevalence of obesity in adults and children has dramatically increased over the past decades. Obesity has been declared a chronic progressive disease and is a risk factor for a number of metabolic, inflammatory, and neoplastic diseases. There is clear epidemiologic and preclinical evidence that obesity is a risk factor for pancreatic cancer. Among various potential mechanisms linking obesity with pancreatic cancer, the adipose tissue and obesity-associated adipose tissue inflammation play a central role. The current review discusses selected topics and mechanisms that attracted recent interest and that may underlie the promoting effects of obesity in pancreatic cancer. These topics include the impact of obesity on KRAS activity, the role of visceral adipose tissue, intrapancreatic fat, adipose tissue inflammation, and adipokines on pancreatic cancer development. Current research on lipocalin-2, fibroblast growth factor 21, and Wnt5a is discussed. Furthermore, the significance of obesity-associated insulin resistance with hyperinsulinemia and obesity-induced gut dysbiosis with metabolic endotoxemia is reviewed. Given the central role that is occupied by the adipose tissue in obesity-promoted pancreatic cancer development, preventive and interceptive strategies should be aimed at attenuating obesity-associated adipose tissue inflammation and/or at targeting specific molecules that mechanistically link adipose tissue with pancreatic cancer in obese patients.

• adipokine
• adipose tissue
• gut microbiome
• inflammation
• intrapancreatic fat
• obesity
• pancreatic cancer

Although comprising a much smaller proportion of the human microbiome, the fungal community has gained much more attention lately due to its multiple and yet undiscovered interactions with the human bacteriome and the host. Head and neck cancer carcinoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma have been associated with dissimilarities in the composition of the mycobiome between cases with cancer and non-cancer subjects. In particular, an abundance of Malassezia has been associated with the onset and progression of colorectal carcinoma and pancreatic adenocarcinoma, while the genera Schizophyllum, a member of the oral mycobiome, is suggested to exhibit anti-cancer potential. The use of multi-omics will further assist in establishing whether alterations in the human mycobiome are causal or a consequence of specific types of cancers.

Background: To date, most researchhas focused on the bacterial composition of the human microbiota. In this review, we synopsize recent data on the human mycobiome and cancer, highlighting specific cancer types based on current available evidence, presenting interesting perspectives and limitations of studies and laboratory methodologies. Recent findings: Head and neck cancer carcinoma (HNCC), colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDA) have been associated with dissimilarities in the composition of mycobiota between cancer cases and non-cancer participants. Overall, fungal dysbiosis with decreased fungal richness and diversity was common in cancer patients; however, a specific mycobiotic signature in HNSCC or CRC has not emerged. Different strains of Candida albicans have been identified among cases with HNCC, whilst Lichtheimia corymbifera, a member of the Mucoraceae family, has been shown to predominate among patients with oral tongue cancer. Virulence factors of Candida spp. include the formation of biofilm and filamentation, and the secretion of toxins and metabolites. CRC patients present a dysregulated ratio of Basidiomycota/Ascomycota. Abundance of Malassezia has been linked to the occurrence and progression of CRC and PDA, particularly in animal models of PDA. Interestingly, Schizophyllum, a component of the oral mycobiome, may exhibit anti-cancer potential. Conclusion: The human mycobiome, per se, along with its interactions with the human bacteriome and the host, may be implicated in the promotion and progression of carcinogenesis. Fungi may be used as diagnostic and prognostic/predictive tools or treatment targets for cancer in the coming years. More large-scale, prospective, multicentric and longitudinal studies with an integrative multi-omics methodology are required to examine the precise contribution of the mycobiome in the etiopathogenesis of cancer, and to delineate whether changes that occur in the mycobiome are causal or consequent of cancer.

• cancer
• colorectal cancer
• fungi
• head and neck cancer
• microbiome
• mycobiome
• pancreatic cancer

• cancer
• immune system
• immunotherapy
• inflammation
• leptin
• obesity

• Adaptive Immunity
• Animals
• Humans
• Immunotherapy
• Leptin/immunology
• Neoplasm Proteins/immunology
• Neoplasms/immunology
• Neoplasms/therapy
• Obesity/immunology

Opium addiction is a serious public health concern in the Middle East countries causing various illnesses. Opium use is associated with an increased risk of several cancers; however, the underlying mechanisms are not yet fully elucidated. Altered levels of adiponectin and its related main receptors, Adiponectin receptor 1 and 2 (AdipoR1 and AdipoR2) have been associated with several malignancies. Opium users are at risk of various cancers. All together let us to the hypothesis that probable overexpression of AdipoRs in opium users might be linked to the occurrence of cancer in this population.

One hundred opium users along with 100 healthy non-opium users were enrolled in the study. Opium users were followed up for 5 years (2014–2019) to evaluate the occurrence of malignancies. AdipoR1 and AdipoR2 expressions were measured using a flow cytometry method.

Expression of AdipoR1 and AdipoR2 was significantly higher in opium users compared with the healthy control group (P=0.0001 and 0.0001, respectively). Eight opium users developed cancer during the follow-up period. Subjects abusing opium developed cancer by 8.6 folds comparing to non-opium users (P=0.034; OR=8.6; 95% CI (1.06–70.1)). Expression of these two receptors was significantly higher in opium users developing cancer compared with cancer-free opium (P=0.001).

Considering the significant overexpression of AdipoR1 and AdipoR2 in opium users and in opium users who developed malignancies and the association between upregulation of these receptors in most cancers affecting opium users and assessment of AdipoRs may serve as an early detection tool of cancer in this population.

• addiction
• adiponectin
• adiponectin receptors
• cancer
• opium

• TAA
• biomarkers
• chemotherapy
• computational analysis
• immune complexes
• pancreatic cancer
• proteomics

• 15257 Associazione Italiana per la Ricerca sul Cancro
• RF-2013-02354892 Ministero della Salute
• R01GM088342 NIH HHS

Pancreatic ductal adenocarcinoma (PDAC) is expected to soon become the second leading cause of cancer related deaths in the United States. This may be due to the rising obesity prevalence, which is a recognized risk factor for PDAC. There is great interest in deciphering the underlying driving mechanisms of the obesity–PDAC link. Visceral adiposity has a strong correlation to certain metabolic diseases and gastrointestinal cancers, including PDAC. In fact, our own data strongly suggest that visceral adipose tissue inflammation is a strong promoter for PDAC growth and progression in a genetically engineered mouse model of PDAC and diet-induced obesity. In this review, we will discuss the relationship between obesity-associated adipose tissue inflammation and PDAC development, with a focus on the key molecular and cellular components in the dysfunctional visceral adipose tissue, which provides a tumor permissive environment.

• adipose tissue inflammation
• obesity
• pancreatic ductal adenocarcinoma

• Adipokine
• Adiponectin
• Biomarker
• Cancer
• Inflammation
• Microbiome
• Obesity
• Resistin
• Visfatin

• Female
• Humans
• Male
• Neoplasms/complications
• Neoplasms/epidemiology
• Obesity/complications
• Obesity/epidemiology
• Risk
• Sex Characteristics

• Bisphenol
• Cancer
• Endocrine disrupting chemical
• Head and neck cancer
• Oral cancer
• Oropharyngeal cancer

• Benzhydryl Compounds/adverse effects
• Carcinogenesis
• Endocrine Disruptors/adverse effects
• Humans
• Incidence
• Mouth Neoplasms/chemically induced
• Mouth Neoplasms/epidemiology
• Oropharyngeal Neoplasms/chemically induced
• Oropharyngeal Neoplasms/epidemiology
• Phenols/adverse effects

Adipokines are emerging as a link between obesity and obesity-related cancers, including pancreatic cancer. Adiponectin is an abundant adipokine with pleiotropic beneficial roles in metabolic disorders. Low adiponectin levels are commonly observed in human obesity and have been associated with increased pancreatic cancer risk in prospective epidemiologic studies. Here, we investigated the direct effect of adiponectin on human pancreatic cancer in vitro and in vivo. Our results showed that adiponectin treatment significantly inhibited the proliferation of human pancreatic cancer cells. Knockdown of adiponectin receptors completely eliminated the antiproliferation effect of adiponectin and markedly promoted the growth of human pancreatic cancer xenografts in nude mice. Further analysis revealed that adiponectin blocked the phosphorylation/inactivation of GSK-3β, suppressed the intracellular accumulation of β-catenin, reduced the expression of cyclin D1, and consequently caused cell cycle accumulation at the G₀-G₁ phase in pancreatic cancer cells. Adiponectin-mediated attenuation of cell proliferation was abrogated by the GSK-3β inhibitor. In addition, a microarray analysis revealed that adiponectin also downregulated the expression of TCF7L2, a coactivator of β-catenin, at the transcriptional level in pancreatic cancer cells. These results indicated that the protective role of adiponectin against human pancreatic cancer might be attributed to its attenuating effect on the β-catenin signaling pathway. Taken together, our findings support a causal link between hypoadiponectinemia and increased pancreatic cancer risk, and suggest that activating adiponectin signaling could be a novel therapeutic strategy for obesity-related pancreatic cancer.

• GSK-3β
• adiponectin
• cell proliferation
• pancreatic cancer
• β-catenin

• Adipocytokine
• Adipokine
• Adiponectin
• Apelin
• Cancer
• Chemerin
• Leptin
• Nesfatin
• Nicotinamide phosphoribosyl transferase
• Obesity
• Omentin
• Oncostatin
• Osteopontin
• Resistin
• Retinol-binding protein 4
• Vaspin
• Visfatin

• Adipokines/analysis
• Adipokines/physiology
• Female
• Humans
• Male
• Neoplasms/diagnosis
• Neoplasms/metabolism
• Neoplasms/physiopathology
• Obesity/metabolism
• Obesity/physiopathology

The association between lower circulating adiponectin (APN) levels and the development of pancreatic cancer has been reported. However, the effect of APN on the growth and survival of pancreatic cancer cells remains elusive. Here, we investigate the effects of the anti-diabetic APN receptor (AdipoR) agonist AdipoRon and APN on human pancreatic cancer cells. We found that AdipoRon, but not APN, induces MIAPaCa-2 cell death, mainly through necroptosis. Mechanistically, although both AdipoRon and APN activate AMPK and p38 MAPK in an AdipoR-dependent manner that elicits survival signals, only AdipoRon induces rapid mitochondrial dysfunction through mitochondrial Ca²⁺ overload, followed by superoxide production via RIPK1 and ERK1/2 activation. Oral administration of AdipoRon suppresses MIAPaCa-2 tumour growth without severe adverse effects and kills cancer cells isolated from patients with pancreatic cancer. Thus, AdipoRon could be a therapeutic agent against pancreatic cancer as well as diabetes.

• Adipokines
• adiponectin
• esophageal cancer
• head and neck cancer
• leptin
• oral squamous cell carcinoma
• salivary gland tumors
• thyroid cancer.

• AdipoR1
• AdipoR2
• Adiponectin
• T-cadherin
• cancer
• obesity

• Adiponectin
• Cancer
• Cardiovascular disease
• Inflammation
• Insulin resistance
• Malignancies
• Obesity

• Adiponectin
• Humans
• Inflammation
• Insulin Resistance
• Neoplasms
• Obesity

Advanced glycation end products (AGEs) dysregulate adipokines and induce inflammation by binding to their adipocyte receptor (RAGE). Soluble RAGE (sRAGE) prevents AGEs/RAGE signaling. We performed a nested case–control study of the association between sRAGE, adipokines, and incident pancreatic cancer risk in the prospective Women's Health Initiative Study. We individually matched controls (n = 802) to cases (n = 472) on age, race, and blood draw date. We evaluated serum concentrations of sRAGE, adiponectin, leptin, monocyte chemotactic protein 1 (MCP1), and plasminogen activator inhibitor‐1 (PAI1) using immunoassay. We used conditional logistic regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for pancreatic cancer over biomarker quartiles (Q1–Q4). We used principal component analysis to create two composite biomarkers and performed a confirmatory factor analysis to examine the association between composite biomarker scores (CBS) and pancreatic cancer risk. Baseline serum sRAGE concentrations were inversely associated with pancreatic cancer risk (aOR_{Q4 vs. Q1} = 0.70, 95% CI: 0.50–0.99). High MCP1 (aOR _{Q4 vs. Q1} = 2.55, 95% CI: 1.41–4.61) and the higher CBS including MCP1, PAI1, and leptin (aOR_{Q4 vs. Q1} = 1.82, 95% CI = 1.04–3.18) were also associated with increased pancreatic cancer risk among women with BMI <25 kg/m² (P values for interaction <0.05). We found an inverse association between prediagnostic sRAGE concentrations and risk of incident pancreatic cancer in postmenopausal women. A proinflammatory CBS was associated with increased risk only in women with normal BMI. MCP1 was not modulated by sRAGE.

• Biomarker
• CCL2
• body weight
• composite biomarker
• pancreatic cancer
• prospective
• sRAGE

Early detection of cancers is challenging for lack of specific biomarkers. Adiponectin is an adipokine predominantly derived from adipocytes and hypoadiponectinemia has been reported to associate with risk of many types of cancers. However, available evidence is controversial. Some studies show that increased adiponectin levels correlate with cancer risk. Therefore, we performed a meta-analysis of the association between circulating adiponectin levels and cancer development. A systematic search of PubMed, EMBASE, Wiley Online Library and Cochrane Library was conducted for eligible studies involving circulating adiponectin and malignancies from inception to August 8, 2015. Standard mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated by use of a random-effect model. Funnel plot and Egger's linear regression test were conducted to examine the risk of publication bias. 107 studies were included with 19,319 cases and 25,675 controls. The pooled analysis indicated that circulating adiponectin levels were lower in patients with various cancers than in controls, with a pooled SMD of −0.334 μg/ml (95% CI, −0.465 to −0.203, P = 0.000). No evidence of publication bias was observed. Circulating high molecular weight adiponectin levels were also lower in cancer patients than in controls, with a pooled SMD of −0.502 μg/ml (95% CI, −0.957 to −0.047, P = 0.000). This meta-analysis provides further evidence that decreased adiponectin levels is associated with risk of various cancers. Hypoadiponectinemia may represent a useful biomarker for early detection of cancers.

• adiponectin
• biomarker
• diagnosis
• malignancy
• meta-analysis

• NSCLC
• adiponectin
• bronchoalveolar lavage
• serum

Obesity is a significant risk factor for pancreatic cancer, harboring a chronic inflammatory condition characterized by dysregulation of the adipokines, leptin and adiponectin, that in turn alter oncogenic signaling pathways. We and others have shown that leptin promotes the proliferation and an invasive potential of pancreatic cancer cells through STAT3 mediated signaling. However, the role of adiponectin on the tumorigenicity of pancreatic cancer has not been elucidated. Adiponectin represents an important negative regulator of cytokines, which acts through two receptors, ADIPOR1 and ADIPOR2, to elicit pro-apoptotic, anti-inflammatory, and anti-angiogenic responses. We show that the level and expression of both adiponectin receptors are decreased in pancreatic tumors relative to normal pancreatic tissue. In vitro stimulation with adiponectin or a small molecule adiponectin receptor agonist, AdipoRon, increases apoptosis while inhibiting pancreatic cancer cell proliferation, colony formation, and anchorage independent growth. In addition, adiponectin receptor agonism inhibits leptin mediated STAT3 activation. In vivo, treatment of mice with AdipoRon inhibits orthotopic pancreatic tumor growth. These results demonstrate that adiponectin receptor activation is a key regulator of pancreatic cancer growth and AdipoRon provides a rational agent for the development of novel therapeutic strategies for pancreatic cancer.

• AdipoRon
• STAT3
• adipokine
• adiponectin
• pancreatic adenocarcinoma

• AMP-Activated Protein Kinases/genetics
• Apoptosis/genetics
• Carcinogenesis/genetics
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Gene Expression Regulation, Neoplastic
• Glioblastoma/genetics
• Glioblastoma/pathology
• Humans
• MicroRNAs/genetics
• Neoplasm Invasiveness/genetics
• Neoplasm Invasiveness/pathology
• Receptors, Adiponectin/genetics
• Signal Transduction
• Sirtuin 1/genetics

Growing evidence has raised the important roles of adipocytes as an active player in the tumor microenvironment. In many tumors adipocytes are in close contact with cancer cells. They secrete various factors that can mediate local and systemic effects. The adipocyte-cancer cell crosstalk leads to phenotypical and functional changes of both cell types, which can further enhance tumor progression. Moreover, obesity, which is associated with an increase in adipose mass and an alteration of adipose tissue, has been established as a risk factor for cancer incidence and cancer-related mortality. In this review, we summarize the mechanisms of the adipocyte-cancer cell crosstalk in both obese and lean conditions as well as its impact on cancer cell growth, local invasion, metastatic spread and resistance to treatments. Better characterization of cancer-associated adipocytes and the key molecular events in the adipocyte-cancer cell crosstalk will provide insights into tumor biology and suggest efficient therapeutic opportunities.

• adipocytes
• adipose tissue
• cancer progression
• invasion
• resistance

Adiponectin receptor-1 (AdipoR1) has been reported to be associated with the risk of obesity-associated malignancies, including epithelial ovarian cancer (EOC). The aim of this study was to determine if AdipoR1 could serve as a prognosis indicator for patients with EOC.

In this study, expression of AdipoR1 in 73 EOC patients consecutively admitted to our hospital was detected by immunohistochemical staining. Univariate and multivariate analyses were performed to assess the relationship between AdipoR1 expression level and progression-free survival (PFS) and overall survival (OS) rates in patients.

A relatively lower expression of AdipoR1 in the cancerous tissues was detected compared to normal ovarian tissues, but the difference was not significant (p>0.05). AdipoR1 expression level in EOC patients was negatively correlated with advanced FIGO stages in patients and tumor differentiation, but had no correlation with pathological types, presenting of ascites, shorter platinum-free interval (PFI), diabetes, preoperative and postoperative body mass index (BMI), or platelet counts (p>0.05). Moreover, patients with AdipoR1 expression had a significantly longer PFS and OS compared to the negative expression group (p<0.001).

Our findings suggest that AdipoR1 expression level in cancerous tissues might serve as an independent prognostic indicator in EOC patients and is associated with longer PFS and OS.

• Diabetes mellitus
• Glucose-dependent insulinotropic peptide
• Pancreatic ductal adenocarcinoma
• Pancreatic polypeptide

• Adiponectin
• cancer
• therapeutic target

• Adipokines
• Advanced cancer
• Cancer cachexia
• Cytokines
• Inflammation
• Pancreatic cancer

Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients’ survival.

We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I.

CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients’ cohort.

We herein provide novel evidence regarding the possible interactions between the components of AGE-RAGE axis, GLO-I and adiponectin receptors in CRC. AGE and AdipoR1 are possibly involved in colorectal carcinogenesis, whereas AdipoR2 and GLO-I emerged as novel independent prognostic biomarkers of adverse significance for patients with early disease stage. Further studies are warranted to extend our observations and investigate their potential therapeutic significance.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.

• Insulin
• Pancreatic cancer
• Adipose tissue
• Metformin
• Nuclear receptor
• Leptin
• Adiponectin
• Inflammation
• Thiazolidinediones

• Animals
• Anti-Obesity Agents/therapeutic use
• Antineoplastic Agents/therapeutic use
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/epidemiology
• Carcinoma, Pancreatic Ductal/metabolism
• Diabetes Mellitus/drug therapy
• Diabetes Mellitus/epidemiology
• Diabetes Mellitus/metabolism
• Humans
• Hypoglycemic Agents/therapeutic use
• Obesity/drug therapy
• Obesity/epidemiology
• Obesity/metabolism
• PPAR gamma/agonists
• PPAR gamma/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/epidemiology
• Pancreatic Neoplasms/metabolism
• Risk Factors
• Signal Transduction/drug effects

• Hyperinsulinemia
• Pancreatic neoplasms
• Prognosis
• Type 2 diabetes mellitus

• Chronic pancreatitis
• Cytokines
• Inflammation
• Pancreatic adenocarcinoma

Elevated levels of serum leptin are associated with increased adiposity and production of pro-inflammatory cytokines. Both cytokines and body adiposity have been shown to predict cardiovascular events and mortality. The primary objective of the present study is to explore the associations between serum leptin and all-cause mortality and mortality from cardiovascular disease (CVD) over a span of 10 years, controlling for body adiposity and proinflammatory cytokines.

The Health, Aging and Body Composition (Health ABC) study is a prospective cohort of 3,075 older adults aged 70 to 79 years. This analysis includes 2,919 men and women with complete serum leptin and vital status data. Data on all-cause mortality and incident cardiovascular events (including Coronary Heart Disease and Congestive Heart Failure) were collected over 10 years of follow-up (mean 8.4 years).

Women with leptin in quartile 2 and 3 were at lower risk of all-cause mortality, and those with leptin in quartile 2 were at lower risk of mortality from CVD as compared to women with lowest leptin values when adjusted for age, race, site, years of education, alcohol use, smoking, and physical activity. When these associations were additionally adjusted for body fat, C-reactive protein and pro-inflammatory cytokines, women with leptin values in quartile 3 were at lower risk of all-cause mortality and women with leptin in quartile 2 and 3 were at lower risk of mortality from CVD than women with lowest leptin values. These associations were not significant among men after adjusting for body fat and cytokines.

The present study suggests that moderately elevated concentrations of serum leptin are independently associated with lower risk of all-cause mortality and CVD-related mortality among older women. Among men, serum leptin is not associated with reduced risk of all-cause and CVD mortality after controlling for body fat and cytokines.

• adiposity
• insulin resistance
• leptin
• pancreatic cancer

• Aged
• Biomarkers, Tumor/blood
• Case-Control Studies
• Cohort Studies
• Early Detection of Cancer
• Female
• Follow-Up Studies
• Humans
• Incidence
• Insulin Resistance
• Leptin/blood
• Logistic Models
• Male
• Middle Aged
• Odds Ratio
• Pancreatic Neoplasms/blood
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/epidemiology
• Risk Assessment
• Risk Factors
• United States/epidemiology

• N01-RC-45035 CCR NIH HHS
• HHSN261201000006C NCI NIH HHS
• Intramural NIH HHS
• HHSN261201000006C NCI NIH HHS
• N01RC37004 CCR NIH HHS
• N01 CN045165 NCI NIH HHS

Studies have come to conflicting conclusions about whether polymorphisms in the adiponectin receptor 1 gene (ADIPOR1) are associated with cancer risk. To help resolve this question, we meta-analyzed case-control studies in the literature.

PubMed, EMBASE, Cochrane Library, the Chinese Biological Medical Database and the Chinese National Knowledge Infrastructure Database were systematically searched to identify all case-control studies published through February 2015 examining any ADIPOR1 polymorphisms and risk of any type of cancer. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated.

A total of 13 case-control studies involving 5,750 cases and 6,762 controls were analyzed. Analysis of the entire study population revealed a significant association between rs1342387(G/A) and overall cancer risk using a homozygous model (OR 0.82, 95%CI 0.72 to 0.94), heterozygous model (OR 0.84, 95%CI 0.76 to 0.93), dominant model (OR 0.85, 95%CI 0.75 to 0.97) and allele contrast model (OR 0.88, 95%CI 0.80 to 0.97). However, subgroup analysis showed that this association was significant only for Asians in the case of colorectal cancer. No significant associations were found between rs12733285(C/T) or rs7539542(C/G) and cancer risk, either in analyses of the entire study population or in analyses of subgroups.

Our meta-analysis suggests that the ADIPOR1 rs1342387(G/A) polymorphism, but not rs12733285(C/T) or rs7539542(C/G), may be associated with cancer risk, especially risk of colorectal cancer in Asians. Large, well-designed studies are needed to verify our findings.

Adiponectin is an adipocyte-secreted adipokine with pleiotropic actions. Clinical evidence has shown that serum adiponectin levels are increased and that adiponectin can protect pancreatic beta cells against apoptosis, which suggests that adiponectin may play an anti-apoptotic role in pancreatic cancer (PC). Here, we investigated the effects of adiponectin on PC development and elucidated the underlying molecular mechanisms. Adiponectin deficiency markedly attenuated pancreatic tumorigenesis in vivo. We found that adiponectin significantly inhibited the apoptosis of both human and mouse pancreatic cancer cells via adipoR1, but not adipoR2. Furthermore, adiponectin can increase AMP-activated protein kinase (AMPK) phosphorylation and NAD-dependent deacetylase sirtuin-1 (Sirt1) of PC cells. Knockdown of AMPK or Sirt1 can increase the apoptosis in PC cells. AMPK up-regulated Sirt1, and Sirt1 can inversely phosphorylate AMPK. Further studies have shown that Sirt1 can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which can increase the expression levels of mitochondrial genes. Thus, adiponectin exerts potent anti-apoptotic effects on PC cells via the activation of AMPK/Sirt1/PGC1α signaling. Finally, adiponectin can elevate β-catenin levels. Taken together, these novel findings reveal an unconventional role of adiponectin in promoting pancreatic cancers, and suggest that the effects of adiponectin on tumorigenesis are highly tissue-dependent.