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Nueraihemaiti N, Dilimulati D, Baishan A, Hailati S, Maihemuti N, Aikebaier A, Paerhati Y, Zhou W. Shared Genomic Features Between Lung Adenocarcinoma and Type 2 Diabetes: A Bioinformatics Study. BIOLOGY 2025; 14:331. [PMID: 40282196 PMCID: PMC12025072 DOI: 10.3390/biology14040331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/14/2025] [Accepted: 03/21/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) is a common histopathological variant of non-small cell lung cancer. Individuals with type 2 diabetes (T2DM) face an elevated risk of developing LUAD. We examined the common genomic characteristics between LUAD and T2DM through bioinformatics analysis. METHODS We acquired the GSE40791, GSE25724, GSE10072, and GSE71416 datasets. Differentially expressed genes (DEGs) were identified through R software, particularly its version 4.1.3 and analyzed via gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Subsequently, we analyzed the relationship between immune cell infiltration and DEGs. we constructed a protein-protein interaction network using STRING and visualized it with Cytoscape. Moreover, gene modules were identified utilizing the MCODE plugin, and hub genes were selected through the CytoHubba plugin. Additionally, we evaluated the predictive significance of hub genes using receiver operating characteristic curves and identified the final central hub genes. Finally, we forecasted the regulatory networks of miRNA and transcription factors for the central hub genes. RESULTS A total of 748 DEGs were identified. Analysis of immune infiltration showed a notable accumulation of effector-memory CD8 T cells, T follicular helper cells, type 1 T helper cells, activated B cells, natural killer cells, macrophages, and neutrophils in both LUAD and T2DM. Moreover, these DEGs were predominantly enriched in immune-related pathways, including the positive regulation of I-κB kinase/NF-κB signaling, positive regulation of immunoglobulin production, cellular response to interleukin-7, and cellular response to interleukin-4. The TGF-β signaling pathway was significantly important among them. Additionally, seven hub genes were identified, including ATR, RFC4, MCM2, NUP155, NUP107, NUP85, and NUP37. Among them, ATR, RFC4, and MCM2 were identified as pivotal hub genes. Additionally, hsa-mir147a, hsa-mir16-5p, and hsa-mir-1-3p were associated with LUAD and T2DM. SP1 (specific protein 1) and KDM5A (lysine-specific demethylase 5A) regulated MCM2, ATR, and RFC4. CONCLUSIONS Our study elucidates the common mechanisms of immune response, TGF-β signaling pathway, and natural killer cells in LUAD and T2DM, and identifies ATR, RFC4, and MCM2 as key potential biomarkers and therapeutic targets for the comorbidity of these two conditions.
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Affiliation(s)
- Nuerbiye Nueraihemaiti
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Dilihuma Dilimulati
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Alhar Baishan
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Sendaer Hailati
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Nulibiya Maihemuti
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Alifeiye Aikebaier
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Yipaerguli Paerhati
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Wenting Zhou
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (N.N.); (D.D.); (A.B.); (S.H.); (N.M.); (A.A.); (Y.P.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
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Wu J, Tang L, Zheng F, Chen X, Li L. A review of the last decade: pancreatic cancer and type 2 diabetes. Arch Physiol Biochem 2024; 130:660-668. [PMID: 37646618 DOI: 10.1080/13813455.2023.2252204] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/04/2023] [Accepted: 08/21/2023] [Indexed: 09/01/2023]
Abstract
Pancreatic cancer (PC) is a prevalent gastrointestinal tumour known for its high degree of malignancy, resulting in a mere 10% five-year survival rate for most patients. Over the past decade, a growing body of research has shed light on the intricate bidirectional association between PC and Type 2 diabetes (T2DM). The collection of PC- and T2DM-related articles is derived from two comprehensive databases, namely WOS (Web of Science Core Collection) and CNKI (China National Knowledge Infrastructure). This article discusses the last 10 years of research trends in PC and T2DM and explores their potential regulatory relationship as well as related medications.
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Affiliation(s)
- Jiaqi Wu
- Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Nursing, Southern Medical University, Guangzhou, China
| | - Liang Tang
- Department of General Medicine, Zhuzhou Central Hospital, Zhuzhou, China
| | - Feng Zheng
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Xun Chen
- Department of the Trauma center, Zhuzhou Central Hospital, Zhuzhou, China
- Department of hepatobiliary surgery, Zhuzhou Central Hospital, Zhuzhou, China
| | - Lei Li
- Department of Pathology, University of Otago, Dunedin, New Zealand
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3
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Karunakaran U, Ha EY, Elumalai S, Won KC, Moon JS. Mitochondrial ALDH2 improves ß-cell survival and function against doxorubicin-induced apoptosis by targeting CK2 signaling. J Diabetes Investig 2024; 15:684-692. [PMID: 38713732 PMCID: PMC11143424 DOI: 10.1111/jdi.14230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/06/2024] [Accepted: 04/20/2024] [Indexed: 05/09/2024] Open
Abstract
AIMS The aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of β-cell dysfunction and to explore its relationship with mitochondrial aldehyde dehydrogenase-2 (ALDH2). MATERIALS AND METHODS In order to investigate this hypothesis, doxorubicin was administered to INS-1 cells, a rat insulinoma cell line, either with or without several target protein activators and inhibitors. ALDH2 activity was detected with a commercial kit and protein levels were determined with western blot. Mitochondrial ROS, membrane potential, and lipid ROS were determined by commercial fluorescent probes. The cell viability was measured by CCK-assay. RESULTS Exposure of INS-1 cells to doxorubicin decreased active insulin signaling resulting in elevated ALDH2 degradation, compared with control cells by the induction of acid sphingomyelinase mediated ceramide induction. Further, ceramide induction potentiated doxorubicin induced mitochondrial dysfunction. Treatment with the ALDH2 agonist, ALDA1, blocked doxorubicin-induced acid sphingomyelinase activation which significantly blocked ceramide induction and mitochondrial dysfunction mediated cell death. Treatment with the ALDH2 agonist, ALDA1, stimulated casein kinase-2 (CK2) mediated insulin signaling activation. CK2 silencing neutralized the function of ALDH2 in the doxorubicin treated INS-1 cells. CONCLUSIONS Mitochondrial ALDH2 activation could inhibit the progression of doxorubicin induced pancreatic β-cell dysfunction by inhibiting the acid sphingomyelinase induction of ceramide, by regulating the activation of CK2 signaling. Our research lays the foundation of ALDH2 activation as a therapeutic target for the precise treatment of chemotherapy drug induced β-cell dysfunction.
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Affiliation(s)
- Udayakumar Karunakaran
- Institute of Medical ScienceYeungnam University College of MedicineDaeguRepublic of Korea
| | - Eun Yeong Ha
- Department of Internal MedicineYeungnam University College of MedicineDaeguRepublic of Korea
- Department of Internal MedicineKeimyung University Dongsan Hospital, Keimyung University School of MedicineDaeguRepublic of Korea
| | - Suma Elumalai
- Institute of Medical ScienceYeungnam University College of MedicineDaeguRepublic of Korea
| | - Kyu Chang Won
- Institute of Medical ScienceYeungnam University College of MedicineDaeguRepublic of Korea
- Department of Internal MedicineYeungnam University College of MedicineDaeguRepublic of Korea
| | - Jun Sung Moon
- Institute of Medical ScienceYeungnam University College of MedicineDaeguRepublic of Korea
- Department of Internal MedicineYeungnam University College of MedicineDaeguRepublic of Korea
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Pluchart H, Chanoine S, Moro-Sibilot D, Chouaid C, Frey G, Villa J, Degano B, Giaj Levra M, Bedouch P, Toffart AC. Lung cancer, comorbidities, and medication: the infernal trio. Front Pharmacol 2024; 14:1016976. [PMID: 38450055 PMCID: PMC10916800 DOI: 10.3389/fphar.2023.1016976] [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] [Received: 08/11/2022] [Accepted: 09/25/2023] [Indexed: 03/08/2024] Open
Abstract
Most patients with lung cancer are smokers and are of advanced age. They are therefore at high risk of having age- and lifestyle-related comorbidities. These comorbidities are subject to treatment or even polypharmacy. There is growing evidence of a link between lung cancer, comorbidities and medications. The relationships between these entities are complex. The presence of comorbidities and their treatments influence the time of cancer diagnosis, as well as the diagnostic and treatment strategy. On the other hand, cancer treatment may have an impact on the patient's comorbidities such as renal failure, pneumonitis or endocrinopathies. This review highlights how some comorbidities may have an impact on lung cancer presentation and may require treatment adjustments. Reciprocal influences between the treatment of comorbidities and anticancer therapy will also be discussed.
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Affiliation(s)
- Hélène Pluchart
- Pôle Pharmacie, Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, France
- Université Grenoble Alpes, Grenoble, France
- Université Grenoble Alpes, CNRS, Grenoble INP, TIMC UMR5525, Grenoble, France
| | - Sébastien Chanoine
- Pôle Pharmacie, Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, France
- Université Grenoble Alpes, Grenoble, France
- Institut pour l’Avancée des Biosciences, UGA/INSERM U1209/CNRS 5309, Université Grenoble Alpes, La Tronche, France
| | - Denis Moro-Sibilot
- Université Grenoble Alpes, Grenoble, France
- Institut pour l’Avancée des Biosciences, UGA/INSERM U1209/CNRS 5309, Université Grenoble Alpes, La Tronche, France
- Service Hospitalier Universitaire de Pneumologie Physiologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
| | - Christos Chouaid
- Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France
- Inserm U955, UPEC, IMRB, équipe CEpiA, CréteilFrance
| | - Gil Frey
- Service de Chirurgie Thoracique, Vasculaire et Endocrinienne, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
| | - Julie Villa
- Service de Radiothérapie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
| | - Bruno Degano
- Université Grenoble Alpes, Grenoble, France
- Service Hospitalier Universitaire de Pneumologie Physiologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
- Laboratoire HP2, INSERM U1042, Université Grenoble Alpes, Grenoble, France
| | - Matteo Giaj Levra
- Institut pour l’Avancée des Biosciences, UGA/INSERM U1209/CNRS 5309, Université Grenoble Alpes, La Tronche, France
- Service Hospitalier Universitaire de Pneumologie Physiologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
| | - Pierrick Bedouch
- Pôle Pharmacie, Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, France
- Université Grenoble Alpes, Grenoble, France
- Université Grenoble Alpes, CNRS, Grenoble INP, TIMC UMR5525, Grenoble, France
| | - Anne-Claire Toffart
- Université Grenoble Alpes, Grenoble, France
- Institut pour l’Avancée des Biosciences, UGA/INSERM U1209/CNRS 5309, Université Grenoble Alpes, La Tronche, France
- Service Hospitalier Universitaire de Pneumologie Physiologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
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Cozma D, Siatra P, Bornstein SR, Steenblock C. Sensitivity of the Neuroendocrine Stress Axis in Metabolic Diseases. Horm Metab Res 2024; 56:65-77. [PMID: 38171373 DOI: 10.1055/a-2201-6641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Metabolic diseases are prevalent in modern society and have reached pandemic proportions. Metabolic diseases have systemic effects on the body and can lead to changes in the neuroendocrine stress axis, the critical regulator of the body's stress response. These changes may be attributed to rising insulin levels and the release of adipokines and inflammatory cytokines by adipose tissue, which affect hormone production by the neuroendocrine stress axis. Chronic stress due to inflammation may exacerbate these effects. The increased sensitivity of the neuroendocrine stress axis may be responsible for the development of metabolic syndrome, providing a possible explanation for the high prevalence of severe comorbidities such as heart disease and stroke associated with metabolic disease. In this review, we address current knowledge of the neuroendocrine stress axis in response to metabolic disease and discuss its role in developing metabolic syndrome.
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Affiliation(s)
- Diana Cozma
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Panagiota Siatra
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Stefan R Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Charlotte Steenblock
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Nayan SI, Rahman MH, Hasan MM, Raj SMRH, Almoyad MAA, Liò P, Moni MA. Network based approach to identify interactions between Type 2 diabetes and cancer comorbidities. Life Sci 2023; 335:122244. [PMID: 37949208 DOI: 10.1016/j.lfs.2023.122244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 10/28/2023] [Accepted: 11/02/2023] [Indexed: 11/12/2023]
Abstract
High blood sugar and insulin insensitivity causes the lifelong chronic metabolic disease called Type 2 diabetes (T2D) which has a higher chance of developing different malignancies. T2D with comorbidities like Cancers can make normal medications for those disorders more difficult. There may be a significant correlation between comorbidities and have an impact on one another's health. These associations may be due to a number of direct and indirect mechanisms. Such molecular mechanisms that underpin T2D and cancer are yet unknown. However, the large volumes of data available on these diseases allowed us to use analytical tools for uncovering their interrelated pathways. Here, we tried to present a system for investigating potential comorbidity relationships between T2D and Cancer disease by looking at the molecular processes involved, analyzing a huge number of freely accessible transcriptomic datasets of various disorders using bioinformatics. Using semantic similarity and gene set enrichment analysis, we created an informatics pipeline that evaluates and integrates Gene Ontology (GO), expression of genes, and biological process data. We discovered genes that are common in T2D and Cancer along with molecular pathways and GOs. We compared the top 200 Differentially Expressed Genes (DEGs) from each selected T2D and cancer dataset and found the most significant common genes. Among all the common genes 13 genes were found most frequent. We also found 4 common GO terms: GO:0000003, GO:0000122, GO:0000165, and GO:0000278 among all the common GO terms between T2d and different cancers. Using these genes and GO term semantic similarity, we calculated the distance between these two diseases. The semantic similarity results of our study showed a higher association of Liver Cancer (LiC), Breast Cancer (BreC), Colorectal Cancer (CC), and Bladder Cancer (BlaC) with T2D. Furthermore we found KIF4A, NUSAP1, CENPF, CCNB1, TOP2A, CCNB2, RRM2, HMMR, NDC80, NCAPG, and IGFBP5 common hub proteins among different cancers correlated to T2D. AGE-RAGE signaling pathway in diabetic complications, Osteoclast differentiation, TNF signaling pathway, IL-17 signaling pathway, p53 signaling pathway, MAPK signaling pathway, Human T-cell leukemia virus 1 infection, and Non-alcoholic fatty liver disease are the 8 most significant pathways found among 18 common pathways between T2D and selected cancers. As a result of our technique, we now know more about disease pathways that are critical between T2D and cancer.
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Affiliation(s)
- Saidul Islam Nayan
- Dept. of Computer Science & Engineering, University of Global Village, Barisal 8200, Bangladesh
| | - Md Habibur Rahman
- Department of Computer Science and Engineering, Islamic University, Kushtia 7003, Bangladesh; Center for Advanced Bioinformatics and Artificial Intelligence Research, Islamic University, Kushtia 7003, Bangladesh
| | - Md Mehedi Hasan
- Dept. of Computer Science & Engineering, University of Global Village, Barisal 8200, Bangladesh
| | | | - Mohammad Ali Abdullah Almoyad
- Department of Basic Medical Sciences, College of Applied Medical Sciences in Khamis Mushyt, King Khalid University, 47 Abha, Mushait, PO Box. 4536, 61412, Saudi Arabia
| | - Pietro Liò
- Computer Laboratory, The University of Cambridge, 15 JJ Thomson Avenue, Cambridge CB3 0FD, UK
| | - Mohammad Ali Moni
- Artificial Intelligence and Cyber Futures Institute, Charles Stuart University, Bathurst, NSW, 2795, Australia.
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Šiaulienė L, Kazlauskaitė J, Jurkėnaitė D, Visockienė Ž, Lazutka JR. Influence of Body Mass Index and Duration of Disease on Chromosome Damage in Lymphocytes of Patients with Diabetes. Life (Basel) 2023; 13:1926. [PMID: 37763329 PMCID: PMC10532915 DOI: 10.3390/life13091926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/07/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
It is well-established that patients with diabetes mellitus (DM) have a higher incidence of several types of cancer. The precise mechanisms of this association are still unknown, but obesity and chronic inflammation-induced reactive oxygen species (ROS) are thought to be the main risk factors. ROS may produce different DNA damage, which could eventually lead to cancer. The main objective of this study was to evaluate the relation of chromosome aberrations (CA) with disease status, demographics, and clinical parameters in 33 subjects with type 1 DM (T1DM), 22 subjects with type 2 DM (T2DM), and 21 controls. CAs were analyzed in cultured peripheral blood lymphocytes and subdivided into chromatid (CTA)- and chromosome (CSA)-type aberrations. Compared with controls, higher levels of CTAs and CSAs were observed in T1DM (p = 0.0053 and p = 0.0203, respectively) and T2DM (p = 0.0133 and p = 0.00002, respectively). While there was no difference in CTAs between T1DM and T2DM, CSAs were higher in T2DM (p = 0.0173). A significant positive association between CTAs and disease duration (rs = 0.2938, p = 0.0099) and between CSAs and disease duration (rs = 0.4306, p = 0.0001), age (rs = 0.3932, p = 0.0004), and body mass index (BMI) (rs = 0.3502, p = 0.0019) was revealed. After multiple regression analysis, duration of disease remained significant for CTA, CSA, and CAs (p = 0.0042, p = 0.00003, and p = 0.00002, respectively). For CSA, BMI and the use of statins were the other important confounding variables (p = 0.0105 and p = 0.0763). Thus, this study demonstrated that both T1DM and T2DM patients had a higher number of all types of aberrations than controls, which increases with the prolonged disease duration. Higher BMI was associated with a higher frequency of CSA. The use of statins might be beneficial for reducing chromosome damage, but further investigations are needed to confirm this association.
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Affiliation(s)
- Laura Šiaulienė
- Vilnius University Life Sciences Center, Saulėtekio Al. 7, LT-10257 Vilnius, Lithuania; (J.K.); (D.J.)
- Vilnius University Hospital Santaros Klinikos, Santariškių St. 2, LT-08661 Vilnius, Lithuania;
| | - Jūratė Kazlauskaitė
- Vilnius University Life Sciences Center, Saulėtekio Al. 7, LT-10257 Vilnius, Lithuania; (J.K.); (D.J.)
| | - Dalia Jurkėnaitė
- Vilnius University Life Sciences Center, Saulėtekio Al. 7, LT-10257 Vilnius, Lithuania; (J.K.); (D.J.)
| | - Žydrūnė Visockienė
- Vilnius University Hospital Santaros Klinikos, Santariškių St. 2, LT-08661 Vilnius, Lithuania;
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio St. 21, LT-03101, Vilnius, Lithuania
| | - Juozas R. Lazutka
- Vilnius University Life Sciences Center, Saulėtekio Al. 7, LT-10257 Vilnius, Lithuania; (J.K.); (D.J.)
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8
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Aydın PK, Turkyılmaz IB, Gul IB, Bulan OK, Yanardag R. Drug repurposing: Metformin's effect against liver tissue damage in diabetes and prostate cancer model. J Diabetes Metab Disord 2023; 22:225-236. [PMID: 37255805 PMCID: PMC10225428 DOI: 10.1007/s40200-022-01109-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 08/08/2022] [Indexed: 06/01/2023]
Abstract
Background There are evidences linking diabetes to the pathogenesis and progression of various cancers. Metformin is a well-known antidiabetic drug that reduces the levels of circulating glucose and insulin in patients with both insulin resistance and hyperinsulinemia. Aim of the present study was to evaluate the effect of metformin on the liver of rats bearing prostate cancer, diabetes and prostate cancer + diabetes via histopathological and biochemical methods. Methods Male Copenhagen rats were divided into six groups. Control group, diabetic group, cancer group, diabetic + cancer group, diabetic + cancer + metformin group, cancer + metformin group. Diabetes was induced by injecting single dose of streptozotocin (65 mg/kg) to Copenhagen rats, cancer induced 2 × 104 Mat-LyLu cells. Metformin treatment was administered daily by gavage following inocculation of the Mat- Lylu cells to fifth and sixth group. The experiment was terminated on the 14th day following Mat-LyLu cell injection. At the end of the experimental period, the rats were sacrificed, and liver tissue was taken. Liver damage was scored. Biochemically, serum prostate-specific antigen level was determined by employing Enzyme Linked Immuno Sorbent Assay method. In addition, the activities of different enzyme and biochemical parameters were determined spectrophotometrically inform the hepatic tissue specimens. Results The findings of this study reveal that histopathological and biochemical damage in cancer and diabetic + cancer groups decreased significantly in the metformin treated groups. Conclusion These highlights that the antidiabetic drug metformin can be repositioned for attenuating liver tissue damage associated with prostate cancer and diabetes.
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Affiliation(s)
- Pınar Koroglu Aydın
- Faculty of Medicine, Department of Histology and Embryology, Halic University, Istanbul, Turkey
| | - Ismet Burcu Turkyılmaz
- Faculty of Engineering, Department of Chemistry, Istanbul University- Cerrahpasa, Istanbul, Turkey
| | - Ilknur Bugan Gul
- Faculty of Science, Department of Biology, Istanbul University, Vezneciler, Istanbul, Turkey
| | - Omur Karabulut Bulan
- Faculty of Science, Department of Biology, Istanbul University, Vezneciler, Istanbul, Turkey
| | - Refiye Yanardag
- Faculty of Engineering, Department of Chemistry, Istanbul University- Cerrahpasa, Istanbul, Turkey
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Chen N, Zhou J, Wang K, Li X, Li Z. Non-obese or lean non-alcoholic fatty liver disease was associated with increased risk of cancer in patients with type 2 diabetes mellitus. BMJ Open Diabetes Res Care 2023; 11:11/1/e003066. [PMID: 36792168 PMCID: PMC9933753 DOI: 10.1136/bmjdrc-2022-003066] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/31/2023] [Indexed: 02/17/2023] Open
Abstract
INTRODUCTION Risk of non-obese or lean non-alcoholic fatty liver disease (NAFLD) for cancer in patients with type 2 diabetes mellitus (T2DM) is less known. We aimed to evaluate independent associations of NAFLD, especially non-obese or lean NAFLD, and body mass index (BMI) on risks of cancer in patients with T2DM. RESEARCH DESIGN AND METHODS Cross-sectional analyses of baseline information on a cohort of 233 patients with T2DM were conducted in Xiamen, China. NAFLD was identified by hepatic ultrasonography diagnosis of hepatic steatosis without excessive alcohol consumption, viral or autoimmune liver disease. Fibrosis-4 (FIB-4) score was calculated to quantify severity of hepatic fibrosis. RESULTS All types of cancers were diagnosed on 19 (8.2%) patients. Prevalence of cancer was significantly higher in those with NAFLD than those without (15.5% vs 4.0%, p=0.002), but were not significantly different among BMI categories (6.8%, 13.7% and 6.5% for those with underweight or normal weight (n=74), overweight (n=51) and obesity (n=108), respectively, p=0.258). With adjustment for potential confounding factors in the multivariable logistic regression models, NAFLD was significantly associated with increased risk of cancer with the adjusted OR (95% CI) of 5.969 (1.349 to 26.413, p=0.019). Stratified analyses across BMI categories found similar association of NAFLD with risk of cancer for those non-obese or lean (the adjusted OR (95% CI) 17.446 (1.690 to 180.095, p=0.016)) but not for those with either overweight (OR (95% CI) 11.642 (0.832 to 162.963, p=0.068) or obesity (OR (95% CI) 0.917 (0.170 to 4.954, p=0.920). FIB-4 score was not significantly associated with risk of cancer for all subjects or stratified across BMI categories. BMI was not significantly associated with risk of cancer for all patients or stratified by NAFLD. CONCLUSIONS NAFLD, even non-obese or lean NAFLD, was independently associated with increased risk of cancer in patients with T2DM. Screening and management of NAFLD, especially for those with underweight or normal weight, should be strengthened from the perspective of improving prevention and management of cancer in patients with T2DM.
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Affiliation(s)
- Ning Chen
- Department of Endocrinology, Zhongshan Hospital Fudan University Xiamen Branch, Xiamen, Fujian, China
| | - Jingqi Zhou
- Department of Endocrinology, Zhongshan Hospital Fudan University Xiamen Branch, Xiamen, Fujian, China
| | - Kai Wang
- Department of Endocrinology, Zhongshan Hospital Fudan University Xiamen Branch, Xiamen, Fujian, China
| | - Xiaoying Li
- Department of Endocrinology, Fudan University Xiamen Branch, Xiamen, Fujian, China
- Department of Endocrinology, Fudan University Shanghai, Yangpu, Shanghai, China
| | - Zhibin Li
- Epidemiology Research Unit, Translational Medicine Research Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
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10
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Metformin Attenuates Inflammation and Fibrosis in Thyroid-Associated Ophthalmopathy. Int J Mol Sci 2022; 23:ijms232415508. [PMID: 36555150 PMCID: PMC9778898 DOI: 10.3390/ijms232415508] [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] [Received: 10/21/2022] [Revised: 11/17/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
The pathogenesis of thyroid-associated ophthalmopathy (TAO) is still unclear, and therapeutic drugs have great limitations. As metformin has multiple therapeutic effects in many autoimmune diseases, we explored the effects of metformin on TAO in an in vitro fibroblast model. We used orbital connective tissues and fibroblasts that were obtained from TAO patients and normal controls. The activity of adenosine monophosphate-activated protein kinase (AMPK) and the levels of inflammatory or fibrotic factors were examined by immunofluorescence (IF) and immunohistochemistry (IHC). Quantitative real-time polymerase chain reaction (qPCR), cytokine quantification by enzyme-linked immunosorbent sssay (ELISA), IF, and western blotting (WB) were used to measure the expression of factors related to inflammation, fibrosis, and autophagy. To determine the anti-inflammatory and antifibrotic mechanisms of metformin, we pretreated cells with metformin, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, an AMPK activator) or compound C (CC, an AMPK inhibitor) for 24 h and used WB to verify the changes in protein levels in the AMPK/mammalian target of rapamycin (mTOR) pathway. We determined that the low activity of AMPK in the periorbital tissue of TAO patients may be closely related to the occurrence and development of inflammation and fibrosis, and metformin exerts multiple effects by activating AMPK in TAO. Furthermore, we suggest that AMPK may be a potential target of TAO therapy.
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11
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Luo M, Wang YT, Wang XK, Hou WH, Huang RL, Liu Y, Wang JQ. A multi-granularity convolutional neural network model with temporal information and attention mechanism for efficient diabetes medical cost prediction. Comput Biol Med 2022; 151:106246. [PMID: 36343403 DOI: 10.1016/j.compbiomed.2022.106246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/30/2022] [Accepted: 10/22/2022] [Indexed: 12/27/2022]
Abstract
As the cost of diabetes treatment continues to grow, it is critical to accurately predict the medical costs of diabetes. Most medical cost studies based on convolutional neural networks (CNNs) ignore the importance of multi-granularity information of medical concepts and time interval characteristics of patients' multiple visit sequences, which reflect the frequency of patient visits and the severity of the disease. Therefore, this paper proposes a new end-to-end deep neural network structure, MST-CNN, for medical cost prediction. The MST-CNN model improves the representation quality of medical concepts by constructing a multi-granularity embedding model of medical concepts and incorporates a time interval vector to accurately measure the frequency of patient visits and form an accurate representation of medical events. Moreover, the MST-CNN model integrates a channel attention mechanism to adaptively adjust the channel weights to focus on significant medical features. The MST-CNN model systematically addresses the problem of deep learning models for temporal data representation. A case study and three comparative experiments are conducted using data collected from Pingjiang County. Through experiments, the methods used in the proposed model are analyzed, and the super contribution of the model performance is demonstrated.
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Affiliation(s)
- Min Luo
- School of Business, Central South University, Changsha, 410083, PR China
| | - Yi-Ting Wang
- School of Business, Central South University, Changsha, 410083, PR China
| | - Xiao-Kang Wang
- School of Business, Central South University, Changsha, 410083, PR China
| | - Wen-Hui Hou
- School of Business, Central South University, Changsha, 410083, PR China
| | - Rui-Lu Huang
- School of Business, Central South University, Changsha, 410083, PR China
| | - Ye Liu
- School of Business, Central South University, Changsha, 410083, PR China
| | - Jian-Qiang Wang
- School of Business, Central South University, Changsha, 410083, PR China.
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12
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Matrone A, Basolo A, Santini F, Elisei R. Understanding the effect of obesity on papillary thyroid cancer: is there a need for tailored diagnostic and therapeutic management? Expert Rev Endocrinol Metab 2022; 17:475-484. [PMID: 36203362 DOI: 10.1080/17446651.2022.2131529] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 09/29/2022] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Several studies have focused on the relationship between obesity and differentiated thyroid carcinoma (DTC), particularly papillary histotype (PTC). However, the association of obesity with both incidence and aggressiveness of PTC is still incompletely understood. AREAS COVERED We reviewed the mechanisms underlying the cross talk between obesity and thyroid carcinomas and described the most recent evidence evaluating the effect of obesity on the development of PTC, as well as the impact of excessive body weight on the clinicopathologic features and outcome of this type of cancer. EXPERT OPINION Available evidence suggests that excessive body weight is linked with a higher risk of getting PTC, while its impact on the aggressiveness of the disease, if present, is still not clear. Therefore, while attention should be paid to discover thyroid cancer in patients with obesity earlier, once diagnosed it should be managed following a conventional workup as in normal weight patients, based on the clinical presentation of the disease and including active surveillance if appropriate, as recommended by referral guidelines.
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Affiliation(s)
- Antonio Matrone
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa - via Paradisa 2, Pisa, Italy
| | - Alessio Basolo
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa - via Paradisa 2, Pisa, Italy
| | - Ferruccio Santini
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa - via Paradisa 2, Pisa, Italy
| | - Rossella Elisei
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa - via Paradisa 2, Pisa, Italy
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13
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Systematic Review of the Role of Alpha-Protein Kinase 1 in Cancer and Cancer-Related Inflammatory Diseases. Cancers (Basel) 2022; 14:cancers14184390. [PMID: 36139553 PMCID: PMC9497133 DOI: 10.3390/cancers14184390] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 11/19/2022] Open
Abstract
Simple Summary Aside from the basic phosphorylation function of alpha-kinase 1 (ALPK1), little is known about its major functions. Researchers have used various forms of biotechnology and human, animal, and cellular models to better understand the relationship of ALPK1 with cancer and cancer-related inflammatory diseases. ALPK1 is involved in the progression of breast, lung, colorectal, oral, and skin cancer as well as lymphoblastic leukemia. ALPK1 has also been implicated in gout, diabetes, and chronic kidney disease, which are thought to be associated with breast, lung, colorectal, urinary tract, pancreatic, and endometrial cancers and lymphoblastic leukemia. ALPK1 upregulates inflammatory cytokines and chemokines during carcinogenesis. The major cytokine involved in carcinogenesis is TNF-α, which activates the NF-κB pathway, and similar inflammatory responses exist in gout, diabetes, and chronic kidney disease. ALPK1 regulates downstream inflammatory mechanisms that lead to cancer development through certain pathways and plays a key role in cancer initiation and metastasis. Abstract Background: Deregulation of conventional protein kinases is associated with the growth and development of cancer cells. Alpha-kinase 1 (ALPK1) belongs to a newly discovered family of serine/threonine protein kinases with no sequence homology to conventional protein kinases, and its function in cancer is poorly understood. Methods: In this systematic review, we searched for and analyzed studies linking ALPK1 to cancer development and progression. Results: Based on the current evidence obtained using human, animal, cellular, and tissue models, ALPK1 is located upstream and triggers cancer cell development and metastasis by regulating the inflammatory response through phosphorylation. Its mRNA and protein levels were found to correlate with advanced tumor size and lymph node metastasis, which occur from the cellular cytoplasm into the nucleus. ALPK1 is also strongly associated with gout, chronic kidney disease, and diabetes, which are considered as inflammatory diseases and associated with cancer. Conclusion: ALPK1 is an oncogene involved in carcinogenesis. Chronic inflammation is the common regulatory mechanism between cancer and these diseases. Future research should focus on identifying inhibitors of serine/threonine and ALPK1 at their phosphorylation sites, which would block various signal transductions and potentially offer kinase-targeted therapeutic agents for patients with cancer and inflammatory diseases.
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14
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McVicker L, Cardwell CR, Edge L, McCluggage WG, Quinn D, Wylie J, McMenamin ÚC. Survival outcomes in endometrial cancer patients according to diabetes: a systematic review and meta-analysis. BMC Cancer 2022; 22:427. [PMID: 35439978 PMCID: PMC9019948 DOI: 10.1186/s12885-022-09510-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 04/04/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Diabetes is an established risk factor for endometrial cancer development but its impact on prognosis is unclear and epidemiological studies to date have produced inconsistent results. We aimed to conduct the first systematic review and meta-analysis to compare survival outcomes in endometrial cancer patients with and without pre-existing diabetes. METHODS We conducted a systematic search of MEDLINE, EMBASE and Web of Science databases up to February 2022 for observational studies that investigated the association between pre-existing diabetes and cancer-specific survival in endometrial cancer patients. Secondary outcomes included overall survival and progression or recurrence-free survival. Quality assessment of included studies was undertaken using the Newcastle-Ottawa Scale and a random-effects model was used to produce pooled hazard ratios (HRs) and 95% confidence intervals (CIs). (PROSPERO 2020 CRD42020196088). RESULTS In total, 31 studies were identified comprising 55,475 endometrial cancer patients. Pooled results suggested a worse cancer-specific survival in patients with compared to patients without diabetes (n = 17 studies, HR 1.15, 95% CI 1.00-1.32, I2 = 62%). Similar results were observed for progression or recurrence-free survival (n = 6 studies, HR 1.23, 95% CI 1.02-1.47, I2 = 0%) and for overall survival (n = 24 studies, HR 1.42, 95% CI 1.31-1.54, I2 = 46%). CONCLUSION In this systematic review and meta-analysis, we show that diabetes is associated with a worse cancer-specific and overall survival in endometrial cancer patients.
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Affiliation(s)
- Lauren McVicker
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK.
| | | | - Lauren Edge
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, Northern Ireland, UK
| | - Declan Quinn
- Department of Obstetrics and Gynaecology, Antrim Area Hospital, Northern Health and Social Care Trust, Antrim, Northern Ireland, UK
| | - James Wylie
- Department of Obstetrics and Gynaecology, Antrim Area Hospital, Northern Health and Social Care Trust, Antrim, Northern Ireland, UK
| | - Úna C McMenamin
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK
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15
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Le Moli R, Vella V, Tumino D, Piticchio T, Naselli A, Belfiore A, Frasca F. Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management. Front Endocrinol (Lausanne) 2022; 13:959276. [PMID: 36060941 PMCID: PMC9437482 DOI: 10.3389/fendo.2022.959276] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/03/2022] [Indexed: 11/25/2022] Open
Abstract
Obesity is strongly associated with chronic low-grade inflammation. Obese patients have an increased risk to develop thyroid autoimmunity and to became hypothyroid, suggesting a pathogenetic link between obesity, inflammation and autoimmunity. Moreover, type 2 diabetes and dyslipidemia, also characterized by low-grade inflammation, were recently associated with more aggressive forms of Graves' ophthalmopathy. The association between obesity and autoimmune thyroid disorders may also go in the opposite direction, as treating autoimmune hyper and hypothyroidism can lead to weight gain. In addition, restoration of euthyroidism by L-T4 replacement therapy is more challenging in obese athyreotic patients, as it is difficult to maintain thyrotropin stimulation hormone (TSH) values within the normal range. Intriguingly, pro-inflammatory cytokines decrease in obese patients after bariatric surgery along with TSH levels. Moreover, the risk of thyroid cancer is increased in patients with thyroid autoimmune disorders, and is also related to the degree of obesity and inflammation. Molecular studies have shown a relationship between the low-grade inflammation of obesity and the activity of intracellular multiprotein complexes typical of immune cells (inflammasomes). We will now highlight some clinical implications of inflammasome activation in the relationship between obesity and thyroid disease.
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16
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Ichimura-Shimizu M, Kageyama T, Oya T, Ogawa H, Matsumoto M, Sumida S, Kakimoto T, Miyakami Y, Nagatomo R, Inoue K, Cheng C, Tsuneyama K. Verification of the Impact of Blood Glucose Level on Liver Carcinogenesis and the Efficacy of a Dietary Intervention in a Spontaneous Metabolic Syndrome Model. Int J Mol Sci 2021; 22:ijms222312844. [PMID: 34884650 PMCID: PMC8657638 DOI: 10.3390/ijms222312844] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Metabolic syndrome (MS) is a risk factor for type 2 diabetes mellitus, vascular inflammation, atherosclerosis, and renal, liver, and heart diseases. Non-alcoholic steatohepatitis (NASH) is a progressive representative liver disease and may lead to the irreversible calamities of cirrhosis and hepatocellular carcinoma. Metabolic disorders such as hyperglycemia have been broadly reported to be related to hepatocarcinogenesis in NASH; however, direct evidence of a link between hyperglycemia and carcinogenesis is still lacking. Tsumura Suzuki Obese Diabetic (TSOD) mice spontaneously develop metabolic syndrome, including obesity, insulin resistance, and NASH-like liver phenotype, and eventually develop hepatocellular carcinomas. TSOD mice provide a spontaneous human MS-like model, even with significant individual variations. In this study, we monitored mice in terms of their changes in blood glucose levels, body weights, and pancreatic and liver lesions over time. As a result, liver carcinogenesis was delayed in non-hyperglycemic TSOD mice compared to hyperglycemic mice. Moreover, at the termination point of 40 weeks, liver tumors appeared in 18 of 24 (75%) hyperglycemic TSOD mice; in contrast, they only appeared in 5 of 24 (20.8%) non-hyperglycemic mice. Next, we investigated three kinds of oligosaccharide that could lower blood glucose levels in hyperglycemic TSOD mice. We monitored the levels of blood and urinary glucose and assessed pancreatic lesions among the experimental groups. As expected, significantly lower levels of blood and urinary glucose and smaller deletions of Langerhans cells were found in TSOD mice fed with milk-derived oligosaccharides (galactooligosaccharides and lactosucrose). At the age of 24 weeks, mild steatohepatitis was found in the liver but there was no evidence of liver carcinogenesis. Steatosis in the liver was alleviated in the milk-derived oligosaccharide-administered group. Taken together, suppressing the increase in blood glucose level from a young age prevented susceptible individuals from diabetes and the onset of NAFLD/NASH, as well as carcinogenesis. Milk-derived oligosaccharides showed a lowering effect on blood glucose levels, which may be expected to prevent liver carcinogenesis.
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Affiliation(s)
- Mayuko Ichimura-Shimizu
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (M.I.-S.); (T.K.); (H.O.); (S.S.); (T.K.); (Y.M.)
| | - Takeshi Kageyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (M.I.-S.); (T.K.); (H.O.); (S.S.); (T.K.); (Y.M.)
| | - Takeshi Oya
- Department of Molecular Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (T.O.); (M.M.)
| | - Hirohisa Ogawa
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (M.I.-S.); (T.K.); (H.O.); (S.S.); (T.K.); (Y.M.)
| | - Minoru Matsumoto
- Department of Molecular Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (T.O.); (M.M.)
| | - Satoshi Sumida
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (M.I.-S.); (T.K.); (H.O.); (S.S.); (T.K.); (Y.M.)
| | - Takumi Kakimoto
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (M.I.-S.); (T.K.); (H.O.); (S.S.); (T.K.); (Y.M.)
| | - Yuko Miyakami
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (M.I.-S.); (T.K.); (H.O.); (S.S.); (T.K.); (Y.M.)
| | - Ryosuke Nagatomo
- Laboratory of Clinical and Analytical Chemistry, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan; (R.N.); (K.I.)
| | - Koichi Inoue
- Laboratory of Clinical and Analytical Chemistry, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan; (R.N.); (K.I.)
| | - Chunmei Cheng
- Pharmacology and Histopathology, Novo Nordisk Research Centre China, Beijing 102206, China;
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (M.I.-S.); (T.K.); (H.O.); (S.S.); (T.K.); (Y.M.)
- Department of Molecular Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; (T.O.); (M.M.)
- Correspondence: ; Tel.: +81-88-633-7065; Fax: +81-88-633-7067
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Shahid RK, Ahmed S, Le D, Yadav S. Diabetes and Cancer: Risk, Challenges, Management and Outcomes. Cancers (Basel) 2021; 13:5735. [PMID: 34830886 PMCID: PMC8616213 DOI: 10.3390/cancers13225735] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/03/2021] [Accepted: 11/12/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Diabetes mellitus and cancer are commonly coexisting illnesses, and the global incidence and prevalence of both are rising. Cancer patients with diabetes face unique challenges. This review highlights the relationship between diabetes and cancer and various aspects of the management of diabetes in cancer patients. METHODS A literature search using keywords in PubMed was performed. Studies that were published in English prior to July 2021 were assessed and an overview of epidemiology, cancer risk, outcomes, treatment-related hyperglycemia and management of diabetes in cancer patients is provided. RESULTS Overall, 8-18% of cancer patients have diabetes as a comorbid medical condition. Diabetes is a risk factor for certain solid malignancies, such as pancreatic, liver, colon, breast, and endometrial cancer. Several novel targeted compounds and immunotherapies can cause hyperglycemia. Nevertheless, most patients undergoing cancer therapy can be managed with an appropriate glucose lowering agent without the need for discontinuation of cancer treatment. Evidence suggests that cancer patients with diabetes have higher cancer-related mortality; therefore, a multidisciplinary approach is important in the management of patients with diabetes and cancer for a better outcome. CONCLUSIONS Future studies are required to better understand the underlying mechanism between the risk of cancer and diabetes. Furthermore, high-quality prospective studies evaluating management of diabetes in cancer patients using innovative tools are needed. A patient-centered approach is important in cancer patients with diabetes to avoid adverse outcomes.
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Affiliation(s)
- Rabia K. Shahid
- Department of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada;
| | - Shahid Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK S7N 4H4, Canada; (D.L.); (S.Y.)
| | - Duc Le
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK S7N 4H4, Canada; (D.L.); (S.Y.)
| | - Sunil Yadav
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK S7N 4H4, Canada; (D.L.); (S.Y.)
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Therapeutic approaches targeting molecular signaling pathways common to diabetes, lung diseases and cancer. Adv Drug Deliv Rev 2021; 178:113918. [PMID: 34375681 DOI: 10.1016/j.addr.2021.113918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/23/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus (DM), is the most common metabolic disease and is characterized by sustained hyperglycemia. Accumulating evidences supports a strong association between DM and numerous lung diseases including chronic obstructive pulmonary disease (COPD), fibrosis, and lung cancer (LC). The global incidence of DM-associated lung disorders is rising and several ongoing studies, including clinical trials, aim to elucidate the molecular mechanisms linking DM with lung disorders, in particular LC. Several potential mechanisms, including hyperglycemia, hyperinsulinemia, glycation, inflammation, and hypoxia, are cited as plausible links between DM and LC. In addition, studies also propose a connection between the use of anti-diabetic medications and reduction in the incidence of LC. However, the exact cause for DM associated lung diseases especially LC is not clear and is an area under intense investigation. Herein, we review the biological links reported between DM and lung disorders with an emphasis on LC. Furthermore, we report common signaling pathways (eg: TGF-β, IL-6, HIF-1, PDGF) and miRNAs that are dysregulated in DM and LC and serve as molecular targets for therapy. Finally, we propose a nanomedicine based approach for delivering therapeutics (eg: IL-24 plasmid DNA, HuR siRNA) to disrupt signaling pathways common to DM and LC and thus potentially treat DM-associated LC. Finally, we conclude that the effective modulation of commonly regulated signaling pathways would help design novel therapeutic protocols for treating DM patients diagnosed with LC.
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Kumar Das B, Gadad PC. Impact of diabetes on the increased risk of hepatic cancer: An updated review of biological aspects. DIABETES EPIDEMIOLOGY AND MANAGEMENT 2021; 4:100025. [DOI: 10.1016/j.deman.2021.100025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Molina-Montes E, Coscia C, Gómez-Rubio P, Fernández A, Boenink R, Rava M, Márquez M, Molero X, Löhr M, Sharp L, Michalski CW, Farré A, Perea J, O'Rorke M, Greenhalf W, Iglesias M, Tardón A, Gress TM, Barberá VM, Crnogorac-Jurcevic T, Muñoz-Bellvís L, Dominguez-Muñoz JE, Renz H, Balcells J, Costello E, Ilzarbe L, Kleeff J, Kong B, Mora J, O'Driscoll D, Poves I, Scarpa A, Yu J, Hidalgo M, Lawlor RT, Ye W, Carrato A, Real FX, Malats N. Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses. Gut 2021; 70:319-329. [PMID: 32409590 DOI: 10.1136/gutjnl-2019-319990] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 04/07/2020] [Accepted: 04/12/2020] [Indexed: 12/21/2022]
Abstract
OBJECTIVES To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). DESIGN Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. RESULTS T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). CONCLUSION Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
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Affiliation(s)
- Esther Molina-Montes
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Claudia Coscia
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Paulina Gómez-Rubio
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Alba Fernández
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
| | - Rianne Boenink
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
| | - Marta Rava
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
| | - Mirari Márquez
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Xavier Molero
- Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Barcelona, Spain
- Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain
| | - Matthias Löhr
- Gastrocentrum, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Linda Sharp
- National Cancer Registry Ireland, Cork, Ireland
- HRB Clinical Research Facility, University College Cork, Cork, Ireland
| | - Christoph W Michalski
- Department of Surgery, Technical University of Munich, Munich, Germany
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-Universitat Halle-Wittenberg, Halle, Germany
| | - Antoni Farré
- Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - José Perea
- Department of Surgery, Hospital 12 de Octubre, Madrid, Spain
- Department of Surgery, Health Research Institute, Fundación Jiménez Díaz, Madrid, Spain
| | - Michael O'Rorke
- Centre for Public Health, Queen's University Belfast, Belfast, UK
- College of Public Health, University of Iowa, Iowa City, Iowa, USA
| | - William Greenhalf
- Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UK
| | - Mar Iglesias
- CIBERONC, Madrid, Spain
- Hospital del Mar-Parc de Salut Mar, Barcelona, Spain
| | - Adonina Tardón
- Department of Medicine, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Thomas M Gress
- Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, Germany
| | - Victor M Barberá
- Molecular Genetics Laboratory, University General Hospital of Elche, Elche, Spain
| | | | - Luis Muñoz-Bellvís
- Department of Surgery, Hospital Universitario de Salamanca, Salamanca, Spain
| | - J Enrique Dominguez-Muñoz
- Department of Gastroenterology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Phillips University of Marburg, Marburg, Germany
| | - Joaquim Balcells
- Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain
- Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Barcelona, Spain
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UK
| | - Lucas Ilzarbe
- Department of Gastroenterology, Hospital del Mar - Parc de Salut Mar, Barcelona, Spain
| | - Jörg Kleeff
- Department of Surgery, Technical University of Munich, Munich, Germany
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-Universitat Halle-Wittenberg, Halle, Germany
| | - Bo Kong
- Department of Surgery, Technical University of Munich, Munich, Germany
| | - Josefina Mora
- Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Damian O'Driscoll
- National Cancer Registry Ireland, Cork, Ireland
- HRB Clinical Research Facility, University College Cork, Cork, Ireland
| | - Ignasi Poves
- Hospital del Mar - Parc de Salut Mar, Barcelona, Spain
| | - Aldo Scarpa
- ARC-Net Research Centre and Department of Diagnostics and Public Health-Section of Pathology, University of Verona, Verona, Italy
| | - Jingru Yu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Manuel Hidalgo
- Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Rita T Lawlor
- ARC-Net Research Centre and Department of Diagnostics and Public Health-Section of Pathology, University of Verona, Verona, Italy
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Alfredo Carrato
- CIBERONC, Madrid, Spain
- Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain
| | - Francisco X Real
- CIBERONC, Madrid, Spain
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, Madrid, Spain
| | - Núria Malats
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
- CIBERONC, Madrid, Spain
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de Groot S, Röttgering B, Gelderblom H, Pijl H, Szuhai K, Kroep JR. Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma. Cancers (Basel) 2020; 12:cancers12123568. [PMID: 33260481 PMCID: PMC7759976 DOI: 10.3390/cancers12123568] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/22/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and survival. After promising results with targeting and inhibiting the receptor in vitro, multiple different IGF1R targeting compounds have been clinically tried but showed limited efficacy. Here we discuss several possible resistance mechanisms which could explain why IGF1R targeting fails in the clinic and discuss possible ways to overcome these resistances. Abstract Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor.
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Affiliation(s)
- Stefanie de Groot
- Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (S.d.G.); (H.G.)
| | - Bas Röttgering
- Department of Cell and Chemical Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands;
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (S.d.G.); (H.G.)
| | - Hanno Pijl
- Department of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands;
| | - Karoly Szuhai
- Department of Cell and Chemical Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands;
- Correspondence: (K.S.); (J.R.K.); Tel.: +31-715266922 (K.S.); +31-715263464 (J.R.K.)
| | - Judith R. Kroep
- Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (S.d.G.); (H.G.)
- Correspondence: (K.S.); (J.R.K.); Tel.: +31-715266922 (K.S.); +31-715263464 (J.R.K.)
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Milluzzo A, Vigneri P, Martorana F, Vigneri R, Sciacca L. Type 2 diabetes and cancer: problems and suggestions for best patient management. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Diabetes and cancer are widespread worldwide and the number of subjects presenting both diseases increased over the years. The management of cancer patients having diabetes represents a challenge not only because of the complexity and heterogeneity of these pathologies but also for the lack of standardised clinical guidelines. The diagnosis of cancer is traumatizing and monopolizes the attention of both patients and caregivers. Thus, pre-existent or new-onset diabetes can be overshadowed thus increasing the risk for short- and long-term adverse events. Moreover, drugs used for each disease can interfere with the clinical course of the concomitant disease, making challenging the management of these patients. Over the years, this issue has become more relevant because of the increased patients’ life expectancy due to the improved efficacy of diabetes and cancer therapies.
The purpose of this review is to highlight what is known and what should be taken into consideration to optimise the clinical management of patients with diabetes and cancer. Due to the complexity of these diseases, a multidisciplinary, shared approach, including all the protagonists involved, is necessary to improve patients’ quality of life and lifespan.
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Affiliation(s)
- Agostino Milluzzo
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy
| | - Paolo Vigneri
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico-Vittorio Emanuele, 95124 Catania, Italy
| | - Federica Martorana
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico-Vittorio Emanuele, 95124 Catania, Italy
| | - Riccardo Vigneri
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy; Institute of Crystallography, Catania Section, National Research Council, CNR, 95126 Catania, Italy
| | - Laura Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy
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Linkeviciute-Ulinskiene D, Patasius A, Kincius M, Zabuliene L, Smailyte G. Preexisting diabetes, metformin use and long-term survival in patients with prostate cancer. Scand J Urol 2020; 54:401-407. [PMID: 32748714 DOI: 10.1080/21681805.2020.1798502] [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: 10/23/2022]
Abstract
OBJECTIVE To assess prostate cancer-specific and overall survival in prostate cancer patients with or without preexisting type 2 diabetes mellitus (T2DM) with regards to metformin use. METHODS Patients diagnosed with prostate cancer in the Lithuanian population between 2001 and 2005 were identified through the Lithuanian Cancer Registry and followed until 2016, date of death, loss to follow-up or whichever came first. Information regarding the diagnosis of T2DM and antihyperglycemic medications were obtained from the National Health Insurance Fund database. Prostate cancer-specific and overall survival outcomes were analysed using univariate and multivariate Cox proportional hazard models. RESULTS Out of 6689 men included, 254 (3.8%) had preexisting T2DM. There were 4807 deaths during follow-up, including 2084 from prostate cancer. No differences were found in prostate cancer-specific survival between men with or without T2DM. The risk of overall mortality was higher (HR = 1.24, 95% CI = 1.07-1.43) in diabetic men. Univariate analysis showed cancer stage at diagnosis and age to be significant predictors of survival. After adjustment for age and stage at diagnosis, there was no difference in prostate-specific survival between non-diabetic patients compared to metformin users or metformin non-users. However, overall survival was lower in T2DM patients, with a higher mortality risk for metformin non-users (HR = 1.63, 95% CI = 1.27-2.10). Prostate cancer-specific mortality risk was insignificantly lower in diabetic men on metformin (HR = 0.74, 95% CI = 0.54-1.02). CONCLUSION There was no difference in long-term prostate cancer-specific survival in patients with or without T2DM. Overall survival was lower in T2DM patients not treated with metformin.
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Affiliation(s)
- Donata Linkeviciute-Ulinskiene
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius, Lithuania.,Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Marius Kincius
- Department of Oncourology, National Cancer Institute, Vilnius, Lithuania
| | - Lina Zabuliene
- Clinic of Rheumatology, Orthopaedics, Traumatology and Reconstructive Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius, Lithuania.,Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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Frittitta L, Tumminia A. "Adiponectin Paradox" and Cancer Risk: Is It Time for a Reevaluation of the Beneficial Effect of this Adipokine? J Clin Endocrinol Metab 2020; 105:5818155. [PMID: 32270197 DOI: 10.1210/clinem/dgaa181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 04/08/2020] [Indexed: 02/13/2023]
Affiliation(s)
- Lucia Frittitta
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Diabetes, Obesity and Dietetic Center, Garibaldi-Nesima Medical Center, Catania, Italy
| | - Andrea Tumminia
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Zhang X, Gill D, He Y, Yang T, Li X, Monori G, Campbell H, Dunlop M, Tsilidis KK, Timofeeva M, Theodoratou E. Non-genetic biomarkers and colorectal cancer risk: Umbrella review and evidence triangulation. Cancer Med 2020; 9:4823-4835. [PMID: 32400092 PMCID: PMC7333850 DOI: 10.1002/cam4.3051] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/20/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023] Open
Abstract
Several associations between non-genetic biomarkers and colorectal cancer (CRC) risk have been detected, but the strength of evidence and the direction of associations are not confirmed. We aimed to evaluate the evidence of these associations and integrate results from different approaches to assess causal inference. We searched Medline and Embase for meta-analyses of observational studies, meta-analyses of randomized clinical trials (RCTs), and Mendelian randomization (MR) studies measuring the associations between non-genetic biomarkers and CRC risk and meta-analyses of RCTs on supplementary micronutrients. We repeated the meta-analyses using random-effects models and categorized the evidence based on predefined criteria. We described each MR study and evaluated their credibility. Seventy-two meta-analyses of observational studies and 18 MR studies on non-genetic biomarkers and six meta-analyses of RCTs on micronutrient intake and CRC risk considering 65, 42, and five unique associations, respectively, were identified. No meta-analyses of RCTs on blood level biomarkers have been found. None of the associations were classified as convincing or highly suggestive, three were classified as suggestive, and 26 were classified as weak. For three biomarkers explored in MR studies, there was evidence of causality and seven were classified as likely noncausal. For the first time, results from both observational and MR studies were integrated by triangulating the evidence for a wide variety of non-genetic biomarkers and CRC risk. At blood level, lower vitamin D, higher homeostatic model assessment-insulin resistance, and human papillomavirus infection were associated with higher CRC risk while increased linoleic acid and oleic acid and decreased arachidonic acid were likely causally associated with lower CRC risk. No association was found convincing in both study types.
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Affiliation(s)
- Xiaomeng Zhang
- Centre for Global HealthUsher InstituteThe University of EdinburghEdinburghUK
| | - Dipender Gill
- Department of Epidemiology and BiostatisticsSchool of Public HealthImperial College LondonLondonUK
| | - Yazhou He
- Centre for Global HealthUsher InstituteThe University of EdinburghEdinburghUK
| | - Tian Yang
- Centre for Global HealthUsher InstituteThe University of EdinburghEdinburghUK
| | - Xue Li
- Centre for Global HealthUsher InstituteThe University of EdinburghEdinburghUK
| | - Grace Monori
- Department of Epidemiology and BiostatisticsSchool of Public HealthImperial College LondonLondonUK
| | - Harry Campbell
- Centre for Global HealthUsher InstituteThe University of EdinburghEdinburghUK
| | - Malcolm Dunlop
- Colon Cancer Genetics GroupMedical Research Council Human Genetics UnitInstitute of Genetics and Molecular MedicineWestern General HospitalUniversity of EdinburghEdinburghUK
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and BiostatisticsSchool of Public HealthImperial College LondonLondonUK
- Department of Hygiene and EpidemiologyUniversity of Ioannina School of MedicineIoanninaGreece
| | - Maria Timofeeva
- Colon Cancer Genetics GroupMedical Research Council Human Genetics UnitInstitute of Genetics and Molecular MedicineWestern General HospitalUniversity of EdinburghEdinburghUK
- Danish Institute for Advanced StudyDepartment of Public HealthUniversity of Southern DenmarkOdense CDenmark
| | - Evropi Theodoratou
- Centre for Global HealthUsher InstituteThe University of EdinburghEdinburghUK
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Shelby RA, Dorfman CS, Arthur SS, Bosworth HB, Corsino L, Sutton L, Owen L, Erkanli A, Keefe F, Corbett C, Kimmick G. Improving health engagement and lifestyle management for breast cancer survivors with diabetes. Contemp Clin Trials 2020; 92:105998. [PMID: 32289471 PMCID: PMC7590108 DOI: 10.1016/j.cct.2020.105998] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/03/2020] [Accepted: 04/09/2020] [Indexed: 01/19/2023]
Abstract
Breast cancer survivors with type 2 diabetes are at high risk for cancer recurrence, serious health complications, more severe symptoms, psychological distress, and premature death relative to breast cancer survivors without diabetes. Maintaining glycemic control is critical for decreasing symptoms and preventing serious health problems. Many breast cancer survivors with type 2 diabetes have difficulty maintaining diabetes self-management behaviors and achieving glycemic control. Both cancer and diabetes-related symptoms (e.g., physical symptoms and psychological distress) are often barriers to engaging in diabetes self-management strategies. This study evaluates a novel diabetes coping skills training (DCST) intervention for improving breast cancer survivors' abilities to manage symptoms and adhere to recommended diabetes self-management behaviors. The telephone-based DCST protocol integrates three key theory-based strategies: coping skills training for managing symptoms, adherence skills training, and healthy lifestyle skills training. A randomized clinical trial will test the DCST intervention plus diabetes education by comparing it to diabetes education alone. Symptoms, distress, diabetes self-management behaviors, and self-efficacy will be assessed at baseline and 3, 6, and 12 months. Glycosylated hemoglobin (HbA1c) will be assessed at baseline, 6, and 12 months. This study addresses a critical gap in the care of breast cancer survivors by evaluating a novel behavioral intervention to improve the management of symptoms, adherence, and glycemic control in breast cancer survivors with type 2 diabetes. Special considerations for this medically underserved population are also provided. The findings of this study could lead to significant improvements in clinical care and beneficial outcomes for breast cancer survivors. Trials registration: ClinicalTrials.gov, NCT02970344, registered 11/22/2016.
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Affiliation(s)
- Rebecca A Shelby
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States of America.
| | - Caroline S Dorfman
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States of America
| | - Sarah S Arthur
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States of America
| | - Hayden B Bosworth
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States of America; Division of General Internal Medicine, Duke University, Durham, NC, United States of America; Department of Population Health Sciences, Duke University, Durham, NC, United States of America
| | - Leonor Corsino
- Division of Endocrinology, Metabolism and Nutrition, Duke University, Durham, NC, United States of America
| | - Linda Sutton
- Duke Cancer Network, Duke University, Durham, NC, United States of America
| | - Lynda Owen
- Duke Cancer Network, Duke University, Durham, NC, United States of America
| | - Alaattin Erkanli
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, United States of America
| | - Francis Keefe
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States of America
| | - Cheyenne Corbett
- Supportive Care and Survivorship Center, Duke Cancer Institute, Durham, NC, United States of America
| | - Gretchen Kimmick
- Division of Medical Oncology, Duke University Medical Center, Durham, NC, United States of America
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A Cohort Study of Exposure to Antihyperglycemic Therapy and Survival in Patients with Lung Cancer. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17051747. [PMID: 32156062 PMCID: PMC7084663 DOI: 10.3390/ijerph17051747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 12/24/2022]
Abstract
We evaluated the effect of antihyperglycemic therapy on the survival of patients with lung cancer (LC). The analysis included patients with LC and concomitant type 2 diabetes. 15,929 patients were classified into five groups: metformin users, insulin users, metformin and insulin users, sulphonylurea users and non-diabetic group. A multivariate analysis showed that exposure to either metformin or to insulin was associated with a lower risk of LC-specific mortality, and this approached statistical significance (HR 0.82, 95% CI 0.72–92 for metformin and HR 0.65, 95% CI 0.44–95 for insulin). When deaths from all causes were considered, only metformin exposure was associated with a significantly lower risk of death (HR 0.82, 95% CI 0.73–0.92). Users of sulphonylurea were at a higher risk of LC-specific and overall mortality (HRs 1.19, 95% CI 0.99–1.43 and 1.22, 95% CI 1.03–1.45). Our study shows a positive effect of metformin on the survival of patients with LC. Moreover, our results show that exposure to insulin was associated with a lower risk of LC-specific mortality, but not with deaths from all causes. The study results suggested that users of sulphonylurea may be at a higher risk of LC-specific and overall mortality.
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Abstract
The term "adipose tissue" represents a multicellular and multifunctional organ involved in lipid storage, in hormone and temperature regulation, and in the protection of bones and vital organs from impact-based damage. Emerging evidence now suggests a more malignant role of adipose tissue in promoting cancer onset and progression via the release of secreted factors such as interleukin-6 (IL6) and extracellular vesicles (EVs). These adipose-source factors subsequently affect various aspects of tumorigenesis and/or cancer progression by either directly enhancing the tumor cell oncogenic phenotype or indirectly by the stimulating adjacent normal cells to adopt a more pro-cancer phenotype. Due to the recent growing interest in the role of IL6 and EVs released by adipose tissue in cancer promotion and progression, we are focusing on the protumorigenic impact of fat tissue via IL6 and EV secretion.
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Barrea L, Gallo M, Ruggeri RM, Giacinto PD, Sesti F, Prinzi N, Adinolfi V, Barucca V, Renzelli V, Muscogiuri G, Colao A, Baldelli R. Nutritional status and follicular-derived thyroid cancer: An update. Crit Rev Food Sci Nutr 2020; 61:25-59. [PMID: 31997660 DOI: 10.1080/10408398.2020.1714542] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The incidence of differentiated thyroid cancer has been increasing in the last decades all over the world. Such a steady growth cannot be entirely attributable to more intensive thyroid nodule screening and more sensitive diagnostic procedures. Several environmental factors have changed with sufficient rapidity in the same time frame and may represent credible candidates for this increase. They include modified iodine intake, lifestyle-associated risk factors, exposure to various toxic compounds, pollutants and xenobiotics, nutritional deficiencies, eating habits and comorbidities. Foremost, nutritional patterns have gained high interest as possible promoters and modifiable risk factors for thyroid cancer in recent years. The aim of this narrative review is to focus on the relationship between thyroid cancer and nutritional factors, dietary habits and obesity. Low iodine intake has been associated to increased risk of thyroid cancer, favoring the development of more aggressive histotypes. Moreover, correction of iodine deficiency can shift thyroid cancer subtypes toward less aggressive forms, without affecting the overall risk for cancer. Actually, evidence regarding the association between selenium and vitamin D deficiency and thyroid cancer is very limited, despite their well-known anti-cancer potentials, and the clinical usefulness of their supplementation is still uncertain in this setting. Albeit the relationship between single foods and thyroid cancer is difficult to examine, fish and iodine-rich foods, vegetables, and fruits might exert protective effects on thyroid cancer risk. Conversely, no clear association has been found for other foods to date. Lastly, a clear association between obesity and the risk of thyroid cancer, with more aggressive behavior, seems to emerge from most studies, likely involving variations in thyroid function and chronic inflammation mediated by cytokines, insulin, leptin and adiponectins. Although no definite association between dietary factors and thyroid cancer has been firmly established so far, some nutritional patterns, together with excessive weight, seem to play a relevant role in thyroid cancer carcinogenesis as well as in its severity and aggressiveness. These effects may play an additive role to the well-established one exerted by environmental carcinogens, such as pollutants and radiation exposure.
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Affiliation(s)
- Luigi Barrea
- Unit of Endocrinology, Dipartimento di Medicina Clinica e Chirurgia, Federico II University Medical School of Naples, Naples, Italy
| | - Marco Gallo
- Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Rosaria Maddalena Ruggeri
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Paola Di Giacinto
- Endocrinology Unit, Department of Oncology and Medical Specialities, A.O. San Camillo-Forlanini, Rome, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Natalie Prinzi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori Milano, ENETS Center of Excellence, Milan, Italy
| | - Valerio Adinolfi
- Endocrinology and Diabetology Unit, ASL Verbano Cusio Ossola, Domodossola, Italy
| | - Viola Barucca
- Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Valerio Renzelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Giovanna Muscogiuri
- Unit of Endocrinology, Dipartimento di Medicina Clinica e Chirurgia, Federico II University Medical School of Naples, Naples, Italy
| | - Annamaria Colao
- Unit of Endocrinology, Dipartimento di Medicina Clinica e Chirurgia, Federico II University Medical School of Naples, Naples, Italy
| | - Roberto Baldelli
- Endocrinology Unit, Department of Oncology and Medical Specialities, A.O. San Camillo-Forlanini, Rome, Italy
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Schwartz SS, Grant SFA, Herman ME. Intersections and Clinical Translations of Diabetes Mellitus with Cancer Promotion, Progression and Prognosis. Postgrad Med 2019; 131:597-606. [PMID: 31419922 DOI: 10.1080/00325481.2019.1657358] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The association between cancer and dysglycemia has been well documented. It is underappreciated, however, that sustained dysglycemia could potentially be a catalyst toward a pro-cancer physiologic milieu and/or increase the burden of cancer. Hyperglycemia, hyperinsulinemia and energy metabolism at large impact a cascade of growth pathways, epi/genetic modifications, and mitochondrial changes that could feasibly link to tumor processes. Oxidative stress is a recurring motif in cell dysfunction: in diabetes, oxidative stress and reactive oxygen species (ROS) feature prominently in the damage and demise of pancreatic beta cells, as well as cell damage contributing to diabetes-related complications. Oxidative stress may be one intersection at which metabolic and oncogenic processes cross paths with deleterious results in the development of precancer, cancer, and cancer progression. This would augur for tight glucose control. Regrettably, some medical societies have recently relaxed hemoglobin A1c targets. A framework for the hyperglycemic state is presented that helps account and translate the full scope of effects of dysglycemia to ultimately improve clinical best practices.
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Affiliation(s)
- Stanley S Schwartz
- Main Line Health System, Wynnewood, PA, USA.,University of Pennsylvania, Philadelphia, PA, USA
| | - Struan F A Grant
- Center for Spatial and Functional Genomics, Divisions of Human Genetics and Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Mary E Herman
- Montclair State University, Upper Montclair, NJ, USA.,Social Alchemy Ltd. Building Research Competency in the Developing World, Edgewater, NJ, USA
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Tumminia A, Vinciguerra F, Parisi M, Graziano M, Sciacca L, Baratta R, Frittitta L. Adipose Tissue, Obesity and Adiponectin: Role in Endocrine Cancer Risk. Int J Mol Sci 2019; 20:ijms20122863. [PMID: 31212761 PMCID: PMC6628240 DOI: 10.3390/ijms20122863] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/19/2019] [Accepted: 06/10/2019] [Indexed: 12/24/2022] Open
Abstract
Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.
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Affiliation(s)
- Andrea Tumminia
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.
| | - Federica Vinciguerra
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.
| | - Miriam Parisi
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.
| | - Marco Graziano
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.
| | - Laura Sciacca
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.
| | - Roberto Baratta
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.
| | - Lucia Frittitta
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.
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Das BK, Choukimath SM, Gadad PC. Asarone and metformin delays experimentally induced hepatocellular carcinoma in diabetic milieu. Life Sci 2019; 230:10-18. [PMID: 31121175 DOI: 10.1016/j.lfs.2019.05.046] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/09/2019] [Accepted: 05/17/2019] [Indexed: 11/25/2022]
Abstract
AIMS The evidence suggests that the hyperglycemia and hyperinsulinemia of diabetes mellitus (DM) are risk factors for the development of hepatocellular carcinoma (HCC). The aim of the present study was to examine the effect of streptozotocin (STZ)-induced DM on promoting diethylnitrosamine (DEN) induced HCC in male wistar rats. Further, we investigated the administration of (α)-and (β)-asarone and metformin HCl on experimentally induced diabetic-hepatocellular carcinoma. MATERIALS AND METHODS Diabetes was induced by single dose of STZ (55 mg/2 ml/kg b.w. i.p.) and HCC by single dose of DEN (200 mg/ml/kg b.w. i.p.). Another group received the STZ followed by DEN two weeks later to mimic diabetic-HCC. The combined dose of (α)-and (β)-asarone (50 μg/1.5 ml/kg b.w. p.o. in the ratio of 1:1) and metformin HCl (250 mg/1.5 ml/kg b.w. p.o.) treatment was compared with the STZ + DEN group. The blood and liver samples were collected at the end of 12 and 18-weeks to study biochemical and histopathological changes in liver. KEY FINDINGS The STZ induced diabetes promoted the tumor progression due to administration of DEN. The treatment of asarones and metformin significantly reduced the levels of glucose, glycosylated hemoglobin, liver dysfunction markers and tumor biomarkers along with an increase in level of insulin when compared to diabetic-HCC group. Histopathological examination indicated that asarones and metformin attenuate the inflammation, fibrosis, cirrhosis and development of spontaneous HCC. SIGNIFICANCE The STZ can be used to promote the DEN induced HCC. Treatment with (α)-and (β)-asarone attenuates the effect of STZ + DEN induced HCC akin to metformin.
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Affiliation(s)
- Bhrigu Kumar Das
- Department of Pharmacology, KLE College of Pharmacy (A constituent unit of KLE Academy of Higher Education and Research, Belagavi), Vidyanagar, Hubballi 580 031, Karnataka, India; Off-campus Basic and Applied Sciences Research Centre of KLE Academy of Higher Education and Research at KLE College of Pharmacy, Vidyanagar, Hubballi 580 031, Karnataka, India
| | - S M Choukimath
- Department of Pathology, Karnataka Institute of Medical Sciences (KIMS), Vidyanagar, Hubballi 580 031, Karnataka, India
| | - Pramod C Gadad
- Department of Pharmacology, KLE College of Pharmacy (A constituent unit of KLE Academy of Higher Education and Research, Belagavi), Vidyanagar, Hubballi 580 031, Karnataka, India; Off-campus Basic and Applied Sciences Research Centre of KLE Academy of Higher Education and Research at KLE College of Pharmacy, Vidyanagar, Hubballi 580 031, Karnataka, India.
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Milluzzo A, Tumminia A, Vella V, Gianì F, Manzella L, Frittitta L, Belfiore A, Vigneri R, Sciacca L. Short-term adverse effects of anticancer drugs in patients with type 2 diabetes. J Chemother 2019; 31:150-159. [DOI: 10.1080/1120009x.2019.1572297] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Agostino Milluzzo
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Andrea Tumminia
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Veronica Vella
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
- School of Human and Social Science, University “Kore” of Enna, Enna, Italy
| | - Fiorenza Gianì
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania Medical School, Center of Experimental Oncology and Hematology, Catania, Italy
| | - Lucia Frittitta
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Antonino Belfiore
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Riccardo Vigneri
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
- Institute of Bioimages and Biostructures, CNR, Catania, Italy
| | - Laura Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
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Vella V, Milluzzo A, Scalisi NM, Vigneri P, Sciacca L. Insulin Receptor Isoforms in Cancer. Int J Mol Sci 2018; 19:ijms19113615. [PMID: 30453495 PMCID: PMC6274710 DOI: 10.3390/ijms19113615] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/05/2018] [Accepted: 11/13/2018] [Indexed: 12/17/2022] Open
Abstract
The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.
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Affiliation(s)
- Veronica Vella
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
- School of Human and Social Science, University "Kore" of Enna, 94100 Enna, Italy.
| | - Agostino Milluzzo
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
| | - Nunzio Massimo Scalisi
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania Medical School, Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, via Santa Sofia, 78, 95123 Catania, Italy.
| | - Laura Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
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Anastasi E, Filardi T, Tartaglione S, Lenzi A, Angeloni A, Morano S. Linking type 2 diabetes and gynecological cancer: an introductory overview. Clin Chem Lab Med 2018; 56:1413-1425. [PMID: 29427549 DOI: 10.1515/cclm-2017-0982] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 01/03/2018] [Indexed: 01/03/2025]
Abstract
Type 2 diabetes (T2D) is a chronic disease with a growing prevalence and a leading cause of death in many countries. Several epidemiological studies observed an association between T2D and increased risk of many types of cancer, such as gynecologic neoplasms (endometrial, cervical, ovarian and vulvar cancer). Insulin resistance, chronic inflammation and high free ovarian steroid hormones are considered the possible mechanisms behind this complex relationship. A higher risk of endometrial cancer was observed in T2D, even though this association largely attenuated after adjusting for obesity. A clear relationship between the incidence of cervical cancer (CC) and T2D has still not be determined; however T2D might have an impact on prognosis in patients with CC. To date, studies on the association between T2D and ovarian cancer (OC) are limited. The effect of pre-existing diabetes on cancer-specific mortality has been evaluated in several studies, with less clear results. Other epidemiological and experimental studies focused on the potential role of diabetes medications, mainly metformin, in cancer development in women. The correct understanding of the link between T2D and gynecologic cancer risk and mortality is currently imperative to possibly modify screening and diagnostic-therapeutic protocols in the future.
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Affiliation(s)
- Emanuela Anastasi
- Department of Molecular Medicine, University "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy, Phone: +39 064472347, Fax: +39 064478381
| | - Tiziana Filardi
- Department of Experimental Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
| | - Sara Tartaglione
- Department of Molecular Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
| | - Antonio Angeloni
- Department of Experimental Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
| | - Susanna Morano
- Department of Experimental Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
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Bertinat R, Westermeier F, Gatica R, Nualart F. Sodium tungstate: Is it a safe option for a chronic disease setting, such as diabetes? J Cell Physiol 2018; 234:51-60. [DOI: 10.1002/jcp.26913] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 06/13/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Romina Bertinat
- Centro de Microscopía Avanzada, CMA Bio‐Bio Facultad de Ciencias Biológicas, Universidad de Concepción Concepción Chile
| | - Francisco Westermeier
- Department of Health Studies Institute of Biomedical Science, FH JOANNEUM Gesellschaft mbH University of Applied Sciences Graz Austria
- Facultad de Ciencia, Universidad San Sebastián Santiago Chile
| | - Rodrigo Gatica
- Laboratorio de Patología Veterinaria Escuela de Veterinaria, Facultad de Ciencias, Universidad Mayor Santiago Chile
| | - Francisco Nualart
- Centro de Microscopía Avanzada, CMA Bio‐Bio Facultad de Ciencias Biológicas, Universidad de Concepción Concepción Chile
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Sciacca L, Vella V, Frittitta L, Tumminia A, Manzella L, Squatrito S, Belfiore A, Vigneri R. Long-acting insulin analogs and cancer. Nutr Metab Cardiovasc Dis 2018; 28:436-443. [PMID: 29609864 DOI: 10.1016/j.numecd.2018.02.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 02/01/2018] [Accepted: 02/18/2018] [Indexed: 12/13/2022]
Abstract
AIMS Hyperinsulinemia is a recognized risk factor for cancer and plays a major role for the increased cancer incidence in diabetic patients. Whether insulin analogs, and particularly long-acting analogs, worsen the pro-cancer effect of excess insulin is still controversial. DATA SYNTHESIS In this paper we summarize the biological bases for the potential detrimental effect of long-acting analogs on cancer cells and review the in vitro and in vivo evidence on this issue. Because of their different molecular structure relative to native insulin, insulin analogs may activate the insulin receptor (IR) and the post receptor pathways differently. Most, but not all, in vitro evidence indicate that long-acting analogs may have a stronger mitogenic potency than insulin on cancer cells. Notably insulin glargine, the most studied long-acting analog, also has a higher affinity for the insulin-like growth factor (IGF)-1 receptor, a potent growth mediator. In vitro observations, however, may not reflect what occurs in vivo when analogs are metabolized to derivatives with a different mitogenic activity. Clinical studies, mostly retrospective and predominantly concerning glargine, provide contrasting results. The only perspective trial found no cancer increase in patients treated with glargine. All these studies, however, have severe weaknesses because of the insufficient evaluation of important factors such as dose administered, length of exposure, patient follow-up duration and site-specific cancer investigation. Moreover, whether cancer promotion is a long-acting analog class characteristic or a specific effect of a single agent is not clear. CONCLUSIONS In conclusion the carcinogenic risk of long-acting analogs, and specifically glargine, can be neither confirmed nor excluded. A personalized and shared decision, considering all the individual risk factors (metabolic and non-metabolic), is the suggestion for the clinician.
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Affiliation(s)
- L Sciacca
- Endocrinology Section, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
| | - V Vella
- Endocrinology Section, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy; School of Human and Social Science, University "Kore" of Enna, Enna, Italy
| | - L Frittitta
- Endocrinology Section, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy; "S. Signorelli", Diabetes and Obesity Center, Garibaldi-Nesima Hospital, Catania, Italy
| | - A Tumminia
- Endocrinology Section, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy; "S. Signorelli", Diabetes and Obesity Center, Garibaldi-Nesima Hospital, Catania, Italy
| | - L Manzella
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico Vittorio Emanuele, via Santa Sofia 78, 95123 Catania, Italy
| | - S Squatrito
- Endocrinology Section, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy
| | - A Belfiore
- Endocrinology Section, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy
| | - R Vigneri
- Endocrinology Section, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy; CNR, Institute of Bioimages and Biostructures, via Gaifami 18, 95126 Catania, Italy
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Ahmad S, Khan H, Siddiqui Z, Khan MY, Rehman S, Shahab U, Godovikova T, Silnikov V, Moinuddin. AGEs, RAGEs and s-RAGE; friend or foe for cancer. Semin Cancer Biol 2018; 49:44-55. [DOI: 10.1016/j.semcancer.2017.07.001] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 06/22/2017] [Accepted: 07/05/2017] [Indexed: 12/22/2022]
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Gallo M, Muscogiuri G, Felicetti F, Faggiano A, Trimarchi F, Arvat E, Vigneri R, Colao A. Adverse glycaemic effects of cancer therapy: indications for a rational approach to cancer patients with diabetes. Metabolism 2018; 78:141-154. [PMID: 28993227 DOI: 10.1016/j.metabol.2017.09.013] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 09/12/2017] [Accepted: 09/19/2017] [Indexed: 12/13/2022]
Abstract
Diabetes and cancer are common, chronic, and potentially fatal diseases that frequently co-exist. Observational studies have reported an increased risk of cancer in patients with diabetes. Furthermore, many patients with cancer already have diabetes, or develop hyperglycaemia as a consequence of the tumor or of cancer therapies, and coexisting diabetes confers a greater risk of mortality for many malignancies. Managing oncologic patients with diabetes is often complicated, since the co-existence of diabetes and cancer poses several complex clinical questions: what level of glycaemic control to achieve, which therapy to use, how to deal with glucocorticoid therapies and artificial nutrition, how diabetes complications can affect cancer management, which drug-drug interactions should be taken into account, or even how to manage diabetes at the end of life. In the clinical setting, both at hospital and at home, there are little agreed, evidence-based guidelines on the best management and criteria upon which clinical decisions should be based. A practical solution lies in the implementation of care networks based on communication and ongoing collaboration between Oncologists, Endocrinologists, and the nursing staff, with the patient at the centre of the care process. This manuscript aims to review the current evidence on the effect of cancer therapies on glucose metabolism and to address some of the more common challenges of diabetes treatment in patients with cancer.
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Affiliation(s)
- Marco Gallo
- Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy.
| | | | - Francesco Felicetti
- Transition Unit for Childhood Cancer Survivors, Department of Oncology, AOU Cittá della Salute e della Scienza di Torino, Turin, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Francesco Trimarchi
- Accademia Peloritana dei Pericolanti at the University of Messina, Messina, Italy
| | - Emanuela Arvat
- Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Riccardo Vigneri
- Endocrinology, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University "Federico II", Naples, Italy
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Chen H, Li Y, Zhu Y, Wu L, Meng J, Lin N, Yang D, Li M, Ding W, Tong X, Su Q. Advanced glycation end products promote ChREBP expression and cell proliferation in liver cancer cells by increasing reactive oxygen species. Medicine (Baltimore) 2017; 96:e7456. [PMID: 28816938 PMCID: PMC5571675 DOI: 10.1097/md.0000000000007456] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The aim of the study was to elucidate the mechanism by which advanced glycation end products (AGEs) promote cell proliferation in liver cancer cells.We treated liver cancer HepG2 cells with 200 mg/L AGEs or bovine serum albumin (BSA) and assayed for cell viability, cell cycle, and apoptosis. We performed real-time PCR and Western blot analysis for RNA and protein levels of carbohydrate responsive element-binding protein (ChREBP) in AGEs- or BSA-treated HepG2 cells. We analyzed the level of reactive oxygen species (ROS) in HepG2 cells treated with AGEs or BSA.We found that increased S-phase cell percentage and decreased apoptosis contributed to AGEs-induced liver cancer cell proliferation. Real-time PCR and Western blot analysis showed that AGEs stimulated RNA and protein levels of ChREBP, a transcription factor promoting glycolysis and maintaining cell proliferation in liver cancer cells. Intriguingly, the level of ROS was higher in AGEs-treated liver cancer cells. Treating liver cancer cells with antioxidant N-acetyl cystein (NAC) partly blocked AGEs-induced ChREBP expression and cell proliferation.Our results suggest that the AGEs-ROS-ChREBP pathway plays a critical role in promoting ChREBP expression and liver cancer cell proliferation.
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Affiliation(s)
- Hanbei Chen
- Department of Endocrinology, Xinhua Hospital
| | - Yakui Li
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Yemin Zhu
- Department of Endocrinology, Xinhua Hospital
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Lifang Wu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Jian Meng
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Ning Lin
- Department of Endocrinology, Xinhua Hospital
| | - Dianqiang Yang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian
| | - Minle Li
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - WenJin Ding
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuemei Tong
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital
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El Sabaa BM, Talaat IM. Estrogen receptors and progesterone receptors expression in endometrial carcinoma in diabetic versus nondiabetic patients. EGYPTIAN JOURNAL OF PATHOLOGY 2017; 37:42-47. [DOI: 10.1097/01.xej.0000515972.77208.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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42
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Cervical Intraepithelial Neoplasia in Diabetic Patients: A Cross-Sectional Study in Egypt. INDIAN JOURNAL OF GYNECOLOGIC ONCOLOGY 2017. [DOI: 10.1007/s40944-017-0113-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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43
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Higher risk of colorectal cancer in patients with newly diagnosed diabetes mellitus before the age of colorectal cancer screening initiation. Sci Rep 2017; 7:46527. [PMID: 28436468 PMCID: PMC5402260 DOI: 10.1038/srep46527] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 03/22/2017] [Indexed: 12/27/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is associated with greater risk for colorectal cancer (CRC). The age of onset of T2DM is decreasing worldwide. An increased CRC risk in young T2DM patients could be relevant for the age at which to initiate CRC screening. We report on CRC risk in T2DM patients with attention to age of diagnosis. We used pharmacy data (from 1998 to 2010) from the PHARMO Database Network linked to the Eindhoven Cancer Registry. Multivariable time-dependent Cox regression analyses were conducted to calculate hazard ratios (HR) for developing CRC comparing T2DM with non-T2DM. During 2,599,925 years of follow-up, 394 CRC cases among 41,716 diabetes patients (mean age 64.0 yr, 48% men) and 1,939 CRC cases among 325,054 non-diabetic patients (mean age 51.2 yr, 46% men) were identified. Diabetes was associated with an increased CRC risk in both men and women (HR 1.3, 95% CI 1.2-1.5), particularly in the first 6 months after T2DM diagnosis and pronounced in the proximal colon. This risk was even higher in men younger than 55 years (HR 2.0, 95% CI 1.0-3.8). T2DM was associated with a time-varying and subsite-specific increased CRC risk, which was even higher in men aged <55 years.
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44
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Leduc C, Antoni D, Charloux A, Falcoz PE, Quoix E. Comorbidities in the management of patients with lung cancer. Eur Respir J 2017; 49:49/3/1601721. [PMID: 28356370 DOI: 10.1183/13993003.01721-2016] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 11/25/2016] [Indexed: 12/13/2022]
Abstract
Lung cancer represents a major public health issue worldwide. Unfortunately, more than half of them are diagnosed at an advanced stage. Moreover, even if diagnosed early, diagnosis procedures and treatment can be difficult due to the frequent comorbidities observed in these patients. Some of these comorbidities have a common major risk factor, i.e. smoking, whereas others are unrelated to smoking but frequently observed in the general population. These comorbidities must be carefully assessed before any diagnostic and/or therapeutic decisions are made regarding the lung cancer. For example, in a patient with severe emphysema or with diffuse lung fibrosis, transthoracic needle biopsy can be contraindicated, meaning that in some instances a precise diagnosis cannot be obtained; in a patient with chronic obstructive pulmonary disease, surgery may be impossible or should be preceded by intensive rehabilitation; patients with interstitial lung disease are at risk of radiation pneumonitis and should not receive drugs which can worsen the respiratory insufficiency. Patients who belong to what are called "special populations", e.g. elderly or HIV infected, should be treated specifically, especially regarding systemic treatment. Last but not least, psychosocial factors are of great importance and can vary from one country to another according to health insurance coverage.
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Affiliation(s)
- Charlotte Leduc
- Pneumology Dept, Nouvel Hôpital Civil, Strasbourg Cedex, France
| | - Delphine Antoni
- Radiotherapy Dept, Centre Paul Strauss, Strasbourg Cedex, France
| | - Anne Charloux
- Physiology and Functional Explorations Dept, Strasbourg Cedex, France
| | | | - Elisabeth Quoix
- Pneumology Dept, Nouvel Hôpital Civil, Strasbourg Cedex, France
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45
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González N, Prieto I, del Puerto-Nevado L, Portal-Nuñez S, Ardura JA, Corton M, Fernández-Fernández B, Aguilera O, Gomez-Guerrero C, Mas S, Moreno JA, Ruiz-Ortega M, Sanz AB, Sanchez-Niño MD, Rojo F, Vivanco F, Esbrit P, Ayuso C, Alvarez-Llamas G, Egido J, García-Foncillas J, Ortiz A, Diabetes Cancer Connect Consortium. 2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications. Oncotarget 2017; 8:18456-18485. [PMID: 28060743 PMCID: PMC5392343 DOI: 10.18632/oncotarget.14472] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/26/2016] [Indexed: 02/06/2023] Open
Abstract
Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.
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Affiliation(s)
- Nieves González
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Isabel Prieto
- Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Laura del Puerto-Nevado
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Sergio Portal-Nuñez
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Juan Antonio Ardura
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Marta Corton
- Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Oscar Aguilera
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Sebastián Mas
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | | | - Ana Belen Sanz
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
- REDINREN, Madrid, Spain
| | | | - Federico Rojo
- Pathology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Pedro Esbrit
- Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Carmen Ayuso
- Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Jesús García-Foncillas
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Alberto Ortiz
- Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
- REDINREN, Madrid, Spain
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46
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Dai M, Zhu XL, Liu F, Xu QY, Ge QL, Jiang SH, Yang XM, Li J, Wang YH, Wu QK, Ai ZH, Teng YC, Zhang ZG. Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma. Sci Rep 2017; 7:41404. [PMID: 28112250 PMCID: PMC5256103 DOI: 10.1038/srep41404] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 12/19/2016] [Indexed: 12/27/2022] Open
Abstract
3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.
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Affiliation(s)
- Miao Dai
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Xiao-Lu Zhu
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Fei Liu
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Qin-Yang Xu
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Qiu-Lin Ge
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Shu-Heng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Xiao-Mei Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Jun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Ya-Hui Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Qing-Kai Wu
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Zhi-Hong Ai
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Yin-Cheng Teng
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
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47
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Haring A, Murtola TJ, Talala K, Taari K, Tammela TLJ, Auvinen A. Antidiabetic drug use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. Scand J Urol 2017; 51:5-12. [DOI: 10.1080/21681805.2016.1271353] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Antti Haring
- School of Medicine, University of Tampere, Tampere, Finland
| | - Teemu J. Murtola
- School of Medicine, University of Tampere, Tampere, Finland
- Department of Urology, Tampere University Hospital, Tampere, Finland
| | | | - Kimmo Taari
- Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Teuvo L. J. Tammela
- School of Medicine, University of Tampere, Tampere, Finland
- Department of Urology, Tampere University Hospital, Tampere, Finland
| | - Anssi Auvinen
- School of Health Sciences, University of Tampere, Tampere, Finland
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48
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Vigneri R, Goldfine ID, Frittitta L. Insulin, insulin receptors, and cancer. J Endocrinol Invest 2016; 39:1365-1376. [PMID: 27368923 DOI: 10.1007/s40618-016-0508-7] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 06/23/2016] [Indexed: 12/13/2022]
Abstract
Insulin is a major regulator of cell metabolism but, in addition, is also a growth factor. Insulin effects in target cells are mediated by the insulin receptor (IR), a transmembrane protein with enzymatic (tyrosine kinase) activity. The insulin receptor, however, is represented by a heterogeneous family of proteins, including two different IR isoforms and also hybrid receptors resulting from the IR hemireceptor combination with a hemireceptor of the cognate IGF-1 receptor. These different receptors may bind insulin and its analogs with different affinity and produce different biologic effects. Since many years, it is known that many cancer cells require insulin for optimal in vitro growth. Recent data indicate that: (1) insulin stimulates growth mainly via its own receptor and not the IGF-1 receptor; (2) in many cancer cells, the IR is overexpressed and the A isoform, which has a predominant mitogenic effect, is more represented than the B isoform. These characteristics provide a selective growth advantage to malignant cells when exposed to insulin. For this reason, all conditions of hyperinsulinemia, both endogenous (prediabetes, metabolic syndrome, obesity, type 2 diabetes before pancreas exhaustion and polycystic ovary syndrome) and exogenous (type 1 diabetes) will increase the risk of cancer. Cancer-related mortality is also increased in patients exposed to hyperinsulinemia but other factors, related to the different diseases, may also contribute. The complexity of the diseases associated with hyperinsulinemia and their therapies does not allow a precise evaluation of the cancer-promoting effect of hyperinsulinemia, but its detrimental effect on cancer incidence and mortality is well documented.
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Affiliation(s)
- R Vigneri
- Endocrinology, Garibaldi-Nesima Medical Center, Via Palermo 636, 95122, Catania, Italy.
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
- Humanitas, Catania Cancer Center, Catania, Italy.
- CNR, Institute of Bioimages and Biostructures, Catania, Italy.
| | - I D Goldfine
- University of California, San Francisco, CA, USA
| | - L Frittitta
- Endocrinology, Garibaldi-Nesima Medical Center, Via Palermo 636, 95122, Catania, Italy
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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49
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Chang SC, Yang WCV. Hyperglycemia, tumorigenesis, and chronic inflammation. Crit Rev Oncol Hematol 2016; 108:146-153. [PMID: 27931833 DOI: 10.1016/j.critrevonc.2016.11.003] [Citation(s) in RCA: 119] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/08/2016] [Indexed: 12/21/2022] Open
Abstract
Hyperglycemia is the most prominent sign that characterizes diabetes. Hyperglycemia favors malignant cell growth by providing energy to cancer cells. Clinical studies also showed an increased risk of diabetes being associated with different types of cancers. In addition, poorly regulated glucose metabolism in diabetic patients is often found with increased levels of chronic inflammatory markers, e.g., interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, and emerging evidence has highlighted activation of the immune response in the progression and development of cancer cells. Therefore, uncontrolled proinflammatory responses could conceivably create a chronic inflammatory state, promoting a tumor-favorable microenvironment and potentially triggering immune overactivation and cancer growth. To further understand how hyperglycemia contributes to immune overactivation, the tumor microenvironment and the development of chronic inflammation-associated tumors may provide insights into tumor biology and immunology. This paper provides a brief introduction to hyperglycemia-associated diseases, followed by a comprehensive overview of the current findings of regulatory molecular mechanisms of glycosylation on proteoglycans in the extracellular matrix under hyperglycemic conditions. Then, the authors discuss the role of hyperglycemia in tumorigenesis (particularly in prostate, liver, colorectal, and pancreatic cancers), as well as the contribution of hyperglycemia to chronic inflammation. The authors end with a brief discussion on the future perspectives of hyperglycemia/tumorigenesis and potential applications of alternative/effective therapeutic strategies for hyperglycemia-associated cancers.
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Affiliation(s)
- Shu-Chun Chang
- The Ph.D. Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
| | - Wei-Chung Vivian Yang
- The Ph.D. Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
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50
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Moreno Rosales A, Corres Molina M, Góngora Moo J, Romero Morelos P, Bandala C. Breast Cancer Metastasis Associations with Clinicopathological Characteristics in Mexican Women Younger than 40 Years of Age. Asian Pac J Cancer Prev 2016; 17:5019-5023. [PMID: 28032733 PMCID: PMC5454713 DOI: 10.22034/apjcp.2016.17.11.5019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Background: In Mexico, breast cancer (BCa) is in first place regarding cancer mortality and has been established as a priority health issue. The incidence of metastasis from BCa is very high and presents as the principal mortality factor among women younger than 40 years of age. OBJECTIVE. To determine any associations between clinicopathological characteristics and metastasis in Mexican women under 40 years of age. Methods: During the 2010–2015 period, a total of 180 female BCa cases seen at the Navy General High Specialty Hospital, SEMAR, in Mexico City; we collected information on 20 patients with BCa younger than 40 years of age. Statistical analyses were conducted using the Kolmogorov–Smirnov, Students t, Fisher, Chi square, and Mantel–Haenszel tests. Results: The prevalence of women with BCa younger than the age of 40 years during the 2010–2015 period was 13.3%. We found a high frequency of obesity in of these cases (>75%); 100% of obese patients with a history of smoking presented with metastasis (p <0.05). In addition, the hormone phenotype was important; HER2-positive cases were 12 times more likely tto exhibit metastasis (p <0.05), while expression of estrogen and progesterone receptors appeared to be protective. Diabetes mellitus in combination with smoking was also a risk factor for development of metastasis (p <0.05). Conclusion: In this study, we obtained essential data regarding risk of metastasis in young breast cancer cases which could be useful for predicting disease evolution and treatment response.
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