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Khan E, Chakrabarty S, Shariff S, Bardhan M. Genetics and Genomics of Chronic Pancreatitis with a Focus on Disease Biology and Molecular Pathogenesis. Glob Med Genet 2023; 10:324-334. [PMID: 38025192 PMCID: PMC10665123 DOI: 10.1055/s-0043-1776981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023] Open
Abstract
Chronic pancreatitis is a long-term fibroinflammatory condition of the pancreas with varying incidences across countries. The recent increase in its occurrence implies the involvement of genetic, hereditary, and unconventional risk factors. However, there is a lack of updated literature on recent advances in genetic polymorphisms of chronic pancreatitis. Therefore, this review aims to present recent findings on the genetic implications of chronic pancreatitis based on individual gene mechanisms and to discuss epigenetics and epistasis involved in the disease. Four mechanisms have been implicated in the pathogenesis of chronic pancreatitis, including premature activation of proteases, endoplasmic reticulum stress, ductal pathway dysfunction, and inflammatory pathway dysfunction. These mechanisms involve genes such as PRSS1, PRSS2, SPINK, CEL, PNLIP, PNLIPRP2, CFTR, CaSR, CLDN2, Alpha 1 antitrypsin, and GGT1 . Studying genetic polymorphisms on the basis of altered genes and their products may aid clinicians in identifying predispositions in patients with and without common risk factors. Further research may also identify associations between genetic predispositions and disease staging or prognosis, leading to personalized treatment protocols and precision medicine.
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Affiliation(s)
- Erum Khan
- Department of Neurology, Alzheimer's Disease Research Center, The university of Alabama at Birmingham, Birmingham, United States
| | - Soura Chakrabarty
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | | | - Mainak Bardhan
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida, United States
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2
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Li Y, Zhang J, Xu J, Liu S. The Metabolism Symbiosis Between Pancreatic Cancer and Tumor Microenvironment. Front Oncol 2021; 11:759376. [PMID: 34976805 PMCID: PMC8716377 DOI: 10.3389/fonc.2021.759376] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/30/2021] [Indexed: 12/23/2022] Open
Abstract
Complex interactions occur between tumor cells and the tumor microenvironment. Studies have focused on the mechanism of metabolic symbiosis between tumors and the tumor microenvironment. During tumor development, the metabolic pattern undergoes significant changes, and the optimal metabolic mode of the tumor is selected on the basis of its individual environment. Tumor cells can adapt to a specific microenvironment through metabolic adjustment to achieve compatibility. In this study, the effects of tumor glucose metabolism, lipid metabolism, and amino acid metabolism on the tumor microenvironment and related mechanisms were reviewed. Selective targeting of tumor cell metabolic reprogramming is an attractive direction for tumor therapy. Understanding the mechanism of tumor metabolic adaptation and determining the metabolism symbiosis mechanism between tumor cells and the surrounding microenvironment may provide a new approach for treatment, which is of great significance for accelerating the development of targeted tumor metabolic drugs and administering individualized tumor metabolic therapy.
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Affiliation(s)
- Ying Li
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ju Zhang
- Department of Operating Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jie Xu
- Department of Nursing, Zaozhuang Second Health School, Zaozhuang, China
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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Han J, Shen L, Zhan Z, Liu Y, Zhang C, Guo R, Luo Y, Xie Z, Feng Y, Wu G. The long noncoding RNA MALAT1 modulates adipose loss in cancer-associated cachexia by suppressing adipogenesis through PPAR-γ. Nutr Metab (Lond) 2021; 18:27. [PMID: 33691715 PMCID: PMC7944636 DOI: 10.1186/s12986-021-00557-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/01/2021] [Indexed: 12/20/2022] Open
Abstract
Background Cancer-associated cachexia is a multifactorial syndrome defined by progressive weight loss with ongoing loss of adipose tissue and skeletal muscle. Adipose loss occurs in the early stage of cachexia and is associated with reduced quality of life and survival time. Although numerous lncRNAs are regarded as novel regulators in adipose metabolism, the role of lncRNAs that selectively modulate the development of adipose loss in cachexia remains limited. Methods In this study, we analyzed microarray data of lncRNAs in adipose loss and further explored the function and mechanism of MALAT1 in adipose loss. First, we explored the expression and function of MALAT1 in adipose cell by quantitative PCR and RNA knockdown. Subsequently, the mechanism of MALAT1 involvement in adipose loss was analyzed via RNA-seq, bioinformatics analysis and reporter gene assay. Finally, we explored the clinical significance of MALAT1 through correlation analysis. Results Cellular experiments revealed that knocking down MALAT1 significantly inhibited the process of adipogenesis. RNA-seq data showed that numerous adipogenic genes were downregulated upon MALAT1 knockdown. A protein–protein interaction network analysis identified PPAR-γ as the central node transcription factor, the inhibition of which explains the downregulation of numerous adipogenic genes. A reporter gene assay suggested that MALAT1 can regulate the gene expression of PPAR-γ at the transcriptional level. Moreover, MALAT1 was weakly expressed in the subcutaneous white adipose tissue of cancer-associated cachexia patients and was related to low fat mass index and poor prognosis in cancer patients. Conclusions This study indicated that MALAT1 is associated with adipose loss in cancer-associated cachexia by regulating adipogenesis through PPAR-γ, which may potentially be a novel target for the diagnosis and treatment of cancer-associated cachexia in the clinic. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00557-0.
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Affiliation(s)
- Jun Han
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lei Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zheng Zhan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Yuguo Liu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Chang Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Ruochen Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Yangjun Luo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Zhiqin Xie
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Ying Feng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
| | - Guohao Wu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Ye ZM, Li LJ, Luo MB, Qing HY, Zheng JH, Zhang C, Lu YX, Tang YM. A systematic review and network meta-analysis of single nucleotide polymorphisms associated with pancreatic cancer risk. Aging (Albany NY) 2020; 12:25256-25274. [PMID: 33226370 PMCID: PMC7803556 DOI: 10.18632/aging.104128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/19/2020] [Indexed: 12/12/2022]
Abstract
In this meta-analysis, we systematically investigated the correlation between single nucleotide polymorphisms (SNPs) and pancreatic cancer (PC) risk. We searched PubMed, Network Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Periodical Database (VIP), and Wanfang databases up to January 2020 for studies on PC risk-associated SNPs. We identified 45 case-control studies (36,360 PC patients and 54,752 non-cancer individuals) relating to investigations of 27 genes and 54 SNPs for this meta-analysis. Direct meta-analysis followed by network meta-analysis and Thakkinstian algorithm analysis showed that homozygous genetic models for CTLA-4 rs231775 (OR =0.326; 95% CI: 0.218-0.488) and VDR rs2228570 (OR = 1.976; 95% CI: 1.496-2.611) and additive gene model for TP53 rs9895829 (OR = 1.231; 95% CI: 1.143-1.326) were significantly associated with PC risk. TP53 rs9895829 was the most optimal SNP for diagnosing PC susceptibility with a false positive report probability < 0.2 at a stringent prior probability value of 0.00001. This systematic review and meta-analysis suggest that TP53 rs9895829, VDR rs2228570, and CTLA-4 rs231775 are significantly associated with PC risk. We also demonstrate that TP53 rs9895829 is a potential diagnostic biomarker for estimating PC risk.
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Affiliation(s)
- Zhuo-Miao Ye
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China; Ruikang School of Clinical Medicine, Guangxi University of Chinese Medicine, Nanning 530001, China.,Ruikang School of Clinical Medicine, Guangxi University of Chinese Medicine, Nanning 530001, China
| | - Li-Juan Li
- The First Clinical Faculty of Guangxi University of Chinese Medicine, Guangxi University of Chinese Medicine, Nanning 530222, China
| | - Ming-Bo Luo
- Ruikang School of Clinical Medicine, Guangxi University of Chinese Medicine, Nanning 530001, China
| | - Hong-Yuan Qing
- Ruikang School of Clinical Medicine, Guangxi University of Chinese Medicine, Nanning 530001, China
| | - Jing-Hui Zheng
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, China
| | - Chi Zhang
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530001, Guangxi, China
| | - Yun-Xin Lu
- Department of Oncology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, China
| | - You-Ming Tang
- Department of Gastroenterology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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Bazzichetto C, Conciatori F, Luchini C, Simionato F, Santoro R, Vaccaro V, Corbo V, Falcone I, Ferretti G, Cognetti F, Melisi D, Scarpa A, Ciuffreda L, Milella M. From Genetic Alterations to Tumor Microenvironment: The Ariadne's String in Pancreatic Cancer. Cells 2020; 9:cells9020309. [PMID: 32012917 PMCID: PMC7072496 DOI: 10.3390/cells9020309] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/18/2020] [Accepted: 01/23/2020] [Indexed: 02/06/2023] Open
Abstract
The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies
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Affiliation(s)
- Chiara Bazzichetto
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Fabiana Conciatori
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
- Correspondence: ; Tel.: +39-06-52665185
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy;
| | - Francesca Simionato
- Division of Oncology, University of Verona, 37126 Verona, Italy; (F.S.); (M.M.)
| | - Raffaela Santoro
- Medicine-Digestive Molecular Clinical Oncology Research Unit, University of Verona, 37126 Verona, Italy; (R.S.); (D.M.)
| | - Vanja Vaccaro
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Vincenzo Corbo
- ARC-Net Research Centre, University and Hospital Trust of Verona, 37126 Verona, Italy; (V.C.); (A.S.)
| | - Italia Falcone
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Gianluigi Ferretti
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Francesco Cognetti
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Davide Melisi
- Medicine-Digestive Molecular Clinical Oncology Research Unit, University of Verona, 37126 Verona, Italy; (R.S.); (D.M.)
| | - Aldo Scarpa
- ARC-Net Research Centre, University and Hospital Trust of Verona, 37126 Verona, Italy; (V.C.); (A.S.)
| | - Ludovica Ciuffreda
- SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Michele Milella
- Division of Oncology, University of Verona, 37126 Verona, Italy; (F.S.); (M.M.)
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Zhang XQ, Pan LA, He HL, Liu RA, Wu XX, Huang XB. The Association Between the Tumor Necrosis Factor-Alpha Gene -308A/G Polymorphism and Chronic Pancreatitis: A Meta-Analysis. Genet Test Mol Biomarkers 2020; 24:33-37. [PMID: 31880483 DOI: 10.1089/gtmb.2019.0205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Tumor necrosis factor-alpha (TNF-α) is a major proinflammatory cytokine that has been posited to be involved in the development of chronic pancreatitis (CP). Several studies have been carried out that explored the association between the TNF-α -308A/G polymorphism and CP; however, conflicting results have emerged. The aim of this study was to perform a meta-analysis to provide a more precise assessment of the relationship between the TNF-α -308A/G polymorphism and CP risk. Methods: Case-control studies were identified using PubMed, Embase, Web of Science, Cochrane Library, and Chinese National Knowledge Infrastructure through January 2019 from which seven were identified that met all inclusion criteria. Results: This meta-analysis included 695 CP cases and 742 controls. A positive association was found between the A allele and the risk of CP using the additive model (OR [odds ratio] = 1.83, 95% CI [confidence interval] = 1.08-3.10). We also found, after excluding the Hardy-Weinberg equilibrium-violating studies, that the AA genotype was significantly associated with CP in both the additive and recessive models (OR = 2.28, 95% CI = 1.27-4.07; OR = 2.19, 95% CI = 1.26-3.81). Conclusion: This meta-analysis indicates that the A allele of the TNF-α -308A/G polymorphism increases the risk of CP.
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Affiliation(s)
- Xiao-Qin Zhang
- Department of ICU, Affiliated Hospital of University of Electronic Science and Technology & Sichuan Provincial People's Hospital, Chengdu, China
| | - Ling-Ai Pan
- Department of ICU, Affiliated Hospital of University of Electronic Science and Technology & Sichuan Provincial People's Hospital, Chengdu, China
| | - Hong-Li He
- Department of ICU, Affiliated Hospital of University of Electronic Science and Technology & Sichuan Provincial People's Hospital, Chengdu, China
| | - Rong-An Liu
- Department of ICU, Affiliated Hospital of University of Electronic Science and Technology & Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiao-Xiao Wu
- Department of ICU, Affiliated Hospital of University of Electronic Science and Technology & Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiao-Bo Huang
- Department of ICU, Affiliated Hospital of University of Electronic Science and Technology & Sichuan Provincial People's Hospital, Chengdu, China
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The influence of Tumor Necrosis Factor-alpha gene polymorphism on oxidative stress in patients with oral precancerous lesions and oral cancer. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Thriveni K, Raju A, Ramaswamy G, Krishnamurthy S. Impact of gene polymorphism of TNF- α rs 1800629 and TNF- β rs 909253 on plasma levels of South Indian breast cancer patients. Indian J Cancer 2019; 55:179-183. [PMID: 30604733 DOI: 10.4103/ijc.ijc_591_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
AIM Inflammation plays a lead role in the tumor microenvironment and promotes metastasis. Single-nucleotide polymorphism (SNP) in the tumor necrosis factor (TNF) gene locus may alter the expression of genes and proteins. The objective of the study is to find the distribution of genetic polymorphism in the sites of TNF-α -308G>A and TNF- β +252A>G in breast cancer and evaluate polymorphism effects on plasma levels. MATERIALS AND METHODS The study group consisted of 109 invasive ductal primary breast cancer patients and 75 age-matched healthy female controls. Plasma cytokine concentrations were measured by the MILLIPLEX® MAP Human Cytokine/Chemokine Panel magnetic bead kits. The genotyping procedure for SNP included allele-specific polymerase chain reaction for TNFα and restriction fragment length polymorphism for TNFβ. RESULTS Odds ratio with 95% confidence interval showed that these polymorphisms were not a causative risk factor, and both polymorphisms were consistent with Hardy-Weinberg equilibrium. Plasma TNFα and TNFβ median concentrations were significantly higher in cases when compared to controls (P < 0.01). When plasma TNFα levels were grouped under polymorphic subtypes, patients with mutant TNF- α -308A allele showed significantly higher values (P < 0.001). In addition, plasma TNFα values were significantly elevated in mutant TNF-β +252G allele (P < 0.01). CONCLUSION This study demonstrated that there is no significant association between SNPs and breast cancer susceptibility in South Indian population. However, plasma TNFα level is significantly elevated with mutant-recessive TNF-α -308 A and TNF-β +252 G alleles of patients.
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Affiliation(s)
- Karuvaje Thriveni
- Department of Biochemistry, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - Anisha Raju
- Department of Biochemistry, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - Girija Ramaswamy
- Department of Biochemistry, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - S Krishnamurthy
- Department of Surgical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
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Shen L, Han J, Wang H, Meng Q, Chen L, Liu Y, Feng Y, Wu G. Cachexia-related long noncoding RNA, CAAlnc1, suppresses adipogenesis by blocking the binding of HuR to adipogenic transcription factor mRNAs. Int J Cancer 2019; 145:1809-1821. [PMID: 30807648 DOI: 10.1002/ijc.32236] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 02/08/2019] [Accepted: 02/20/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Lei Shen
- Department of General Surgery, Zhongshan Hospital; Fudan University; Shanghai China
| | - Jun Han
- Department of General Surgery, Zhongshan Hospital; Fudan University; Shanghai China
| | - Haiyu Wang
- Department of General Surgery, Zhongshan Hospital; Fudan University; Shanghai China
| | - Qingyang Meng
- Department of General Surgery, Zhongshan Hospital; Fudan University; Shanghai China
| | - Linlin Chen
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences; Shanghai China
| | - Yuguo Liu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences; Shanghai China
| | - Ying Feng
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences; Shanghai China
| | - Guohao Wu
- Department of General Surgery, Zhongshan Hospital; Fudan University; Shanghai China
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Yakovenko A, Cameron M, Trevino JG. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J Gastrointest Surg 2018; 10:95-106. [PMID: 30622678 PMCID: PMC6314860 DOI: 10.4240/wjgs.v10.i9.95] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/01/2018] [Accepted: 11/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) induced cachexia is a complex metabolic syndrome associated with significantly increased morbidity and mortality and reduced quality of life. The pathophysiology of cachexia is complex and poorly understood. Many molecular signaling pathways are involved in PC and cachexia. Though our understanding of cancer cachexia is growing, therapeutic options remain limited. Thus, further discovery and investigation of the molecular signaling pathways involved in the pathophysiology of cachexia can be applied to development of targeted therapies. This review focuses on three main pathophysiologic processes implicated in the development and progression of cachexia in PC, as well as their utility in the discovery of novel targeted therapies.
Skeletal muscle wasting is the most prominent pathophysiologic anomaly in cachectic patients and driven by multiple regulatory pathways. Several known molecular pathways that mediate muscle wasting and cachexia include transforming growth factor-beta (TGF-β), myostatin and activin, IGF-1/PI3K/AKT, and JAK-STAT signaling. TGF-β antagonism in cachectic mice reduces skeletal muscle catabolism and weight loss, while improving overall survival. Myostatin/activin inhibition has a great therapeutic potential since it plays an essential role in skeletal muscle regulation. Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) leads to increased ubiquitination associated proteolysis, inhibition of myogenesis, and decreased muscle mass in PC induced cachexia. IGFBP-3 antagonism alleviates muscle cell wasting.
Another component of cachexia is profound systemic inflammation driven by pro-cachectic cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon gamma (INF-γ). IL-6 antagonism has been shown to reduce inflammation, reduce skeletal muscle loss, and ameliorate cachexia. While TNF-α inhibitors are clinically available, blocking TNF-α signaling is not effective in the treatment of cancer cachexia. Blocking the synthesis or action of acute phase reactants and cytokines is a feasible therapeutic strategy, but no anti-cytokine therapies are currently approved for use in PC. Metabolic alterations such as increased energy expenditure and gluconeogenesis, insulin resistance, fat tissue browning, excessive oxidative stress, and proteolysis with amino acid mobilization support tumor growth and the development of cachexia. Current innovative nutritional strategies for cachexia management include ketogenic diet, utilization of natural compounds such as silibinin, and supplementation with ω3-polyunsaturated fatty acids. Elevated ketone bodies exhibit an anticancer and anticachectic effect. Silibinin has been shown to inhibit growth of PC cells, induce metabolic alterations, and reduce myofiber degradation. Consumption of ω3-polyunsaturated fatty acids has been shown to significantly decrease resting energy expenditure and regulate metabolic dysfunction.
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Affiliation(s)
- Anastasiya Yakovenko
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Miles Cameron
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Jose Gilberto Trevino
- Department of Surgery, University of Florida Health Sciences Center, Gainesville, Florida 32610, United States
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11
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Choe JW, Kim HJ, Kim JS, Cha J, Joo MK, Lee BJ, Park JJ, Bak YT. Usefulness of CA 19-9 for pancreatic cancer screening in patients with new-onset diabetes. Hepatobiliary Pancreat Dis Int 2018; 17:263-268. [PMID: 29752133 DOI: 10.1016/j.hbpd.2018.04.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 02/06/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Generally, carbohydrate antigen 19-9 (CA 19-9) is not useful for screening pancreatic cancer in the asymptomatic general population. This study aimed to evaluate the utility of CA 19-9 level as a screening indicator of pancreatic cancer in asymptomatic patients with new-onset diabetes. METHODS We retrospectively reviewed the medical records of patients who visited our health promotion center for health check-ups without cancer related symptoms from January 2005 to January 2014, and were newly diagnosed with diabetes mellitus (DM) within 2 years before their visit. RESULTS Of the 5111 asymptomatic patients with new-onset DM (<2 years) selected for analyses, 87 (1.7%) eventually developed pancreatic cancer after the health check-up. In the subgroup of 322 patients with high total bilirubin levels (>1.7 mg/dL) at the screening time, 42 (73.7%) of 57 patients with high CA 19-9 levels (>37 IU/mL) had been diagnosed as pancreatic cancer during follow-up period and 12 (4.5%) of 265 patients with normal CA 19-9 levels had finally developed pancreatic cancer (OR = 16.3). In the subgroup of 4789 patients with normal bilirubin levels, pancreatic cancer had been detected in 20 (3.8%) of 522 patients with high CA 19-9 level, while only 13 (0.3%) in 4267 patients with normal CA 19-9 levels (OR = 12.6), respectively. CONCLUSION CA 19-9 levels after a diagnosis of new-onset DM could be a useful biomarker of pancreatic cancer, especially in patients with high serum bilirubin.
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Affiliation(s)
- Jung Wan Choe
- Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea
| | - Hyo Jung Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea.
| | - Jae Seon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea
| | - Jaehyung Cha
- Department of Biostatistics, Korea University Medical Center, Seoul 08308, Korea
| | - Moon Kyung Joo
- Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea
| | - Beom Jae Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea
| | - Jong-Jae Park
- Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea
| | - Young-Tae Bak
- Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea
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12
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Guo D, Wang C, Wang Q, Qiao Z, Tang H. Pantoprazole blocks the JAK2/STAT3 pathway to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response. Oncotarget 2018; 8:39640-39648. [PMID: 28489606 PMCID: PMC5503639 DOI: 10.18632/oncotarget.17387] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 03/27/2017] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Cancer cachexia is often present in patients with advanced malignant tumors, and the subsequent body weight reduction results in poor quality of life. However, there has been no progress in developing effective clinical therapeutic strategies for skeletal muscle wasting in cancer cachexia. Herein, we explored the functions of pantoprazole on cancer cachexia skeletal muscle wasting. METHODS The mouse colon adenocarcinoma cell line C26 was inoculated in the right forelimb of male BALB/C mice to establish a cancer cachexia model. The animals were treated with or without different concentrations of pantoprazole orally, and the body weight, tumor growth, spontaneous activity, and muscle functions were determined at various time points. Two weeks later, the levels of serum IL-6 and TNF-α, the mRNA levels of gastrocnemius JAK2 and STAT3, and the expression levels of p-JAK2, p-STAT3, Fbx32, and MuRF1 were examined with ELISA assay, qRT-PCR assay, and Western blotting, respectively. Further studies were performed to assess the levels of Fbx32 and MuRF1 expression and morphological changes. RESULTS Pantoprazole can alleviate cancer cachexia-induced body weight reduction and inhibit skeletal muscle wasting in a dose-dependent manner. Our results indicated that pantoprazole treatment can decrease the levels of serum IL-6 and TNF-α (56.3% and 67.6%, respectively), and inhibit the activation of the JAK2/STAT3 signaling pathway. Moreover, the expression levels of MuRF1 and Fbx32 were also suppressed after pantoprazole treatment. CONCLUSION Our findings suggested that pantoprazole can alleviate cancer cachexia skeletal muscle wasting by inhibiting the inflammatory response and blocking the JAK2/STAT3 or ubiquitin proteasome pathway.
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Affiliation(s)
- Dunwei Guo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China
| | - Chaoyi Wang
- Department of Breast Surgery, Chongqing Three Gorges Central Hospital, Chongqing 404000, China
| | - Qiang Wang
- Department of Gastrointestinal Surgery, Suining Municipal Central Hospital, Suining, Sichuan 629000, China
| | - Zhongpeng Qiao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China
| | - Hua Tang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University Chongqing 400016, China
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Farajzadeh Valilou S, Keshavarz-Fathi M, Silvestris N, Argentiero A, Rezaei N. The role of inflammatory cytokines and tumor associated macrophages (TAMs) in microenvironment of pancreatic cancer. Cytokine Growth Factor Rev 2018; 39:46-61. [PMID: 29373197 DOI: 10.1016/j.cytogfr.2018.01.007] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/24/2017] [Accepted: 01/11/2018] [Indexed: 02/07/2023]
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14
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Yang C, Bork U, Schölch S, Kulu Y, Kaderali L, Bolstorff UL, Kahlert C, Weitz J, Rahbari NN, Reissfelder C. Postoperative course and prognostic value of circulating angiogenic cytokines after pancreatic cancer resection. Oncotarget 2017; 8:72315-72323. [PMID: 29069789 PMCID: PMC5641132 DOI: 10.18632/oncotarget.20315] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 07/31/2017] [Indexed: 12/30/2022] Open
Abstract
Background Circulating angiogenic cytokines (CACs) have been confirmed as prognostic biomarkers and therapeutic targets in several solid tumors. However, their role as prognostic biomarkers in resected pancreatic ductal adenocarcinoma (PDAC) is unknown. Results The expression of CACs in patients with PDAC differs from those with CP both pre- and postoperatively. Correlation analyses show significant correlations between circulating levels of CACs: VEGF was correlated with IL-6 (r = 0.457), FGF (r = 0.44), G-CSF (r = 0.543), HGF (r = 0.586) and SDF-1α (r = 0.784) before the surgery. The circulating levels of TNF-α correlated with the serum concentration of IL-4 before (r= 0.656) and after the resection (r = 0.776 on POD 3, r = 0.865 on POD 7). Gender did not show any correlation with serum levels of CAC, except for significantly higher levels of EGF in males (P = 0.002). Other clinicopathological variables such as age (< 65 vs. > 65 years), T, N, or UICC stage did not have an association with the cytokine levels. The multivariate model including the entire angiogenic panel revealed that postoperative increasing levels of EGF (P = 0.023), PDGFA-A (P = 0.024), TNF-α (P = 0.001) and IL-8 (P = 0.049) were associated with a favorable prognosis, whereas elevating levels of VEGF (P = 0.005) correlated with a poor cancer-specific survival. Materials and Methods Preoperative and postoperative blood samples were collected in patients undergoing surgery for PDAC (n = 40) or chronic pancreatitis (CP; n = 9). Serum levels of 13 angiogenic cytokines (IL-4, IL-6, FGF-b, G-CSF, TNF-α, VEGF, HGF, SDF-1α, IL-8, EGF, Ang-1, PDGF-AA and PlGF) were analyzed using ELISA and Multiplex. Prognostic factors were identified by a Cox proportional hazards model. Conclusions Postoperative changes of serum levels of certain angiogenic cytokines correlate with patients’ prognosis after resection for pancreatic cancer. CACs should thus be considered as biomarkers in patients with resected pancreatic cancer.
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Affiliation(s)
- Cui Yang
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ulrich Bork
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Sebastian Schölch
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Yakup Kulu
- Department of General, Gastrointestinal and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Lars Kaderali
- Institute of Bioinformatics, University of Greifswald, Greifswald, Germany
| | - Uta L Bolstorff
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Christoph Kahlert
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Nuh N Rahbari
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Christoph Reissfelder
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Shen C, Zhou J, Wang X, Yu XY, Liang C, Liu B, Pan X, Zhao Q, Song JL, Wang J, Bao M, Wu C, Li Y, Song YH. Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway. EBioMedicine 2017; 16:238-250. [PMID: 28161398 PMCID: PMC5474518 DOI: 10.1016/j.ebiom.2017.01.040] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 01/20/2017] [Accepted: 01/27/2017] [Indexed: 12/14/2022] Open
Abstract
While angiotensin II (ang II) has been implicated in the pathogenesis of cardiac cachexia (CC), the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. Ang II infusion led to skeletal muscle wasting in wild type (WT) but not in TNF alpha type 1 receptor knockout (TNFR1KO) mice, suggesting that ang II induced muscle loss is mediated by TNF-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h) as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC), the product of Ch25h, resulted in muscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.
Ang II induced muscle wasting is mediated by TNF-α, which in turn up regulates Ch25h Knockout of TNFR1 inhibits the production of 25-OHC and blocks ang II induced muscle loss in mice 25-OHC injection induces muscle wasting in mice by activating GSK3β A GSK3β inhibitor blocks ang II induced muscle atrophy, which paves the way for targeted therapy to treat muscle wasting Cardiac cachexia (CC), a condition characterized by weight loss and muscle wasting, is a serious complication that occurs in patients with chronic heart failure. This condition impairs patient's daily physical activity and their quality of life. Specific therapy for CC is currently unavailable because the pathogenesis remains unknown. Previous studies have identified angiotensin II (ang II) as an important mediator of CC. We now report a previously unrecognized role of 25-hydroxycholesterol (25-OHC) in mediating ang II induced muscle loss. The identification of 25-OHC as a muscle wasting inducer has implications for the development of therapeutic intervention in preserving muscle mass.
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Affiliation(s)
- Congcong Shen
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China
| | - Jin Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, PR China.
| | - Xiaoxiao Wang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China
| | - Xi-Yong Yu
- Guangdong Cardiovascular Institute, Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Chun Liang
- Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415, Fengyang Road, Shanghai, PR China
| | - Bin Liu
- Cardiovascular Disease Center, The First Hospital of Ji Lin University, Changchun, Jilin 130021, PR China
| | - Xiangbin Pan
- Department of Cardiac Surgery, Fuwai Hospital, PR China
| | - Qiong Zhao
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China
| | - Jenny Lee Song
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China
| | - Jiajun Wang
- Department of Gynecology, The Affiliated Maternity and Child Health Hospital of Nanjing Medical University, Wuxi, PR China
| | - Meiyu Bao
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China
| | - Chaofan Wu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China
| | - Yangxin Li
- The Department of Cardiovascular Surgery of the First Affiliated Hospital and the Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu 215123, PR China.
| | - Yao-Hua Song
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
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Yamashita AS, das Neves RX, Rosa-Neto JC, Lira FDS, Batista ML, Alcantara PS, Otoch JP, Seelaender M. White adipose tissue IFN-γ expression and signalling along the progression of rodent cancer cachexia. Cytokine 2017; 89:122-126. [PMID: 26987263 DOI: 10.1016/j.cyto.2016.02.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 02/27/2016] [Accepted: 02/29/2016] [Indexed: 12/11/2022]
Abstract
Cachexia is associated with increased morbidity and mortality in cancer. The White adipose tissue (WAT) synthesizes and releases several pro-inflammatory cytokines that play a role in cancer cachexia-related systemic inflammation. IFN-γ is a pleiotropic cytokine that regulates several immune and metabolic functions. To assess whether IFN-γ signalling in different WAT pads is modified along cancer-cachexia progression, we evaluated IFN-γ receptors expression (IFNGR1 and IFNGR2) and IFN-γ protein expression in a rodent model of cachexia (7, 10, and 14days after tumour implantation). IFN-γ protein expression was heterogeneously modulated in WAT, with increases in the mesenteric pad and decreased levels in the retroperitoneal depot along cachexia progression. Ifngr1 was up-regulated 7days after tumour cell injection in mesenteric and epididymal WAT, but the retroperitoneal depot showed reduced Ifngr1 gene expression. Ifngr2 gene expression was increased 7 and 14days after tumour inoculation in mesenteric WAT. The results provide evidence that changes in IFN-γ expression and signalling may be perceived at stages preceding refractory cachexia, and therefore, might be employed as a means to assess the early stage of the syndrome.
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Affiliation(s)
- Alex Shimura Yamashita
- Department of Physiology and Biophysics, Institute of Biomedical Sciences and Faculdade de Medicina, University of Sao Paulo, São Paulo, Brazil
| | - Rodrigo Xavier das Neves
- Cancer Metabolism Research Group, Institute of Biomedical Sciences and Faculdade de Medicina, University of Sao Paulo, São Paulo, Brazil
| | - José Cesar Rosa-Neto
- Cancer Metabolism Research Group, Institute of Biomedical Sciences and Faculdade de Medicina, University of Sao Paulo, São Paulo, Brazil
| | - Fábio Dos Santos Lira
- Immunometabolism Research Group, Department of Physical Education, Universidade Estadual Paulista (UNESP), Presidente Prudente, SP, Brazil
| | - Miguel Luís Batista
- Laboratory of Adipose Tissue Biology, Center for Integrated Biotechnology, University of Mogi das Cruzes, Mogi das Cruzes, São Paulo, Brazil
| | - Paulo Sérgio Alcantara
- Cancer Metabolism Research Group, Institute of Biomedical Sciences and Faculdade de Medicina, University of Sao Paulo, São Paulo, Brazil; Department of Clinical Surgery, University Hospital, University of Sao Paulo, São Paulo, Brazil
| | - José Pinhata Otoch
- Cancer Metabolism Research Group, Institute of Biomedical Sciences and Faculdade de Medicina, University of Sao Paulo, São Paulo, Brazil; Department of Clinical Surgery, University Hospital, University of Sao Paulo, São Paulo, Brazil
| | - Marília Seelaender
- Cancer Metabolism Research Group, Institute of Biomedical Sciences and Faculdade de Medicina, University of Sao Paulo, São Paulo, Brazil.
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Hannes S, Abhari BA, Fulda S. Smac mimetic triggers necroptosis in pancreatic carcinoma cells when caspase activation is blocked. Cancer Lett 2016; 380:31-8. [DOI: 10.1016/j.canlet.2016.05.036] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Revised: 05/30/2016] [Accepted: 05/31/2016] [Indexed: 10/21/2022]
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Subclinical Inflammation and Endothelial Dysfunction in Patients with Chronic Pancreatitis and Newly Diagnosed Pancreatic Cancer. Dig Dis Sci 2016; 61:1121-9. [PMID: 26597191 PMCID: PMC4789226 DOI: 10.1007/s10620-015-3972-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 11/11/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recent studies have suggested that various cytokines may be important players in the development and progression of chronic pancreatitis (CP) and pancreatic adenocarcinoma (PC). AIMS We studied endothelial dysfunction and subclinical inflammation in patients with newly diagnosed pancreatic adenocarcinoma and CP. METHODS A total of 45 patients were included in the present investigation, 27 with CP and 18 with PC. In addition, the study included 13 age- and body weight-matched healthy subjects served as controls. In all subjects, plasma adiponectin, TNF-alfa, interleukin 6 (IL-6), interleukin 1beta (IL-1β), E-selectin, thrombomodulin, adhesion molecules ICAM and VCAM, and endothelin-1 were assessed. RESULTS PC and CP patients as compared with controls had significantly greater plasma adiponectin (13,292 and 12,227 vs 5408 ng/ml; p < 0.0003), TNF-alfa (22.1 and 23.1 vs 13 pg/ml; p < 0.0002), and IL-6 (6.6 and 7.3 vs 3.3 pg/ml; p < 0.0001). Moreover, there was significantly higher concentration of ICAM (931 and 492 vs 290 ng/ml; p < 0.005) and VCAM (1511 and 1080 vs 840 ng/ml; p < 0.01) in PC and CP patients. When PC and CP patients with and without diabetes were considered separately, there was no difference in adiponectin, cytokines, and parameters of endothelial dysfunction. CONCLUSION In summary, our data indicate that patients with CP and PC express high levels of several cytokines compared with healthy individuals, especially adiponectin, TNF-α and IL-6. Serum TNF-α and ICAM concentrations coordinately increase in advanced CP. Furthermore, especially in PC subjects, elevated markers of endothelial dysfunction are present. This study provides additional evidence that changes in inflammatory cytokine and adhesion molecules in PC and CP are not likely related to endocrine disorders.
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Jin X, Wu Y. Diagnostic utility of clinical and biochemical parameters in pancreatic head malignancy patients with normal carbohydrate antigen 19-9 levels. Afr Health Sci 2015; 15:123-30. [PMID: 25834540 PMCID: PMC4370120 DOI: 10.4314/ahs.v15i1.17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Carbohydrate antigen (CA)19-9 that is the most widely used biomarker for pancreatic cancer has certain limitations in diagnosis, which results in a tough job to distinguish pancreatic cancer from benign tumors with normal CA19-9. The aim of this study was to investigate the diagnostic utility of clinical parameters and serum markers in patients with pancreatic head masses but without elevated CA19-9. METHODS Retrospectively, 106 (69 malignant, 37 benign) of 487 patients admitted for pancreatic head masses were enrolled with CA19-9 level of <37u/ml. Clinical parameters and serum biomarkers were assessed. Among the patients with pancreatic head mass, male individuals (p=0.025) and elder individuals (p<0.001) were more likely to have cancer; and cancer patients were more likely to present with abdominal-pain (p=0.023), weight-loss (p=0.013) and jaundice (p<0.001). Serum bilirubin levels among malignancies, including total bilirubin (p<0.001), direct bilirubin (p<0.001) and indirect bilirubin (p<0.001), were considerably higher than those of benign ones. Logistic regression further concluded that age-distribution, abdominal-pain and direct-bilirubin were three independent factors correlating with final diagnosis. However, CEA (p=0.156) was not sufficient enough to exclude pancreatic cancer. CONCLUSIONS In patients with pancreatic head masses and CA19-9 of <37u/ml, age-distribution, abdominal-pain and direct bilirubin might be helpful in differential diagnosis. CEA was insufficient for exclusion of malignancy.
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Affiliation(s)
- Xiaoli Jin
- Department of Surgery, Sir Run Run Shaw Hospital College of Medicine, Zhejiang University, 3 Qingchun Road East, Hangzhou, Zhejiang Province 310016, P.R. China
| | - Yulian Wu
- Department of Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang Province 310009, P.R. China
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20
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Dietary inflammatory index and risk of pancreatic cancer in an Italian case-control study. Br J Nutr 2014; 113:292-8. [PMID: 25515552 DOI: 10.1017/s0007114514003626] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Previous studies have shown that various dietary components may be implicated in the aetiology of pancreatic cancer. However, the possible relationship between diet-related inflammation and the risk of pancreatic cancer has not yet been investigated. We examined the ability of a newly developed literature-derived dietary inflammatory index (DII) to predict the risk of pancreatic cancer in a case-control study conducted in Italy between 1991 and 2008. This included 326 incident cases and 652 controls admitted to the major teaching and general hospitals for non-neoplastic diseases, frequency-matched to cases by study centre, sex and age. The DII was computed based on dietary intake assessed using a validated and reproducible seventy-eight-item FFQ. Logistic regression models were used to estimate multivariable OR adjusted for age, sex, study centre, education, BMI, smoking status, alcohol drinking and history of diabetes. Energy adjustment was performed using the residual method. Subjects with higher DII scores (i.e., representing a more pro-inflammatory diet) had a higher risk of pancreatic cancer, with the DII being used as both a continuous variable (ORcontinuous 1.24, 95% CI 1.11, 1.38) and a categorical variable (i.e., compared with the subjects in the lowest quintile of the DII, those in the second, third, fourth and fifth quintiles had, respectively, OR(quintile2 v. 1) 1.70, 95% CI 1.02, 2.80; OR(quintile3 v. 1) 1.91, 95% CI 1.16, 3.16; OR(quintile4 v. 1) 1.98, 95% CI 1.20, 3.27; OR(quintile5 v. 1) 2.48, 95% CI 1.50, 4.10; P trend= 0.0015). These data suggest that a pro-inflammatory diet increases the risk of pancreatic cancer.
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Sałagacka A, Żebrowska M, Jeleń A, Mirowski M, Balcerczak E. Investigation of -308G>A and -1031T>C polymorphisms in the TNFA promoter region in Polish peptic ulcer patients. Gut Liver 2014; 8:632-6. [PMID: 25368751 PMCID: PMC4215449 DOI: 10.5009/gnl13224] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 09/27/2013] [Accepted: 10/21/2013] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND/AIMS Tumor necrosis factor α (TNF-α) encoded by TNFA is a key mediator in inflammation, a precursor condition for peptic ulceration. Promoter polymorphisms of TNFA that influence its transcriptional activity and TNF-α production are known. TNFA-308G>A (rs1800629) and TNFA-1031T>C (rs1799964), which are responsible for increased TNFA transcription, could influence the risk of peptic ulceration. This study aimed to investigate these polymorphisms and to evaluate their association with peptic ulcer disease and Helicobacter pylori infection in the Polish population. METHODS Gastric mucosa specimens obtained from 177 Polish peptic ulcer patients were used to conduct rapid urease tests and to assess the investigated polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data were compared with the results obtained from healthy individuals of Polish origin. RESULTS There were no significant differences in genotype and allele frequency of the investigated polymorphisms between peptic ulcer patients and healthy individuals. No associations between the frequencies of particular genotypes and alleles for both single-nucleotide polymorphisms (SNPs) and the presence of H. pylori infection in peptic ulcer patients and in subgroups of men and women with peptic ulcer disease were found. CONCLUSIONS The investigated SNPs are not risk factors for either peptic ulcer or H. pylori infection development in the Polish population. The results require verification in a larger cohort.
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Affiliation(s)
- Aleksandra Sałagacka
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Marta Żebrowska
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Agnieszka Jeleń
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Marek Mirowski
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Ewa Balcerczak
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry, Medical University of Lodz, Lodz, Poland
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Yu JH, Kim H. Oxidative stress and cytokines in the pathogenesis of pancreatic cancer. J Cancer Prev 2014; 19:97-102. [PMID: 25337577 PMCID: PMC4204162 DOI: 10.15430/jcp.2014.19.2.97] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 06/17/2014] [Accepted: 06/17/2014] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the most aggressive, drug-resistant and lethal types of cancer with poor prognosis. Various factors including reactive oxygen species, cytokines, growth factors, and extracellular matrix proteins are reported to be involved in the development of pancreatic cancer. However, the pathogenesis of pancreatic cancer has not been completely elucidated. Oxidative stress has been shown to contribute to the development of pancreatic cancer. Evidences supporting the role of reactive oxygen species and cytokines as a risk for pancreatic cancer and the concept of antioxidant supplementation as a preventive approach for pancreatic cancer have been proposed. Here, we review the literature on oxidative stress, cytokine expression, inflammatory signaling, and natural antioxidant supplementation in relation to pancreatic cancer.
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Affiliation(s)
- Ji Hoon Yu
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
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Ge YZ, Wang YD, Xu Z, Xu LW, Wang YP, Gu MH, Ding AX, Zhu XB, Wu R, Li WC, Xu YD, Jia RP. Lack of association between interferon gamma +874 T/A polymorphism and cancer risk: an updated meta-analysis. Tumour Biol 2014; 35:6405-14. [PMID: 24671824 DOI: 10.1007/s13277-014-1861-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 03/18/2014] [Indexed: 01/30/2023] Open
Abstract
Interferon gamma (IFN-γ) is a potent proinflammatory cytokine which plays a pivotal role in the antiviral, antiproliferative, and antitumor activities. A T-to-A transition at the position +874 of human IFN-γ gene (IFNG) has been reported to influence the secretion of IFN-γ and affect cancer susceptibility. However, results from published studies on the association between IFNG +874 T/A polymorphism and cancer risk are inconclusive or even controversial. In order to derive a more precise estimation of the association, a meta-analysis of 38 eligible studies including 5,630 cases and 6,096 controls was conducted with odds ratio (OR) and its corresponding 95 % confidence interval (95 % CI). Overall, no significant association was detected in allelic model (A allele vs. T allele-OR = 0.96, 95 % CI, 0.86-1.08), homozygote comparison (AA vs. TT-OR = 0.97, 95 % CI, 0.79-1.21), heterozygote comparison (AT vs. TT-OR = 1.03, 95 % CI, 0.87-1.23), dominant model (AA + AT vs. TT-OR = 1.00, 95 % CI, 0.87-1.15), nor recessive model (AA vs. AT + TT-OR = 0.93, 95 % CI, 0.78-1.12). Further subgroup analyses based on ethnicity, cancer types, and Hardy-Weinberg equilibrium status failed to demonstrate any significant relationship except in African population under recessive model (AA vs. AT + TT-OR = 0.68, 95 % CI, 0.47-0.97). In conclusion, the current meta-analysis suggested that IFNG +874 T/A polymorphism may not contribute to cancer susceptibility, and further well-designed studies with large sample size are warranted to validate our conclusion.
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Affiliation(s)
- Yu-Zheng Ge
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Overexpressing TNF-alpha in pancreatic ductal adenocarcinoma cells and fibroblasts modifies cell survival and reduces fatty acid synthesis via downregulation of sterol regulatory element binding protein-1 and activation of acetyl CoA carboxylase. J Gastrointest Surg 2014; 18:257-68; discussion 268. [PMID: 24091913 DOI: 10.1007/s11605-013-2370-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Accepted: 09/20/2013] [Indexed: 01/31/2023]
Abstract
The effect of tumor necrosis factor-alpha (TNF-α) gene delivery has been suggested as a potentially useful therapeutic approach to improve the chemotherapeutic treatment of patients with pancreatic ductal adenocarcinoma (PDA), but the exact mechanism of its action is not clearly understood. In this study, we analyzed the expression profile of TNF-α in PDA tissue and explored its potential role in fatty acid synthase (FAS) regulation in PDA cells and in fibroblasts. Quantitative real-time polymerase chain reaction was used to examine the expression of TNF-α in PDA, matching adjacent tissues, and benign lesions. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan-Meier survival curves were generated. In vitro, we overexpressed the TNF-α gene in PDA cells and fibroblasts and analyzed its effect on cell survival, migration, and on members of the FAS signaling pathway. We also evaluated TNF-α effects on a panel of inflammation-, angiogenesis-, and metastasis-related markers. In the tumor tissue of PDA patients, compared with their matched adjacent tissue, expression levels of TNF-α were not statistically different and did not correlate with survival or any other examined clinicopathological features. Overexpression of TNF-α significantly (p < 0.05) reduced PDA and fibroblast cell migration. In PDA cells that highly overexpress TNF-α, this was associated with a significant reduction of FAS mRNA and protein expression levels and significant (p < 0.05) reduction of SREBP-1 and ACC mRNA. Reduction of FAS by TNF-α was inhibited when either SREBP-1 or ACC was knocked down by siRNA. PDA cells and fibroblasts that overexpress TNF-α displayed differential regulation of several inflammation-related markers and reduced levels of metastasis-related genes. Our data demonstrate a previously unknown multi-targeted involvement of TNF-α in PDA lipogenesis and inflammation and metastasis and suggest that intratumoral introduction of TNF-α may have the potential as a novel therapeutic approach in human PDA.
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Guo XF, Wang J, Yu SJ, Song J, Ji MY, Cao Z, Zhang JX, Wang J, Dong WG. TNF-α-308 polymorphism and risk of digestive system cancers: A meta-analysis. World J Gastroenterol 2013; 19:9461-9471. [PMID: 24409077 PMCID: PMC3882423 DOI: 10.3748/wjg.v19.i48.9461] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/11/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the association between the tumour necrosis factor alpha-308 (TNF-α-308) gene polymorphism and the risk of digestive system cancers.
METHODS: All eligible case-control studies published up to December 2012 were identified by searching PubMed, Web of Science, Embase and China National Knowledge Internet without language restrictions. The risk of digestive system cancers associated with the TNF-α-308 polymorphism was estimated for each study using odds ratio (OR) together with its 95%CI, respectively. Cochrane Collaboration RevMan 5.1 was used to perform the analysis. A χ2-test-based Q statistic test and an I2 test were performed to assess the between-study heterogeneity. When the Q test was significant (P < 0.05) or I2 > 50%, the random effects model was used, otherwise the fixed effects model was used.
RESULTS: Fifty-eight studies from fifty-five publications with a total of 9986 cancer patients and 15511 healthy controls were included. Overall, a significant association was found between the TNF-α-308 polymorphism and the risk of digestive system cancers [dominant model: OR = 1.23, 95%CI: 1.09-1.39, (G/A) vs (G/G): OR = 1.15, 95%CI: 1.02-1.28, (A/A) vs (G/G): OR = 1.44, 95%CI: 1.19-1.73, recessive model: OR = 1.38, 95%CI: 1.15-1.66]. Furthermore, when the analysis was stratified by ethnicity, similar results were observed in both the Asian and Caucasian populations, except for the dominant model and heterozygote comparisons in the Asian population [dominant model: OR = 1.24, 95%CI: 0.99-1.56, (G/A) vs (G/G): OR = 1.09, 95%CI: 0.96-1.24]. When the cancer type subgroups were examined, similar results were detected in gastric and hepatocellular carcinomas; however, no significant association was observed among other digestive system cancers.
CONCLUSION: The TNF-α-308 gene polymorphism may be significantly associated with the risk of gastric and hepatocellular carcinomas, but not colorectal, pancreatic, or oesophageal cancer, in the Asian population.
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Roshani R, McCarthy F, Hagemann T. Inflammatory cytokines in human pancreatic cancer. Cancer Lett 2013; 345:157-63. [PMID: 23879960 DOI: 10.1016/j.canlet.2013.07.014] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Revised: 07/10/2013] [Accepted: 07/15/2013] [Indexed: 12/16/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with poor prognosis. Despite extensive efforts, the current treatment methods have limited success. Therefore, novel therapeutic approaches are required. The pancreatic tumor microenvironment is rich in growth factors and inflammatory cytokines that support tumor growth, and it is highly immunosuppressive. Up-regulation of cytokine pathways has been shown to modulate PDAC progression and immune evasion; therefore targeting cytokines may have therapeutic benefits. In this review we provide an overview of current understanding of pro- and anti-inflammatory cytokines in pancreatic cancer and their potential as therapeutic targets.
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Affiliation(s)
- Rozita Roshani
- Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
| | - Fiona McCarthy
- Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
| | - Thorsten Hagemann
- Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
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Wörmann SM, Diakopoulos KN, Lesina M, Algül H. The immune network in pancreatic cancer development and progression. Oncogene 2013; 33:2956-67. [PMID: 23851493 DOI: 10.1038/onc.2013.257] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/22/2013] [Accepted: 04/22/2013] [Indexed: 02/07/2023]
Abstract
The presence of stromal desmoplasia is a hallmark of spontaneous pancreatic ductal adenocarcinoma, forming a unique microenvironment that comprises many cell types. Only recently, the immune system has entered the pathophysiology of pancreatic ductal adenocarcinoma development. Tumor cells in the pancreas seem to dysbalance the immune system, thus facilitating spontaneous cancer development. This review will try to assemble all relevant data to demonstrate the implications of the immune network on spontaneous cancer development.
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Affiliation(s)
- S M Wörmann
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - K N Diakopoulos
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - M Lesina
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - H Algül
- Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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Naydenov NG, Baranwal S, Khan S, Feygin A, Gupta P, Ivanov AI. Novel mechanism of cytokine-induced disruption of epithelial barriers: Janus kinase and protein kinase D-dependent downregulation of junction protein expression. Tissue Barriers 2013; 1:e25231. [PMID: 24665409 PMCID: PMC3783224 DOI: 10.4161/tisb.25231] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 05/01/2013] [Accepted: 05/31/2013] [Indexed: 12/13/2022] Open
Abstract
The ductal epithelium plays a key role in physiological secretion of pancreatic enzymes into the digestive system. Loss of barrier properties of the pancreatic duct may contribute to the development of pancreatitis and metastatic dissemination of pancreatic tumors. Proinflammatory cytokines are essential mediators of pancreatic inflammation and tumor progression; however, their effects on the integrity and barrier properties of the ductal epithelium have not been previously addressed. In the present study, we investigate mechanisms of cytokine-induced disassembly of tight junctions (TJs) and adherens junctions (AJs) in a model pancreatic epithelium. Exposure of HPAF-II human pancreatic epithelial cell monolayers to interferon (IFN)γ disrupted integrity and function of apical junctions as manifested by increased epithelial permeability and cytosolic translocation of AJ and TJ proteins. Tumor necrosis factor (TNF)α potentiated the effects of IFNγ on pancreatic epithelial junctions. The cytokine-induced increase in epithelial permeability and AJ/TJ disassembly was attenuated by pharmacological inhibition of Janus kinase (JAK) and protein kinase D (PKD). Loss of apical junctions in IFNγ/TNFα-treated HPAF-II cells was accompanied by JAK and PKD dependent decrease in expression of AJ (E-cadherin, p120 catenin) and TJ (occludin, ZO-1) proteins. Depletion of E-cadherin or p120 catenin recapitulated the effects of cytokines on HPAF-II cell permeability and junctions. Our data suggests that proinflammatory cytokines disrupt pancreatic epithelial barrier via expressional downregulation of key structural components of AJs and TJs. This mechanism is likely to be important for pancreatic inflammatory injury and tumorigenesis.
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Affiliation(s)
- Nayden G Naydenov
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA USA
| | - Somesh Baranwal
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA USA
| | - Shadab Khan
- Department of Medicine, University of Rochester School of Medicine, Rochester, NY USA
| | - Alex Feygin
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA USA
| | - Pooja Gupta
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA USA
| | - Andrei I Ivanov
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA USA; ; VCU Institute of Molecular Medicine; Virginia Commonwealth University School of Medicine; Richmond, VA USA ; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA
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Bao Y, Giovannucci EL, Kraft P, Qian ZR, Wu C, Ogino S, Gaziano JM, Stampfer MJ, Ma J, Buring JE, Sesso HD, Lee IM, Rifai N, Pollak MN, Jiao L, Lessin L, Cochrane BB, Manson JE, Fuchs CS, Wolpin BM. Inflammatory plasma markers and pancreatic cancer risk: a prospective study of five U.S. cohorts. Cancer Epidemiol Biomarkers Prev 2013; 22:855-61. [PMID: 23462920 PMCID: PMC3650127 DOI: 10.1158/1055-9965.epi-12-1458] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-α receptor II (TNF-αR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1,094 controls from Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL-6, and TNF-αR2 and the risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 [95% confidence interval (CI), 0.74-1.63; Ptrend = 0.81] for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL-6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. In conclusion, prediagnostic levels of circulating CRP, IL-6, and TNF-αR2 were not associated with the risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.
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Affiliation(s)
- Ying Bao
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
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Yang Z, Qi X, Wu Q, Li A, Xu P, Fan D. Lack of association between TNF-α gene promoter polymorphisms and pancreatitis: a meta-analysis. Gene 2012; 503:229-34. [PMID: 22579868 DOI: 10.1016/j.gene.2012.04.057] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 04/18/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Tumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine involved in the etiology of pancreatitis. The association between pancreatitis and the -308G>A and -238G>A polymorphisms in TNF-α gene has been analyzed in several studies, but results have been inconsistent. The purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility and severity to pancreatitis. METHODS A meta-analysis was performed by searching PubMed, Cochrane Library, and ScienceDirect databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS Our meta-analysis of a total of 1569 pancreatitis cases and 1330 control subjects from twelve published case-control studies for the -308G>A polymorphism (OR 0.98; 95% CI 0.83-1.17), and of 480 cases and 302 controls from four studies for the -238G>A polymorphism (OR 0.92; 95% CI 0.58-1.47) did not show any significant associations of susceptibility to pancreatitis with the variant GA+AA genotypes compared with the GG genotype. An association between severity of acute pancreatitis and -308G>A polymorphism was not found either (OR 0.93; 95% CI 0.69-1.24). CONCLUSION Polymorphisms in two sites of TNF-α gene promoter do not alter the risk of pancreatitis.
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Affiliation(s)
- Zhiping Yang
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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Grote VA, Kaaks R, Nieters A, Tjønneland A, Halkjær J, Overvad K, Skjelbo Nielsen MR, Boutron-Ruault MC, Clavel-Chapelon F, Racine A, Teucher B, Becker S, Pischon T, Boeing H, Trichopoulou A, Cassapa C, Stratigakou V, Palli D, Krogh V, Tumino R, Vineis P, Panico S, Rodríguez L, Duell EJ, Sánchez MJ, Dorronsoro M, Navarro C, Gurrea AB, Siersema PD, Peeters PHM, Ye W, Sund M, Lindkvist B, Johansen D, Khaw KT, Wareham N, Allen NE, Travis RC, Fedirko V, Jenab M, Michaud DS, Chuang SC, Romaguera D, Bueno-de-Mesquita HB, Rohrmann S. Inflammation marker and risk of pancreatic cancer: a nested case-control study within the EPIC cohort. Br J Cancer 2012; 106:1866-74. [PMID: 22617158 PMCID: PMC3364108 DOI: 10.1038/bjc.2012.172] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background: Established risk factors for pancreatic cancer include smoking, long-standing diabetes, high body fatness, and chronic pancreatitis, all of which can be characterised by aspects of inflammatory processes. However, prospective studies investigating the relation between inflammatory markers and pancreatic cancer risk are scarce. Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition, measuring prediagnostic blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble receptors of tumour necrosis factor-α (sTNF-R1, R2) in 455 pancreatic cancer cases and 455 matched controls. Odds ratios (ORs) were estimated using conditional logistic regression models. Results: None of the inflammatory markers were significantly associated with risk of pancreatic cancer overall, although a borderline significant association was observed for higher circulating sTNF-R2 (crude OR=1.52 (95% confidence interval (CI) 0.97–2.39), highest vs lowest quartile). In women, however, higher sTNF-R1 levels were significantly associated with risk of pancreatic cancer (crude OR=1.97 (95% CI 1.02–3.79)). For sTNF-R2, risk associations seemed to be stronger for diabetic individuals and those with a higher BMI. Conclusion: Prospectively, CRP and IL-6 do not seem to have a role in our study with respect to risk of pancreatic cancer, whereas sTNF-R1 seemed to be a risk factor in women and sTNF-R2 might be a mediator in the risk relationship between overweight and diabetes with pancreatic cancer. Further large prospective studies are needed to clarify the role of proinflammatory proteins and cytokines in the pathogenesis of exocrine pancreatic cancer.
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Affiliation(s)
- V A Grote
- Division of Cancer Epidemiology (c020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg 69120, Germany
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Ouyang HQ, Liu LM, Chen Z, Luo JM, Yu EX. Effects of Qingyi Huaji decoction on serum levels of interleukin-6, interleukin-8 and tumor necrosis factor-alpha in nude mice bearing pancreatic tumors. ACTA ACUST UNITED AC 2012; 8:655-61. [PMID: 20619142 DOI: 10.3736/jcim20100709] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To investigate the effects of Qingyi Huaji (QYHJ) decoction, a compound traditional Chinese herbal medicine, on tumor inhibition rate and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) in nude mice with transplanted tumors of human pancreatic cancer. METHODS The tumor-bearing mice model was established by subcutaneously inoculating with xenografts of pancreatic cancer into the right armpit of 40 BALB/c nude mice. After successful modeling, the mice were randomly divided into untreated group (Arabic gum), capecitabine group, low-dose QYHJ decoction group (36 g/kg) and high-dose QYHJ decoction group (72 g/kg), with 10 mice in each group. Citrate buffer solution (containing 5% Arabic gum), capecitabine suspension and QYHJ decoction were administered to four groups by gavage respectively. After 5-week treatment, the concentrations of serum IL-6, IL-8 and TNF-alpha were examined by enzyme-linked immunosorbent assay (ELISA) using blood sample from eye socket. Then the mice were euthanized by cervical dislocation. Tumor weight and the tumor inhibition rate were calculated. RESULTS Tumor weight in the low-dose QYHJ decoction group decreased significantly as compared with the untreated group (P<0.05). Serum levels of IL-6 and TNF-alpha in low- and high-dose QYHJ groups were extremely significantly lower than those in the untreated group (P<0.01). Serum level of IL-8 in the low-dose QYHJ group was significantly lower than that in the untreated group (P<0.05). Correlation analysis showed that transplanted tumor weight of the mice was linearly positively correlated with serum levels of IL-6, IL-8 or TNF-alpha (P<0.01). CONCLUSION Conventional dose of QYHJ decoction is effective in suppressing pancreatic carcinoma in nude mice. The mechanism may be related to down-regulation of serum cytokines such as IL-6, IL-8 and TNF-alpha.
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Affiliation(s)
- Hua-Qiang Ouyang
- Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital, Fudan University, Shanghai 200032, China
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Liu F, Li B, Wei YG, Chen X, Ma Y, Yan LN, Wen TF, Xu MQ, Wang WT, Yang JY. IFN-γ+874 A/T polymorphism and cancer risk: An updated analysis based on 32 case-control studies. Cytokine 2011; 56:200-7. [DOI: 10.1016/j.cyto.2011.06.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 01/30/2011] [Accepted: 06/27/2011] [Indexed: 01/30/2023]
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Mi YY, Yu QQ, Xu B, Zhang LF, Min ZC, Hua LX, Feng NH, Yao Y. Interferon gamma +874 T/A polymorphism contributes to cancer susceptibility: a meta-analysis based on 17 case–control studies. Mol Biol Rep 2010; 38:4461-7. [DOI: 10.1007/s11033-010-0575-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Accepted: 11/19/2010] [Indexed: 11/29/2022]
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Komorowski J, Jurczynska J, Stepien T, Kolomecki K, Kuzdak K, Stepien H. Serum concentrations of TNF α and its soluble receptors in patients with adrenal tumors treated by surgery. Int J Mol Sci 2010; 11:2281-90. [PMID: 20640152 PMCID: PMC2904916 DOI: 10.3390/ijms11062281] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Accepted: 05/21/2010] [Indexed: 11/16/2022] Open
Abstract
The peripheral blood levels of TNF α and its soluble receptors were studied in 39 patients with malignant and benign adrenal tumors treated by adrenalectomy. The concentrations of TNF α were significantly elevated in patients with malignant tumors of the adrenal cortex and in patients with Conn’s syndrome compared to control. In patients with non-functioning adenomas and pheochromocytomas, TNF α levels were similar to those detected in the control. In subjects with myelolipomas, the serum concentration of TNF α was lower compared to the control. After adrenalectomy, the levels of TNF α were decreased in patients with malignant tumors and in patients with Conn’s syndrome, nonfunctioniong adenomas and pheochromocytomas compared to the concentration before surgery. The serum concentrations of soluble receptors of TNF α did not differ among different patient groups and compared to the control. After adrenalectomy, the blood concentrations of TNF α R1 and TNF α R2 were decreased in patients with Conn’s syndrome. However, to confirm practicality of the evaluation of TNF α and its soluble receptors in differential diagnosis in patients with adrenal tumors, a larger study group is needed.
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Affiliation(s)
- Jan Komorowski
- Department of Clinical Endocrinology, First Chair of Endocrinology, Medical University of Lodz, Sterlinga1/3, 91-425 Lodz, Poland
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +48-42-633-1931; Fax: +48-42-636-5427
| | - Jolanta Jurczynska
- Department of Clinical Endocrinology, First Chair of Endocrinology, Medical University of Lodz, Sterlinga1/3, 91-425 Lodz, Poland
| | - Tomasz Stepien
- Department of Endocrine and General Surgery, First Chair of Endocrinology, Pabianicka 62, Medical University of Lodz, 93-513 Lodz, Poland
| | - Krzysztof Kolomecki
- Department of Endocrine and General Surgery, First Chair of Endocrinology, Pabianicka 62, Medical University of Lodz, 93-513 Lodz, Poland
| | - Krzysztof Kuzdak
- Department of Endocrine and General Surgery, First Chair of Endocrinology, Pabianicka 62, Medical University of Lodz, 93-513 Lodz, Poland
| | - Henryk Stepien
- Department of Immunoendocrinology, First Chair of Endocrinology, Medical University of Lodz, Sterlinga1/3, 91-425 Lodz, Poland
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Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor alpha by inhibiting NF-kappaB signaling pathway. Mol Cancer 2010; 9:73. [PMID: 20367887 PMCID: PMC2907730 DOI: 10.1186/1476-4598-9-73] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Accepted: 04/06/2010] [Indexed: 01/21/2023] Open
Abstract
Background Tumor necrosis factor alpha (TNFα) has been used to treat certain tumors in clinic trials. However, the curative effect of TNFα has been undermined by the induced-NF-κB activation in many types of tumor. Maslinic acid (MA), a pharmacological safe natural product, has been known for its important effects as anti-oxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFα though the regulation of NF-κB activation. Results In this study, we demonstrate that MA significantly enhanced TNFα-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNFα-induced cell apoptosis by suppressing TNFα-induced NF-κB activation in a dose- and time-dependent manner. Addition of MA inhibited TNFα-induced IκBα degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-κB-regulated genes, including genes involved in tumor cell proliferation (Cyclin D1, COX-2 and c-Myc), apoptosis (Survivin, Bcl-2, Bcl-xl, XIAP, IAP-1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that MA significantly suppressed pancreatic tumor growth, induced tumor apoptosis, and inhibited NF-κB-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl. Conclusions Our data demonstrate that MA can potentiate the anti-tumor activities of TNFα and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-κB activation and its downstream gene expression. Therefore, MA together with TNFα could be new promising agents in the treatment of pancreatic cancer.
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Abstract
PURPOSE OF REVIEW The present investigation is devoted to uncovering the different signaling pathways - particularly transcriptional factors - involved in muscle wasting. RECENT FINDINGS Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. In this review we describe recent findings about the tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, TWEAK and myostatin actions in cancer cachexia models. SUMMARY The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (mainly cytokines) involved in cancer cachexia since they may represent targets for future promising clinical investigations.
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Current World Literature. Curr Opin Support Palliat Care 2009; 3:305-12. [DOI: 10.1097/spc.0b013e3283339c93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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