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Li Y, Luo Y, Ran Y, Lu F, Qin Y. Biomarkers of inflammation and colorectal cancer risk. Front Oncol 2025; 15:1514009. [PMID: 39980561 PMCID: PMC11839431 DOI: 10.3389/fonc.2025.1514009] [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: 10/19/2024] [Accepted: 01/21/2025] [Indexed: 02/22/2025] Open
Abstract
Globally, colorectal malignancy ranks among the most prevalent forms of cancer and stands as the third principal cause of cancer-associated mortality. Recent studies indicate that inflammatory processes play a significant role in the initiation and advancement of various malignancies, colorectal cancer included. It explores inflammatory biomarkers, with C-reactive protein (CRP) being a key focus. While CRP's elevation during inflammation is linked to tumorigenesis, studies on its association with CRC risk are inconsistent, showing gender and methodological differences. Interleukin-6 (IL-6), TNF - α, and their receptors also play roles in CRC development, yet research findings vary. Adiponectin and leptin, secreted by adipocytes, have complex associations with CRC, with gender disparities noted. In terms of screening, non-invasive methods like fecal occult blood tests (FOBTs) are widely used, and combining biomarkers with iFOBT shows potential. Multi-omics techniques, including genomics and microbiomics, offer new avenues for CRC diagnosis. Overall, while evidence highlights the significance of inflammatory biomarkers in CRC risk prediction, larger prospective studies are urgently needed to clarify their roles due to existing inconsistencies and methodological limitations.
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Affiliation(s)
- Yuting Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Yuexin Luo
- First Clinic School, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue Ran
- Second Clinic School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Furong Lu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - You Qin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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2
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Jang JH, Kim DH, Chun KS. Tumor microenvironment regulation by reactive oxygen species-mediated inflammasome activation. Arch Pharm Res 2025; 48:115-131. [PMID: 39888519 DOI: 10.1007/s12272-025-01532-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
Tumor microenvironment (TME) is composed of diverse cell types whose interactions, both direct and indirect, significantly influence tumorigenesis and therapeutic outcomes. Within TME, reactive oxygen species (ROS) are produced by various cells and exhibit a dual role: moderate ROS levels promote tumor initiation and progression, whereas excessive levels induce cancer cell death, influencing the efficacy of anticancer therapies. Inflammasomes, cytosolic multiprotein complexes, are pivotal in multiple stages of tumorigenesis and play a crucial role in establishing the inflammatory TME. By releasing cytokines such as IL-1β and IL-18, inflammasomes contribute to immune cell recruitment and sustain a chronic inflammatory state that supports tumor growth. ROS are critical regulators of inflammasome activation, with the impact of ROS-mediated activation differing across cell types, leading to distinct influences on tumor progression and therapeutic responses. This review explores how ROS drive inflammasome activation in various TME-associated cells and the reciprocal ROS generation induced by inflammasomes, examining their multifaceted impact on tumorigenesis and therapeutic efficacy. By elucidating the complex interplay between ROS and inflammasomes in TME, we provide insights into potential therapeutic approaches that could modulate cancer progression and enhance treatment outcomes.
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Affiliation(s)
- Jeong-Hoon Jang
- College of Pharmacy, Daegu Catholic University, Gyeongsan-si, Gyeongbuk, 38430, Republic of Korea
| | - Do-Hee Kim
- Department of Chemistry, Kyonggi University, Suwon, 16227, Republic of Korea
| | - Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea.
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3
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Liu J, Lai F, Hou Y, Zheng R. Leptin signaling and leptin resistance. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:363-384. [PMID: 37724323 PMCID: PMC10388810 DOI: 10.1515/mr-2022-0017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/12/2022] [Indexed: 09/20/2023]
Abstract
With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)-signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.
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Affiliation(s)
- Jiarui Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Futing Lai
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Yujia Hou
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Ruimao Zheng
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
- Neuroscience Research Institute, Peking University, Beijing, China
- Key Laboratory for Neuroscience of Ministry of Education, Peking University, Beijing, China
- Key Laboratory for Neuroscience of National Health Commission, Peking University, Beijing 100191, China
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Psychological intervention to treat distress: An emerging frontier in cancer prevention and therapy. Biochim Biophys Acta Rev Cancer 2021; 1877:188665. [PMID: 34896258 DOI: 10.1016/j.bbcan.2021.188665] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/27/2021] [Accepted: 12/01/2021] [Indexed: 02/05/2023]
Abstract
Psychological distress, such as chronic depression and anxiety, is a topical problem. In the context of cancer patients, prevalence rates of psychological distress are four-times higher than in the general population and often confer worse outcomes. In addition to evidence from epidemiological studies confirming the links between psychological distress and cancer progression, a growing body of cellular and molecular studies have also revealed the complex signaling networks which are modulated by psychological distress-derived chronic stress during cancer progression. In this review, aiming to uncover the intertwined networks of chronic stress-driven oncogenesis and progression, we summarize physiological stress response pathways, like the HPA, SNS, and MGB axes, that modulate the release of stress hormones with potential carcinogenic properties. Furthermore, we discuss in detail the mechanisms behind these chronic stimulations contributing to the initiation and progression of cancer through direct regulation of cancer hallmarks-related signaling or indirect promotion of cancer risk factors (including obesity, disordered circadian rhythms, and premature senescence), suggesting a novel research direction into cancer prevention and therapy on the basis of psychological interventions.
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Hu X, Fatima S, Chen M, Xu K, Huang C, Gong RH, Su T, Wong HLX, Bian Z, Kwan HY. Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism. Cell Death Dis 2021; 12:791. [PMID: 34385421 PMCID: PMC8360949 DOI: 10.1038/s41419-021-04076-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/22/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
Although high-fat diet (HFD) has been implicated in the development of colorectal cancer (CRC), the critical signaling molecule that mediates the cancer growth is not well-defined. Identifying the master regulator that controls CRC growth under HFD can facilitate the development of effective therapeutics for the cancer treatment. In this study, the global lipidomics and RNA sequencing data show that, in the tumor tissues of CRC-bearing mouse models, HFD not only increases tumor weight, but also the palmitic acid level and TLR4 expression, which are reduced when HFD is replaced by control diet. These concomitant changes suggest the roles of palmitic acid and TLR4 in CRC growth. Subsequent studies show that palmitic acid regulates TLR4 expression in PU.1-dependent manner. Knockdown of PU.1 or mutations of PU.1-binding site on TLR4 promoter abolish the palmitic acid-increased TLR4 expression. The role of palmitic acid/PU.1/TLR4 axis in CRC growth is further examined in cell model and animal models that are fed either HFD or palmitic acid-rich diet. More importantly, iTRAQ proteomics data show that knockdown of TLR4 changes the metabolic enzyme profiles in the tumor tissues, which completely abolish the HFD-enhanced ATP production and cancer growth. Our data clearly demonstrate that TLR4 is a master regulator for CRC growth under HFD by programming cancer metabolism.
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Affiliation(s)
- Xianjing Hu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Sarwat Fatima
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Minting Chen
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Keyang Xu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Chunhua Huang
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Rui-Hong Gong
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Tao Su
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Hoi Leong Xavier Wong
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Zhaoxiang Bian
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Hiu Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
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Wang Y, Li J, Fu X, Li J, Liu L, Alkohlani A, Tan SC, Low TY, Hou Y. Association of circulating leptin and adiponectin levels with colorectal cancer risk: A systematic review and meta-analysis of case-control studies. Cancer Epidemiol 2021; 73:101958. [PMID: 34020315 DOI: 10.1016/j.canep.2021.101958] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/02/2021] [Accepted: 05/05/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE Leptin and adiponectin are adipokines which have been commonly implicated in carcinogenesis. As such, many studies have investigated the association of circulating leptin and adiponectin levels with colorectal cancer (CRC) risk. However, the results remained inconsistent. METHODS In this work, we performed a systematic review and meta-analysis to precisely examine the association between circulating levels of leptin and adiponectin and CRC risk. A systematic literature search was performed in PubMed/MEDLINE, Scopus, Web of Science, and EMBASE databases from inception until October 2020. The pooled effect size was then estimated by calculating the odds ratio (OR). RESULTS A total of 23 records (comprising 26 studies) were included in the meta-analysis. The overall analysis found that circulating levels of leptin and adiponectin were not significantly associated with CRC risk (P > 0.05). Interestingly, subgroup analysis revealed that a higher level of adiponectin was significantly associated with an increased CRC risk among overweight individuals (OR = 1.16; 95 % CI: 1.02, 1.32), and a decreased CRC risk among normal weight individuals (OR = 0.76; 95 % CI: 0.62, 0.92). Besides, a higher level of adiponectin was also significantly associated with a decreased risk of CRC in men (OR = 0.76; 95 % CI: 0.59, 0.98). CONCLUSIONS In conclusion, circulating leptin level was not associated with CRC risk, but that of adiponectin was associated with CRC risk only in specific subgroups.
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Affiliation(s)
- Yan Wang
- Department of Oncology and Hematology, The First People's Hospital of Longquanyi District, Chengdu, Chengdu, Sichuan, 510100, China
| | - Junyong Li
- Department of Oncology and Hematology, The First People's Hospital of Longquanyi District, Chengdu, Chengdu, Sichuan, 510100, China
| | - Xiaolin Fu
- Department of Oncology and Hematology, The First People's Hospital of Longquanyi District, Chengdu, Chengdu, Sichuan, 510100, China
| | - Jialing Li
- Department of Oncology and Hematology, The First People's Hospital of Longquanyi District, Chengdu, Chengdu, Sichuan, 510100, China
| | - Lihua Liu
- Department of Oncology and Hematology, The First People's Hospital of Longquanyi District, Chengdu, Chengdu, Sichuan, 510100, China
| | | | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Yue Hou
- Department of Oncology and Hematology, The First People's Hospital of Longquanyi District, Chengdu, Chengdu, Sichuan, 510100, China.
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Fang Z, Hang D, Wang K, Joshi A, Wu K, Chan AT, Ogino S, Giovannucci EL, Song M. Risk prediction models for colorectal cancer: Evaluating the discrimination due to added biomarkers. Int J Cancer 2021; 149:1021-1030. [PMID: 33948940 DOI: 10.1002/ijc.33621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/07/2021] [Accepted: 04/20/2021] [Indexed: 02/05/2023]
Abstract
Most risk prediction models for colorectal cancer (CRC) are based on questionnaires and show a modest discriminatory ability. Therefore, we aim to develop risk prediction models incorporating plasma biomarkers for CRC to improve discrimination. We assessed the predictivity of 11 biomarkers in 736 men in the Health Professionals Follow-up Study and 639 women in the Nurses' Health Study. We used stepwise logistic regression to examine whether a set of biomarkers improved the predictivity on the basis of predictors in the National Cancer Institute's (NCI) Colorectal Cancer Risk Assessment Tool. Model discrimination was assessed using C-statistics. Bootstrap with 500 randomly sampled replicates was used for internal validation. The models containing each biomarker generated a C-statistic ranging from 0.50 to 0.59 in men and 0.50 to 0.54 in women. The NCI model demonstrated a C-statistic (95% CI) of 0.67 (0.62-0.71) in men and 0.58 (0.54-0.63) in women. Through stepwise selection of biomarkers, the C-statistic increased to 0.70 (0.66-0.74) in men after adding growth/differentiation factor 15, total adiponectin, sex hormone binding globulin and tumor necrosis factor receptor superfamily member 1B (P for difference = 0.008); and increased to 0.62 (0.57-0.66) in women after further including insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 (P for difference = .06). The NCI + selected biomarkers model was internally validated with a C-statistic (95% CI) of 0.73 (0.70-0.77) in men and 0.66 (0.61-0.70) in women. Circulating plasma biomarkers may improve the performance of risk factor-based prediction model for CRC.
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Affiliation(s)
- Zhe Fang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Dong Hang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Kai Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Amit Joshi
- Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.,Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Jia J, Dai Y, Zhang Q, Tang P, Fu Q, Xiong G. Stromal Score-Based Gene Signature: A Prognostic Prediction Model for Colon Cancer. Front Genet 2021; 12:655855. [PMID: 34054919 PMCID: PMC8150004 DOI: 10.3389/fgene.2021.655855] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/19/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Growing evidence has revealed the crucial roles of stromal cells in the microenvironment of various malignant tumors. However, efficient prognostic signatures based on stromal characteristics in colon cancer have not been well-established yet. The present study aimed to construct a stromal score-based multigene prognostic prediction model for colon cancer. METHODS Stromal scores were calculated based on the expression profiles of a colon cancer cohort from TCGA database applying the ESTIMATE algorithm. Linear models were used to identify differentially expressed genes between low-score and high-score groups by limma R package. Univariate, LASSO, and multivariate Cox regression models were used successively to select the prognostic gene signature. Two independent datasets from GEO were used as external validation cohorts. RESULTS Low stromal score was demonstrated to be a favorable factor to the overall survival of colon cancer patients in TCGA cohort (p = 0.0046). Three hundred and seven stromal score-related differentially expressed genes were identified. Through univariate, LASSO, and multivariate Cox regression analyses, a gene signature consisting of LEP, NOG, and SYT3 was recognized to build a prognostic prediction model. Based on the predictive values estimated by the established integrated model, patients were divided into two groups with significantly different overall survival outcomes (p < 0.0001). Time-dependent Receiver operating characteristic curve analyses suggested the satisfactory predictive efficacy for the 5-year overall survival of the model (AUC value = 0.733). A nomogram with great predictive performance combining the multigene prediction model and clinicopathological factors was developed. The established model was validated in an external cohort (AUC value = 0.728). In another independent cohort, the model was verified to be of significant prognostic value for different subgroups, which was demonstrated to be especially accurate for young patients (AUC value = 0.763). CONCLUSION The well-established model based on stromal score-related gene signature might serve as a promising tool for the prognostic prediction of colon cancer.
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Affiliation(s)
- Jing Jia
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuhan Dai
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Qing Zhang
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Peiyu Tang
- The School of Stomatology, Nanjing Medical University, Nanjing, China
| | - Qiang Fu
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guanying Xiong
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Wang J, Zhou F, Li F, Wang B, Hu Y, Li X. Autocrined leptin promotes proliferation of non-small cell lung cancer (NSCLC) via PI3K/AKT and p53 pathways. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:568. [PMID: 33987266 DOI: 10.21037/atm-20-7482] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Circulating leptin can directly act on tumor cells. However, a recent meta-analysis showed that plasma leptin concentration had no significant effect on the survival of lung cancer patients. So does Leptin have an effect on lung cancer? Or there may be other factors that influence the effect. Methods Genome sequencing database Oncomine was searched to learn the differential expression of leptin between tumors and normal lungs. Fresh tumor specimens and paired normal lung tissue from six lung adenocarcinoma patients were collected, and validate the expression level of leptin. Clinicopathological information and tumor slices from 60 non-small cell lung cancer (NSCLC) patients were analyzed to evaluate the prognostic value of autocrined leptin. Whole genome sequencing data from the cancer genome atlas (TCGA) was analyzed to predict the underlying mechanism of leptin regulating tumor proliferation. Finally, these findings were confirmed by using cell lines H1299, A549, H460, and H322 to explore the promoting effect and mechanism of leptin on cell proliferation in vitro. Results Five datasets in Oncomine reported the expression of the LEP gene in NSCLC, and 4 datasets showed that leptin was up-regulated in tumors compared with normal lungs. Leptin was also overexpressed in 5 out of 6 clinical lung adenocarcinoma specimens. The analysis of the 60 NSCLC patients revealed that autocrined leptin could serve as an auxiliary prognostic factor, and a higher expression of leptin indicated a higher survival risk. Gene set enrichment analysis (GSEA) showed that the PI3K/AKT/mTOR signaling pathway was positively enriched when the LEP gene was highly expressed, while the P53 signaling pathway was negatively enriched. Leptin promoted cell cycle and clone formation in H1299 and A549 cells, up-regulation or down-regulation of leptin in these two cell lines led to enhanced or declined proliferation. Finally, it was confirmed that the PI3K/AKT/mTOR signaling pathway was positively regulated by leptin expression, while the P53 signaling pathway was negatively regulated. Conclusions Autocrined leptin was observed in majority of NSCLC tissue, which could serve as an auxiliary prognostic factor for NSCLC patients. Autocrined leptin had a promoting effect on the proliferation of NSCLC cells, which probably positively regulating the PI3K/AKT/mTOR signaling pathway and negatively regulate the P53 signaling pathway.
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Affiliation(s)
- Jin Wang
- Department of Immunology, Dalian Medical University, Dalian, China.,Department of Thoracic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fachen Zhou
- Department of Thoracic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fengzhou Li
- Department of Thoracic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bing Wang
- Department of Immunology, Dalian Medical University, Dalian, China
| | - Yiying Hu
- Department of Neuroelectrophysiology, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xia Li
- Department of Immunology, Dalian Medical University, Dalian, China
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A Study on the Immunohistochemical Expressions of Leptin and Leptin Receptor in Clear Cell Renal Cell Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3682086. [PMID: 32802842 PMCID: PMC7424391 DOI: 10.1155/2020/3682086] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 06/22/2020] [Indexed: 12/17/2022]
Abstract
Background The mechanisms that link obesity and cancer development are not well-defined. Investigation of leptin and leptin receptor expressions may help define some of the mechanisms. These proteins are known for associating with the immune response, angiogenesis and, signalling pathways such as JAK2/STAT3, PI3K, and AKT pathways. Tissue proteins can be easily detected with immunohistochemistry (IHC), a technique widely used both in diagnostic and research laboratories. The identification of altered levels of leptin and leptin receptor proteins in tumour tissues may lead to targeted treatment for cancer. Objective The objective of this study was to use IHC to compare leptin and leptin receptor expressions in clear cell renal cell carcinomas (ccRCC) in non-obese and obese patients to determine the association between these proteins with the clinicopathological features and prognosis of ccRCC. Patients and Methods. The study involved 60 patients who underwent nephrectomy of which 34 were obese, as assessed using body mass index (BMI). Nephrectomy samples provided tissues of ccRCC and adjacent non-cancerous kidney. The intensity and localization of leptin and leptin receptor protein expressions were evaluated using IHC and correlated with clinicopathological features and clinical outcomes. Aperio ImageScope morphometry and digital pathology were applied to assess the IHC results. The chi-square test was used to determine if there was any significant association between the proteins and the clinicopathological features. The Kaplan-Meier test was used to determine the overall survival, disease-free survival, and recurrence-free survival. A value of p < 0.05 was considered significant. Results There was neither significant difference in the overall cellular and nuclear expressions of leptin and leptin receptor between non-cancerous kidney and ccRCC tissues nor in non-obese and obese individuals with ccRCC. Conclusion In this present study, it was revealed that leptin and leptin receptor were not associated with tumour characteristics and progression of ccRCC patients. Interestingly, nuclear expression of leptin was significantly associated with overall survival. However, the significance of these proteins as biomarkers in other RCC histotypes is still unclear.
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11
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Guinter MA, Gapstur SM, McCullough ML, Flanders WD, Wang Y, Rees-Punia E, Alcaraz KI, Pollak MN, Campbell PT. Prospective Association of Energy Balance Scores Based on Metabolic Biomarkers with Colorectal Cancer Risk. Cancer Epidemiol Biomarkers Prev 2020; 29:974-981. [PMID: 32094199 DOI: 10.1158/1055-9965.epi-19-1382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/09/2020] [Accepted: 02/13/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Energy balance-related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear. METHODS We used reduced rank regression to derive three energy balance scores that associate lifestyle factors with combinations of prediagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A1c (HbA1c) among 2,498 participants in the Cancer Prevention Study-II Nutrition Cohort. Among 114,989 participants, we verified 2,228 colorectal cancer cases. We assessed associations of each score with colorectal cancer incidence and by tumor molecular phenotypes using Cox proportional hazards regression. RESULTS The derived scores comprised BMI, physical activity, screen time, and 14 food groups, and explained 5.1% to 10.5% of the variation in biomarkers. The HR and 95% confidence interval (CI) for quartile 4 versus 1 of the HbA1c+C peptide-based score and colorectal cancer was 1.30 (1.15-1.47), the hsCRP-based score was 1.35 (1.19-1.53), and the hsCRP, C-peptide, and HbA1c-based score was 1.35 (1.19-1.52). The latter score was associated with non-CIMP tumors (HRQ4vsQ1: 1.59; 95% CI: 1.17-2.16), but not CIMP-positive tumors (P heterogeneity = 0.04). CONCLUSIONS These results further support hypotheses that systemic biomarkers of metabolic health-inflammation and abnormal glucose homeostasis-mediate part of the relationship between several energy balance-related modifiable factors and colorectal cancer risk. IMPACT Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet, and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors.
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Affiliation(s)
- Mark A Guinter
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
| | - Susan M Gapstur
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Marjorie L McCullough
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - W Dana Flanders
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
- Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Ying Wang
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Erika Rees-Punia
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Kassandra I Alcaraz
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Michael N Pollak
- Center for Translational Research in Cancer, McGill University, Montreal, Quebec, Canada
| | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
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12
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Circulating adipokines and risk of obesity related cancers: A systematic review and meta-analysis. Obes Res Clin Pract 2019; 13:329-339. [DOI: 10.1016/j.orcp.2019.03.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/13/2019] [Accepted: 03/27/2019] [Indexed: 12/21/2022]
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13
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Raut PK, Kim SH, Choi DY, Jeong GS, Park PH. Growth of breast cancer cells by leptin is mediated via activation of the inflammasome: Critical roles of estrogen receptor signaling and reactive oxygen species production. Biochem Pharmacol 2019; 161:73-88. [PMID: 30633869 DOI: 10.1016/j.bcp.2019.01.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/07/2019] [Indexed: 12/12/2022]
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14
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Nikolaou S, Qiu S, Fiorentino F, Rasheed S, Tekkis P, Kontovounisios C. The prognostic and therapeutic role of hormones in colorectal cancer: a review. Mol Biol Rep 2018; 46:1477-1486. [PMID: 30535551 DOI: 10.1007/s11033-018-4528-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 11/23/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the commonest cancers in Western society with a poor prognosis in patients with advanced disease. Targeted therapy is of increasing interest and already, targeted hormone treatment for breast and prostate cancer has improved survival. The aim of this literature review is to summarise the role of hormones in CRC prognosis and treatment. A literature review of all human and animal in vivo and in vitro studies in the last 20 years, which assessed the role of hormones in CRC treatment or prognosis, was carried out. The hormones described in this review have been subdivided according to their secretion origin. Most of the studies are based on in vitro or animal models. The main findings point to adipokines, insulin and the insulin growth factor axis as key players in the link between obesity, type 2 diabetes mellitus and a subset of CRC. Gut-derived hormones, especially uroguanylin and guanylin are being increasingly investigated as therapeutic targets, with promising results. Using hormones as prognostic and therapeutic markers in CRC is still in the preliminary stages for only a fraction of the hormones affecting the GIT. In light of the increasing interest in tailoring treatment strategies, hormones are an important area of focus in the future of CRC management.
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Affiliation(s)
- Stella Nikolaou
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK. .,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK. .,Department of Surgery and Cancer, Imperial College, London, UK. .,Department of Surgery and Cancer, Imperial College London, Royal Marsden Hospital, Fulham Road & Chelsea and Westminster Campus, 369 Fulham Road, London, SW10 9NH, UK.
| | - Shengyang Qiu
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | | | - Shahnawaz Rasheed
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - Paris Tekkis
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - Christos Kontovounisios
- Department of Colorectal Surgery, Chelsea & Westminster Hospital, London, UK.,Department of Colorectal Surgery, Royal Marsden Hospital, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
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15
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Chun KA, Kocarnik JM, Hardikar SS, Robinson JR, Berndt SI, Chan AT, Figueiredo JC, Lindor NM, Song M, Schoen RE, Hayes RB, Potter JD, Nassir R, Bézieau S, Le Marchand L, Slattery ML, White E, Peters U, Newcomb PA. Leptin gene variants and colorectal cancer risk: Sex-specific associations. PLoS One 2018; 13:e0206519. [PMID: 30379922 PMCID: PMC6209341 DOI: 10.1371/journal.pone.0206519] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/15/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk. METHODS We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance. RESULTS Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men. CONCLUSIONS Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.
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Affiliation(s)
- Kelsey A. Chun
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Jonathan M. Kocarnik
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Institute of Translational Health Sciences, University of Washington, Seattle, WA, United States of America
| | - Sheetal S. Hardikar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States of America
| | - Jamaica R. Robinson
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Institute of Translational Health Sciences, University of Washington, Seattle, WA, United States of America
| | - Sonja I. Berndt
- Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD, United States of America
| | - Andrew T. Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Cambridge, MA, United States of America
| | - Jane C. Figueiredo
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States of America
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Noralane M. Lindor
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, United States of America
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Cambridge, MA, United States of America
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States of America
| | - Robert E. Schoen
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Richard B. Hayes
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, United States of America
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Department of Epidemiology, University of Washington, Seattle, WA, United States of America
| | - Rami Nassir
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Davis, CA, United States of America
| | - Stéphane Bézieau
- Service de Génétique Médicale, Université de Nantes, Nantes, France
| | - Loic Le Marchand
- Epidemiology Program, University of Hawai‘i Cancer Center, Honolulu, HI, United States of America
| | - Martha L. Slattery
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, United States of America
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Department of Epidemiology, University of Washington, Seattle, WA, United States of America
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Department of Epidemiology, University of Washington, Seattle, WA, United States of America
| | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Department of Epidemiology, University of Washington, Seattle, WA, United States of America
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16
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Li YR, Ro V, Tchou JC. Obesity, Metabolic Syndrome, and Breast Cancer: From Prevention to Intervention. CURRENT SURGERY REPORTS 2018; 6:7. [PMID: 31293823 PMCID: PMC6619425 DOI: 10.1007/s40137-018-0204-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity contributes to an estimated forty-percent, or 630,000 cases, of malignant neoplasms diagnosed in the United States[1] and higher body mass index (BMI) has been associated with at least seventeen types of solid tumors, including 9% of all breast cancer cases. In this review, we discuss the impact of obesity and consequences of obesity, including the metabolic syndrome and type 2 diabetes mellitus, on breast cancer risk and recurrence. Recent work has identified multiple molecular mechanisms that may underlie the association between obesity and breast cancer. In particular, insulin resistance, increased inflammatory cytokines, leptin signaling, and adipokine signaling have been shown to affect breast cancer risk and outcomes. While obesity is associated with higher breast cancer incidences and worse breast cancer outcomes, several risk reduction methods have been shown to attenuate these risks. Both metformin and statins have been shown to improve disease free survival and overall survival compared to non-users. Metformin also has been associated with lower risk of breast cancer incidence. Furthermore, increased physical activity and weight loss have been shown to decrease risk of breast cancer, especially in post-menopausal women. These studies have emphasized the potential impact that lifestyle changes can have on breast cancer risk and outcomes, and demonstrate the need for randomized control trials to evaluate the roles of metformin and statins for the treatment and chemoprevention of breast cancer.
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Affiliation(s)
- Yun Rose Li
- Department of Endocrine and Oncologic Surgery, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA, 19104
- Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California
San Francisco, San Francisco, CA, 94143
| | - Vicky Ro
- Department of Endocrine and Oncologic Surgery, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA, 19104
| | - Julia C. Tchou
- Department of Endocrine and Oncologic Surgery, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA, 19104
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17
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Abstract
Leptin is an adipocyte-derived hormone, which contributes to the homeostatic regulation of energy balance and metabolism through humoral and neural pathways. Leptin acts on the neurons in certain brain areas such as the hypothalamus, hippocampus, and brain stem to regulate food intake, thermogenesis, energy expenditure, and homeostasis of glucose/lipid metabolism. The pathologically increased circulating leptin is a biomarker of leptin resistance, which is common in obese individuals. Leptin resistance is defined by a reduced sensitivity or a failure in response of the brain to leptin, showing a decrease in the ability of leptin to suppress appetite or enhance energy expenditure, which causes an increased food intake and finally leads to overweight, obesity, cardiovascular diseases, and other metabolic disorders. Leptin resistance is a challenge for clinical treatment or drug discovery of obesity. Until recently, emerging evidence has been showing novel mechanisms of the leptin resistance. Here, we summarized the advances and controversy of leptin resistance and associated diseases, for better understanding the physiology and pathophysiology of leptin as well as the new strategies for treating obesity and metabolic disorders.
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18
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A prospective, multicenter pilot study to investigate the feasibility and safety of a 1-year controlled exercise training after adjuvant chemotherapy in colorectal cancer patients. Support Care Cancer 2017; 26:1345-1352. [PMID: 29168033 DOI: 10.1007/s00520-017-3961-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 11/06/2017] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Despite advances in adjuvant chemotherapy, 20-30% of patients in stages II-III colorectal cancer will eventually relapse. Observational studies showed a reduction in relapse rate, colon cancer-specific mortality, and overall mortality by physical activity. Results from prospective randomized interventional studies to confirm these observational data are lacking. The aims of this prospective single-arm multicenter pilot study are to evaluate feasibility and safety of exercise training after adjuvant chemotherapy in colorectal cancer patients. PATIENTS AND METHODS The training was performed three times per week for 1 year and was increased gradually in three phases until reaching 18 metabolic equivalent task hours per week. RESULTS Overall, 30 patients were included. The planned training intensity could be achieved in all three phases. Patients experienced a performance increase of median 35.5 watt, a weight-loss of a median of 3.0 kg, and a reduction in body fat content of median 1.0% during this exercise training. The analysis showed early study termination due to non-compliance in 10/30 patients (33.3%), disease progression in 4 patients (13.3%), and serious adverse events in 2 patients (6.7%). About half of patients (46.7%) completed the pilot study as planned. Biomarker analysis from 20 patients showed a non-significant reduction in insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2) and insulin-like growth factor binding protein 3 (IGF-BP3) levels, significant increases in adiponectin and leptin levels, and a non-significant increase in C-peptide levels. CONCLUSION Exercise training is feasible in patients with colorectal cancer after completion of adjuvant chemotherapy. The main problem encountered during the study was compliance. To improve compliance of exercise training, several measures were adapted for the upcoming prospective randomized ABCSG C08 Exercise II study.
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19
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Kwan HY, Chao X, Su T, Fu X, Tse AKW, Fong WF, Yu ZL. The anticancer and antiobesity effects of Mediterranean diet. Crit Rev Food Sci Nutr 2017; 57:82-94. [PMID: 25831235 DOI: 10.1080/10408398.2013.852510] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cancers have been the leading cause of death worldwide and the prevalence of obesity is also increasing in these few decades. Interestingly, there is a direct association between cancer and obesity. Each year, more than 90,000 cancer deaths are caused by obesity or overweight. The dietary pattern in Crete, referred as the traditional Mediterranean diet, is believed to confer Crete people the low mortality rates from cancers. Nevertheless, the antiobesity effect of the Mediterranean diet is less studied. Given the causal relationship between obesity and cancer, the antiobesity effect of traditional Mediterranean diet might contribute to its anticancer effects. In this regard, we will critically review the anticancer and antiobesity effects of this diet and its dietary factors. The possible mechanisms underlying these effects will also be discussed.
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Affiliation(s)
- Hiu Yee Kwan
- a Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong , Hong Kong , China
| | - Xiaojuan Chao
- a Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong , Hong Kong , China
| | - Tao Su
- a Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong , Hong Kong , China
| | - Xiuqiong Fu
- a Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong , Hong Kong , China
| | - Anfernee Kai Wing Tse
- a Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong , Hong Kong , China
| | - Wang Fun Fong
- a Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong , Hong Kong , China
| | - Zhi-Ling Yu
- a Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong , Hong Kong , China
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20
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Saetang J, Sangkhathat S. Diets link metabolic syndrome and colorectal cancer development (Review). Oncol Rep 2017; 37:1312-1320. [PMID: 28098913 DOI: 10.3892/or.2017.5385] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Accepted: 01/13/2017] [Indexed: 02/07/2023] Open
Abstract
Diets have been believed to be an important factor in the development of metabolic syndrome and colorectal cancer (CRC). In recent years, many studies have shown an intimate relationship between mucosal immunity, metabolism and diets, which has led to a greater understanding of the pathophysiology of metabolic syndrome and CRC development. Although the precise effects of diets on oncogenesis have not been compl-etely elucidated, microbiota changes and inflammation are believed to be important factors that influence the development of CRC. Moreover, increased release of pro-inflammatory cytokines and alteration of adipokine levels have been observed in patients with colorectal adenoma and/or CRC, and these all have been considered as the important mechanisms that link diets to the development of metabolic syndrome and CRC. Importantly, a high-fat, low-fiber diet is associated with dysbiosis, and as the gut signature becomes more important in metabolic syndrome and CRC, an increased understanding of diets on bacterial activity in the pathogenesis of metabolic syndrome and CRC will lead to new preventive and therapeutic strategies.
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Affiliation(s)
- Jirakrit Saetang
- Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Surasak Sangkhathat
- Tumor Biology Research Unit, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
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21
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Fukumura D, Incio J, Shankaraiah RC, Jain RK. Obesity and Cancer: An Angiogenic and Inflammatory Link. Microcirculation 2016; 23:191-206. [PMID: 26808917 DOI: 10.1111/micc.12270] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 01/20/2016] [Indexed: 12/15/2022]
Abstract
With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
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Affiliation(s)
- Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joao Incio
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.,Department of Internal Medicine, Hospital S. João, Porto, Portugal
| | - Ram C Shankaraiah
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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22
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Mahmoudi T, Farahani H, Nobakht H, Dabiri R, Zali MR. Genetic Variations in Leptin and Leptin Receptor and Susceptibility to Colorectal Cancer and Obesity. IRANIAN JOURNAL OF CANCER PREVENTION 2016; 9:e7013. [PMID: 27703650 PMCID: PMC5038839 DOI: 10.17795/ijcp-7013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 04/15/2016] [Indexed: 01/29/2023]
Abstract
Background Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the fourth leading cause of cancer-related mortality around the world. Objectives With regard to the role of obesity in colorectal cancer (CRC) and the role of leptin in obesity, we investigated whether leptin (LEP) and leptin receptor (LEPR) gene variants are associated with CRC risk. Patients and Methods We evaluated LEP (rs7799039) and LEPR (rs1137101) gene variants by using PCR-RFLP method in 261 cases with CRC and 339 controls. Results No significant difference was found for rs7799039 and rs1137101gene variants between the cases with CRC and controls. However, the LEPR rs1137101 “GG” genotype compared with “AA” genotype and “AA + AG” genotype was associated with increased risks for obesity, and the differences remained significant after adjustment for confounding factors including age, sex, smoking status, and NSAID use (P = 0.015; OR = 2.42, 95%CI = 1.19 - 4.93 and P = 0.016; OR = 2.28, 95%CI = 1.17 - 4.48, respectively). In addition, the LEPR “G” allele compared with the “A” allele was associated with an increased risk for obesity (P = 0.024; OR = 1.44, 95%CI = 1.05 - 1.98). Conclusions Consistent with most previous studies, our findings found no association between LEP (rs7799039) and LEPR (rs1137101) gene variants and CRC risk. However, the LEPR rs1137101 “GG” genotype compared with the “AA” genotype and “AA+AG” genotype was associated with a 2.42-fold and a 2.28-fold increased risk for obesity, respectively.
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Affiliation(s)
- Touraj Mahmoudi
- Department of Cancer, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Hamid Farahani
- Department of Physiology, School of Medicine, Qom University of Medical Sciences, Qom, IR Iran
| | - Hossein Nobakht
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, IR Iran
| | - Reza Dabiri
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, IR Iran
| | - Mohammad Reza Zali
- Department of Cancer, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
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23
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Oh JS, Kim HH, Hwang HS, Yun DY, Kim BS, Lee CH, Han J, Kim HG, Jung JT, Kwon JG, Kim EY. [Comparison of blood leptin concentration and colonic mucosa leptin expression in colon adenoma patients and healthy control]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2016; 63:354-60. [PMID: 24953612 DOI: 10.4166/kjg.2014.63.6.354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND/AIMS Obesity increases the risk of colorectal cancer and adenomatous polyp, and one of the underlying mechanisms of this increase is considered to be due to the growth promoting effects of adipokines, such as leptin. In order to investigate this finding, leptin expression in the colonic tissue and blood leptin concentration of the colonic adenoma patients were compared to those of the control group. METHODS Colonic adenoma tissues were obtained by polypectomy (n=60). In these patients, normal colonic mucosa at remote areas from the polyp was also obtained and blood samples were collected as well. Age and sex matched control subjects were selected among those who showed normal colonic mucosa in health screening colonoscopy (n=60). RESULTS There was no significant difference in serum leptin concentration between the colonic adenoma patients and control subjects. Leptin expression was noted in 43.3% of the colonic adenomas, but only in 6.7% of normal colonic mucosa from the control subjects (p<0.01). There were ten cases of concurrent adenocarcinoma in situ in adenoma patients, eight cases of which expressed leptin (p=0.01). In adenoma group, leptin expression rate was significantly high in larger adenomas and in obese patients (p<0.05). However, there was no statistically significant relationship between leptin expression in colonic mucosa and serum leptin level. CONCLUSIONS Leptin expression was more frequently observed in colonic adenomas, especially in larger adenomas associated with adenocarcinoma in situ, but blood leptin level was not related to tissue leptin expression. Leptin expression was more frequently observed in obese patients from the adenoma group. Therefore, leptin may play an important role in colonic tumorigenesis and progression, especially in obese patient.
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Affiliation(s)
- Jang Seok Oh
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu 705-718, Korea
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24
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Pietrzyk L, Torres A, Maciejewski R, Torres K. Obesity and Obese-related Chronic Low-grade Inflammation in Promotion of Colorectal Cancer Development. Asian Pac J Cancer Prev 2016; 16:4161-8. [PMID: 26028066 DOI: 10.7314/apjcp.2015.16.10.4161] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is a worldwide health problem, being the third most commonly detected cancer in males and the second in females. Rising CRC incidence trends are mainly regarded as a part of the rapid 'Westernization' of life-style and are associated with calorically excessive high-fat/low-fibre diet, consumption of refined products, lack of physical activity, and obesity. Most recent epidemiological and clinical investigations have consistently evidenced a significant relationship between obesity-driven inflammation in particular steps of colorectal cancer development, including initiation, promotion, progression, and metastasis. Inflammation in obesity occurs by several mechanisms. Roles of imbalanced metabolism (MetS), distinct immune cells, cytokines, and other immune mediators have been suggested in the inflammatory processes. Critical mechanisms are accounted to proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-α (TNF-α). These molecules are secreted by macrophages and are considered as major agents in the transition between acute and chronic inflammation and inflammation-related CRC. The second factor promoting the CRC development in obese individuals is altered adipokine concentrations (leptin and adiponectin). The role of leptin and adiponectin in cancer cell proliferation, invasion, and metastasis is attributable to the activation of several signal transduction pathways (JAK/STAT, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), mTOR, and 5'AMPK signaling pathways) and multiple dysregulation (COX-2 downregulation, mRNA expression).
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Affiliation(s)
- Lukasz Pietrzyk
- Laboratory of Biostructure, Department of Human Anatomy, Medical University of Lublin, Military Clinical Hospital, Lublin, Poland E-mail :
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25
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Nimptsch K, Pischon T. Body fatness, related biomarkers and cancer risk: an epidemiological perspective. Horm Mol Biol Clin Investig 2016; 22:39-51. [PMID: 25781710 DOI: 10.1515/hmbci-2014-0043] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/16/2015] [Indexed: 12/15/2022]
Abstract
Higher body fatness is not only associated with a higher risk of hypertension, type 2 diabetes, and coronary heart disease but also with certain types of cancer. The scope of this review is to summarize the epidemiological evidence for an association between body fatness and specific types of cancer and to outline the mediating role of obesity-related biomarkers in this context. Epidemiological studies have gathered convincing evidence that greater body fatness is associated with a higher risk of colorectal cancer, postmenopausal breast cancer, endometrial cancer, esophageal adenocarcinoma, renal cell carcinoma, and pancreatic cancer. Further, evidence for an association between higher body fatness and higher risk of ovarian cancer, advanced prostate cancer, and hepatocellular carcinoma is growing. Abdominal obesity is an independent risk factor for colorectal cancer beyond general obesity, whereas an independent role is less clear for other obesity-related cancer types. Epidemiological biomarker studies have shown that the positive association between body fatness and risk of cancer may be partly explained by hyperinsulinemia and altered concentrations in adipokines and sex-steroid hormones. In addition, obesity-associated low-grade inflammation plays a role in colorectal carcinogenesis. While epidemiology has contributed substantially to the understanding of the role of higher body fatness and related metabolic alterations in the development of cancer, further epidemiological biomarker studies are necessary to elucidate the complex interrelations between mediating pathways as well as to study novel pathways. Knowledge resulting from this research may help identify an obesity phenotype that is particularly strongly associated with cancer risk and thus pave the way for targeted prevention of cancer morbidity and mortality.
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Nimptsch K, Pischon T. Obesity Biomarkers, Metabolism and Risk of Cancer: An Epidemiological Perspective. Recent Results Cancer Res 2016; 208:199-217. [PMID: 27909909 DOI: 10.1007/978-3-319-42542-9_11] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Obesity is associated with metabolic alterations that may pose a biological link between body fatness and risk of cancer. Elucidating the role of obesity-related biomarkers in cancer development is essential for developing targeted strategies aiming at obesity-associated cancer prevention. Molecular epidemiological studies of the past decades have provided evidence that major hormonal pathways linking obesity and cancer risk include the insulin and insulin-like growth factor-1 (IGF-1) axis, sex-steroid hormones, adipokines and chronic low-grade inflammation. These pathways are interrelated with each other, and their importance varies by obesity-related cancer type. The insulin/IGF-1 axis has been implicated to play an important mediating role in the association between obesity and risk of pancreatic, colorectal and prostate cancer. Endogenous sex-steroid hormone concentrations, in particular obesity-associated pre-diagnostic elevations of estrogens and androgens, play an important role in postmenopausal breast cancer and endometrial cancer development. The adipokines adiponectin and leptin and adipocyte-mediated chronic low-grade inflammation represented by the acute-phase C-reactive protein may explain a substantial part of the association between obesity and risk of colorectal cancer. There is less evidence on whether these hormonal pathways play a mediating role in other obesity-associated types of cancer. In this chapter, the molecular epidemiologic evidence from prospective studies relating circulating obesity-related biomarkers to cancer risk is summarized, taking into account available evidence from Mendelian Randomization investigations aiming at improving causal inference.
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Affiliation(s)
- Katharina Nimptsch
- Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125, Berlin, Germany.
| | - Tobias Pischon
- Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125, Berlin, Germany
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Dietary lipids and adipocytes: potential therapeutic targets in cancers. J Nutr Biochem 2014; 26:303-11. [PMID: 25524629 DOI: 10.1016/j.jnutbio.2014.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 11/12/2014] [Accepted: 11/18/2014] [Indexed: 12/22/2022]
Abstract
Lipids play an important role to support the rapid growth of cancer cells, which can be derived from both the endogenous synthesis and exogenous supplies. Enhanced de novo fatty acid synthesis and mobilization of stored lipids in cancer cells promote tumorigenesis. Besides, lipids and fatty acids derived from diet or transferred from neighboring adipocytes also influence the proliferation and metastasis of cancer cells. Indeed, the pathogenic roles of adipocytes in the tumor microenvironment have been recognized recently. The adipocyte-derived mediators or the cross talk between adipocytes and cancer cells in the microenvironment is gaining attention. This review will focus on the impacts of lipids on cancers and the pathogenic roles of adipocytes in tumorigenesis and discuss the possible anticancer therapeutic strategies targeting lipids in the cancer cells.
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Joshi RK, Lee SA. Obesity related adipokines and colorectal cancer: a review and meta-analysis. Asian Pac J Cancer Prev 2014; 15:397-405. [PMID: 24528064 DOI: 10.7314/apjcp.2014.15.1.397] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Obesity has been considered as an important risk factor for the development of colorectal cancer (CRC), but the association has not been fully elucidated. Obesity is linked significantly to adipose tissue dysfunction and to alteration of adipokines in blood; in particular, obesity-induced inflammation is thought to be an important link between obesity and colorectal cancer. Based on epidemiological studies, we undertook a systematic review to understand the association of circulating levels of selected adipokines, including adiponectin, leptin, resistin, IL-6 and TNF-α, with the level of CRC risk. Most prospective studies suggested protective effects of adiponectin, but these were attenuated by body mass index (BMI) and waist circumference (WC) data in our meta-analysis. On the other hand, meta-analyses for leptin and CRC did not demonstrate any association, similar to the results of systematic review. Although it proved difficult to determine whether other selected adipokines (resistin, IL-6 and TNF-α) were related to CRC risk due to small number of reports, the present systematic review suggested a positive association with elevated resistin levels but null associations with IL-6 and TNF-α.
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Affiliation(s)
- Rakhi Kumari Joshi
- Department of Preventive Medicine, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do, South Korea E-mail :
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Muc-Wierzgoń M, Nowakowska-Zajdel E, Dzięgielewska-Gęsiak S, Kokot T, Klakla K, Fatyga E, Grochowska-Niedworok E, Waniczek D, Wierzgoń J. Specific metabolic biomarkers as risk and prognostic factors in colorectal cancer. World J Gastroenterol 2014; 20:9759-9774. [PMID: 25110413 PMCID: PMC4123364 DOI: 10.3748/wjg.v20.i29.9759] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/05/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Advances in genomics, molecular pathology and metabolism have generated many candidate biomarkers of colorectal cancer with potential clinical value. Epidemiological and biological studies suggest a role for adiposity, dyslipidaemia, hyperinsulinemia, altered glucose homeostasis, and elevated expression of insulin-like growth factor (IGF) axis members in the risk and prognosis of cancer. This review discusses some recent past and current approaches being taken by researches in obesity and metabolic disorders. The authors describe three main systems as the most studied metabolic candidates of carcinogenesis: dyslipidemias, adipokines and insulin/IGF axis. However, each of these components is unsuccessful in defining the diseases risk and progression, while their co-occurrence increases cancer incidence and mortality in both men and women.
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Joshi RK, Kim WJ, Lee SA. Association between obesity-related adipokines and colorectal cancer: A case-control study and meta-analysis. World J Gastroenterol 2014; 20:7941-7949. [PMID: 24976730 PMCID: PMC4069321 DOI: 10.3748/wjg.v20.i24.7941] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/24/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the association between obesity-related adipokines (adiponectin, leptin, resistin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and colorectal cancer (CRC) risk.
METHODS: Serum levels of adipokines were measured in 100 CRC patients and age- and sex-matched controls for the data analysis. Unconditional logistic regression models were used for estimating ORs and 95%CIs related to each adipokine. For the meta-analysis, studies published before July 2013 available on Medline/PubMed and EMBASE were retrieved. The analysis included a total of 17 relevant studies (including the present case-control study): nine studies on adiponectin and eight on leptin. The effect sizes of ORs and 95%CIs were estimated using RevMan 5.1. Heterogeneity was evaluated using Cochran’s Q-test and I2 statistics.
RESULTS: Among the five adipokines, only resistin levels were significantly higher in cases than in controls (P < 0.001). The case-control study results showed no association between adiponectin and CRC and a negative association between leptin and CRC. However, the results of the meta-analysis showed a significant inverse association between adiponectin and CRC (OR = 0.91, 95%CI: 0.83-1.00, P = 0.04) and no association between CRC and leptin. After stratification by study design, an inverse association between adiponectin and CRC was observed in prospective studies only (OR = 0.90, 95%CI: 0.82-0.99, P = 0.03), whereas the association between leptin and CRC was inconsistent (prospective studies: OR = 1.14, 95%CI: 1.02-1.27, P = 0.02 and retrospective studies: OR = 0.47, 95%CI: 0.29-0.74, P = 0.001). The associations of resistin and TNF-α with CRC risk were positive, but no association was observed for IL-6.
CONCLUSION: Our results suggest a negative association of leptin, positive associations of resistin and TNF-α, and null associations of adiponectin and IL-6 with CRC. However, further studies with larger number of prospective approaches are needed.
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Higurashi T, Endo H, Uchiyama T, Uchiyama S, Yamada E, Ohkubo H, Sakai E, Takahashi H, Maeda S, Wada K, Natsumeda Y, Hippo Y, Nakajima A, Nakagama H. Conditional knockout of the leptin receptor in the colonic epithelium revealed the local effects of leptin receptor signaling in the progression of colonic tumors in mice. Carcinogenesis 2014; 35:2134-41. [PMID: 24958593 DOI: 10.1093/carcin/bgu135] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Leptin, secreted by the adipose tissue and known to be related to obesity, is considered to be involved in the onset and progression of colorectal cancer. However, the exact role of leptin in colorectal carcinogenesis is still unclear, as several controversial reports have been published on the various systemic effects of leptin. The aim of this study was to clarify the local and precise roles of leptin receptor (LEPR)-mediated signaling in colonic carcinogenesis using intestinal epithelium-specific LEPRb conditional knockout (cKO) mice. We produced and used colonic epithelium-specific LEPRb cKO mice to investigate the carcinogen-induced formation of aberrant crypt foci (ACF) and tumors in the colon, using their littermates as control. There were no differences in the body weight or systemic condition between the control and cKO mice. The tumor sizes and number of large-sized tumors were significantly lower in the cKO mice as compared with those in the control mice. On the other hand, there was no significant difference in the proliferative activity of the normal colonic epithelial cells or ACF formation between the control and cKO mice. In the control mice, marked increase of the LEPRb expression level was observed in the colonic tumors as compared with that in the normal epithelium; furthermore, signal transducer and activator of transcription (STAT3) was activated in the tumor cells. These findings suggest that STAT3 is one of the important molecules downstream of LEPRb, and LEPRb/STAT3 signaling controls tumor cell proliferation. We demonstrated the importance of local/regional LEPR-mediated signaling in colorectal carcinogenesis.
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Affiliation(s)
- Takuma Higurashi
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Hiroki Endo
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Takashi Uchiyama
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Shiori Uchiyama
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Eiji Yamada
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Hidenori Ohkubo
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Eiji Sakai
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Hirokazu Takahashi
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Shin Maeda
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Koichiro Wada
- Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan
| | - Yutaka Natsumeda
- Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and
| | - Yoshitaka Hippo
- Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Atsushi Nakajima
- Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Hitoshi Nakagama
- Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
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Zhou W, Tian Y, Gong H, Guo S, Luo C. Oncogenic role and therapeutic target of leptin signaling in colorectal cancer. Expert Opin Ther Targets 2014; 18:961-71. [PMID: 24946986 DOI: 10.1517/14728222.2014.926889] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Obesity is characterized by high secretion of several cytokines from adipose tissue and is a recognized risk factor for many cancers. Among these cytokines, leptin mainly produced by adipose tissue and cancer cells is the most studied adipokine. Leptin is an activator of cell proliferation, an antiapoptotic molecule and inducer of cancer stem cells in many cell types, and its critical roles in obesity-related tumorigenesis are based on its oncogenic, mitogenic, pro-inflammatory and pro-angiogenic actions. AREAS COVERED These leptin-induced signals and action are critical for their biological effects on energy balance, adiposity, endocrine systems, immunity, angiogenesis as well as oncogenesis. This review focuses on the up-to-date knowledge on the oncogenic role of leptin signaling, clinical significance and specific drug target development in colorectal cancer (CRC). Additionally, leptin-induced angiogenic ability and molecular mechanisms in CRC cells are discussed. EXPERT OPINION Stringent binding affinity of leptin/Ob-R and overexpression of leptin/Ob-R and their targets in cancer cells make it a unique drug target for prevention and treatment of CRC, particularly in obesity colorectal patients.
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Affiliation(s)
- Weiqiang Zhou
- Shenyang Medical College, Key Laboratory of Environmental Pollution and Microecology of Liaoning Province , No.146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro 110034 , PR China
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Abstract
Excess body weight, as defined by the body mass index (BMI), has been associated with several diseases and includes subjects who are overweight (BMI≥25-29.9 kg/m(2)) or obese (BMI≥30 kg/m(2)). Overweight and obesity constitute the fifth leading risk for overall mortality, accounting for at least 2.8 million adult deaths each year. In addition around 11% of colorectal cancer (CRC) cases have been attributed to overweight and obesity in Europe. Epidemiological data suggest that obesity is associated with a 30-70% increased risk of colon cancer in men, whereas the association is less consistent in women. Similar trends exist for colorectal adenoma, although the risk appears lower. Visceral fat, or abdominal obesity, seems to be of greater concern than subcutaneous fat obesity, and any 1 kg/m(2) increase in BMI confers additional risk (HR 1.03). Obesity might be associated with worse cancer outcomes, such as recurrence of the primary cancer or mortality. Several factors, including reduced sensitivity to antiangiogenic-therapeutic regimens, might explain these differences. Except for wound infection, obesity has no significant impact on surgical procedures. The underlying mechanisms linking obesity to CRC are still a matter of debate, but metabolic syndrome, insulin resistance and modifications in levels of adipocytokines seem to be of great importance. Other biological factors such as the gut microbita or bile acids are emerging. Many questions still remain unanswered: should preventive strategies specifically target obese patients? Is the risk of cancer great enough to propose prophylactic bariatric surgery in certain patients with obesity?
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Affiliation(s)
- Marc Bardou
- INSERM-Centre d'Investigations Cliniques Plurithématique 803 (CIC-P 803), CHU du Bocage, Dijon, France.
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Riondino S, Roselli M, Palmirotta R, Della-Morte D, Ferroni P, Guadagni F. Obesity and colorectal cancer: Role of adipokines in tumor initiation and progression. World J Gastroenterol 2014; 20:5177-5190. [PMID: 24833848 PMCID: PMC4017033 DOI: 10.3748/wjg.v20.i18.5177] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of “adiposopathy”, defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC.
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Pan H, Guo J, Su Z. Advances in understanding the interrelations between leptin resistance and obesity. Physiol Behav 2014; 130:157-69. [PMID: 24726399 DOI: 10.1016/j.physbeh.2014.04.003] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 03/07/2014] [Accepted: 04/02/2014] [Indexed: 02/09/2023]
Abstract
Obesity, which has developed into a global epidemic, is a risk factor in most chronic diseases and some forms of malignancy. The discovery of leptin in 1994 has opened a new field in obesity research. Currently, we know that leptin is the primary signal from energy stores and exerts negative feedback effects on energy intake. However, most individuals with diet-induced obesity (DIO) develop leptin resistance, which is characterized by elevated circulating leptin levels and decreased leptin sensitivity. To date, though various mechanisms have been proposed to explain leptin resistance, the exact mechanisms of leptin resistance in obesity are poorly understood. Consequently, it's an important issue worth discussing regarding what the exact interrelations between leptin resistance and obesity are. Here, we review the latest advancements in the molecular mechanisms of leptin resistance and the exact interrelations between leptin resistance, obesity, and obesity-related diseases, in order to supply new ideas for the study of obesity.
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Affiliation(s)
- Haitao Pan
- Key Research Center of Liver Regulation for Hyperlipidemia SATCM/Class III Laboratory of Metabolism SATCM, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Jiao Guo
- Key Research Center of Liver Regulation for Hyperlipidemia SATCM/Class III Laboratory of Metabolism SATCM, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.
| | - Zhengquan Su
- Key Research Center of Liver Regulation for Hyperlipidemia SATCM/Class III Laboratory of Metabolism SATCM, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.
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Alemán JO, Eusebi LH, Ricciardiello L, Patidar K, Sanyal AJ, Holt PR. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology 2014; 146:357-373. [PMID: 24315827 PMCID: PMC3978703 DOI: 10.1053/j.gastro.2013.11.051] [Citation(s) in RCA: 144] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/30/2013] [Accepted: 11/14/2013] [Indexed: 02/06/2023]
Abstract
Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.
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Affiliation(s)
| | - Leonardo H. Eusebi
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, and Center for Applied Biomedical Research (CRBA), University of Bologna, Italy
| | - Kavish Patidar
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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Gialamas SP, Sergentanis TN, Antonopoulos CN, Dessypris N, Chrousos GP, Petridou ET. Circulating leptin levels and risk of colorectal cancer and adenoma: a case-control study and meta-analysis. Cancer Causes Control 2013; 24:2129-41. [PMID: 24085585 DOI: 10.1007/s10552-013-0290-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 09/11/2013] [Indexed: 12/13/2022]
Abstract
PURPOSE Equivocal results regarding the role of leptin in colorectal cancer (CRC) and adenoma (CRA) have been reported. A case-control study investigating the association of leptin with CRC risk and clinicopathological characteristics along with meta-analysis of published data on both CRC and CRA were conducted. METHODS Pubmed and Embase were searched for the meta-analysis, comprising 28 case-control studies amounting 3,614 CRC and 1,215 CRA cases, along with 5,220 controls. Meticulous contact with the authors of individual studies was undertaken for the provision of additional data. Pooling of standardized mean differences (SMD), relative risks (RR) and 95 % CI (random effects models), subgroup, sensitivity, and meta-regression analyses were conducted. RESULTS The meta-analysis suggested positive association of serum leptin with CRA (RR, 95 % CI 1.35, 1.03 to +1.76), but not CRC either at the pooled analysis on SMDs or RRs (SMD, 95 % CI 0.18, -0.04 to +0.40; RR, 95 % CI 1.04, 0.65 to +1.65). Significant heterogeneity between studies on CRC as well as between studies on CRA providing SMD was noted. Subgroup, meta-regression and sensitivity analyses highlighted potential methodology-, design-, size- and quality-related effect modifiers. CONCLUSIONS Meta-analysis of current evidence suggests positive association of serum leptin with CRA but not with CRC risk. Given the case-control nature of available studies, the limited number of studies on serum leptin and CRA, and the heterogeneity of CRC studies, carefully designed, prospective studies preferably reporting RRs adjusted for a variety of confounders may be warranted.
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Affiliation(s)
- Spyros P Gialamas
- Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, 75 M. Asias Str, Goudi, Athens, 11527, Greece
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Song M, Zhang X, Wu K, Ogino S, Fuchs CS, Giovannucci EL, Chan AT. Plasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective study. Cancer Prev Res (Phila) 2013; 6:875-85. [PMID: 23872505 DOI: 10.1158/1940-6207.capr-13-0169] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Adipokines are adipocyte-secreted hormones that may mediate the etiologic link between obesity and colorectal cancer; however, the evidence from large prospective studies is limited. We prospectively evaluated the association of plasma adiponectin and soluble leptin receptor (sOB-R) with colorectal cancer risk within the Nurses' Health Study (1990-2008) and the Health Professionals Follow-up Study (1994-2008) among 616 incident colorectal cancer cases and 1,205 controls selected using risk-set sampling and matched on age and date of blood draw. In unconditional logistic regression with adjustment for matching factors and multiple risk factors, plasma adiponectin was significantly associated with reduced risk of colorectal cancer among men, but not among women. Compared with men in the lowest quartile of adiponectin, men in the highest quartile had a relative risk (RR) for colorectal cancer of 0.55 [95% confidence interval (CI), 0.35-0.86; Ptrend = 0.02]. The corresponding RR in women was 0.96 (95% CI, 0.67-1.39; Ptrend = 0.74). Plasma sOB-R was not associated with overall colorectal cancer risk in either men or women. A significant heterogeneity was noted in the association between sOB-R and colorectal cancer by subsite in women (Pheterogeneity = 0.004); sOB-R was significantly associated with increased risk of rectal cancer but not colon cancer. These findings support a role for adiponectin in colorectal carcinogenesis in men. Further studies are warranted to confirm these associations and elucidate potential underlying mechanisms.
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Affiliation(s)
- Mingyang Song
- Division of Nutrition, Harvard Medical School, Boston, MA 02114, USA
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Liu L, Zhong R, Wei S, Xiang H, Chen J, Xie D, Yin J, Zou L, Sun J, Chen W, Miao X, Nie S. The leptin gene family and colorectal cancer: interaction with smoking behavior and family history of cancer. PLoS One 2013; 8:e60777. [PMID: 23593308 PMCID: PMC3620466 DOI: 10.1371/journal.pone.0060777] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2012] [Accepted: 03/02/2013] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin. METHODOLOGY/PRINCIPAL FINDINGS A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13-1.76) and 1.74 (95%CI 1.08-2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82 × 10(-10)). CONCLUSIONS/SIGNIFICANCE Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.
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Affiliation(s)
- Li Liu
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rong Zhong
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Wei
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hao Xiang
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, Hubei, China
| | - Jigui Chen
- Department of Surgery, The Eighth Hospital of Wuhan, Wuhan, Hubei, China
| | - Duoshuang Xie
- Department of Infection Control, Taihe Hospital, Yunyang Medical College, Shiyan, Hubei, China
| | - Jieyun Yin
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Li Zou
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jingwen Sun
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Chen
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Miao
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shaofa Nie
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Tourkantonis I, Kiagia M, Peponi E, Tsagouli S, Syrigos KN. The Role of Leptin in Cancer Pathogenesis. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/jct.2013.42080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Tahergorabi Z, Khazaei M. Imbalance of angiogenesis in diabetic complications: the mechanisms. Int J Prev Med 2012; 3:827-38. [PMID: 23272281 PMCID: PMC3530300 DOI: 10.4103/2008-7802.104853] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2012] [Accepted: 10/07/2012] [Indexed: 12/22/2022] Open
Abstract
Type 2 diabetes mellitus is a complex disease and a chronic health-care problem. Nowadays, because of alteration of lifestyle such as lack of exercise, intake of high fat diet subsequently obesity and aging population, the prevalence of diabetes mellitus is increasing quickly in around the world. The international diabetes federation estimated in 2008, that 246 million adults in worldwide suffered from diabetes mellitus and the prevalence of disease is expected to reach to 380 million by 2025. Although, mainly in management of diabetes focused on hyperglycemia, however, it is documented that abnormalities of angiogenesis may contribute in the pathogenesis of diabetes complications. Angiogenesis is the generation of new blood vessels from pre-existing ones. Normal angiogenesis depends on the intricate balance between angiogenic factors (such as VEGF, FGF2, TGF-β, angiopoietins) and angiostatic factors (angiostatin, endostatin, thrombospondins). Vascular abnormalities in different tissues including retina and kidney can play a role in pathogenesis of micro-vascular complications of diabetes; also vascular impairment contributes in macrovascular complications e.g., diabetic neuropathy and impaired formation of coronary collaterals. Therefore, identifying of different mechanisms of the diabetic complications can give us an opportunity to prevent and/or treat the following complications and improves quality of life for patients and society. In this review, we studied the mechanisms of angiogenesis in micro-vascular and macro-vascular complications of diabetes mellitus.
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Affiliation(s)
- Zoya Tahergorabi
- Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
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Aleksandrova K, Nimptsch K, Pischon T. Influence of Obesity and Related Metabolic Alterations on Colorectal Cancer Risk. Curr Nutr Rep 2012; 2:1-9. [PMID: 23396857 PMCID: PMC3562548 DOI: 10.1007/s13668-012-0036-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Obesity and related metabolic alterations have been implicated to play a role in colorectal cancer risk. The metabolic syndrome, as assessed according to current international definitions by the key components, abdominal obesity, dyslipidemia, elevated blood pressure, and abnormal glucose metabolism, is associated with colorectal cancer. Recent studies suggest that abdominal obesity and abnormal glucose metabolism may primarily account for this association. Visceral adipose tissue is physiologically more active than subcutaneous adipose tissue and generates hormones and cytokines with inflammatory, metabolic, and direct carcinogenic potential, which may directly or indirectly increase colorectal cancer risk. Current evidence suggests that obesity acts as a risk factor for colorectal cancer by several mechanisms, including chronic low-grade inflammation, hyperinsulinemia, as well as alterations in insulin-like growth factor and adipokine concentrations. Metabolic biomarkers reflecting these processes may not only provide clues for etiological understanding of colorectal carcinogenesis but also might be an alternative way to define an "obesity phenotype" that is relevant for colorectal cancer development.
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Affiliation(s)
- Krasimira Aleksandrova
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
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Hursting SD, Digiovanni J, Dannenberg AJ, Azrad M, Leroith D, Demark-Wahnefried W, Kakarala M, Brodie A, Berger NA. Obesity, energy balance, and cancer: new opportunities for prevention. Cancer Prev Res (Phila) 2012; 5:1260-72. [PMID: 23034147 DOI: 10.1158/1940-6207.capr-12-0140] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Obesity is associated with increased risk and poor prognosis for many types of cancer. The mechanisms underlying the obesity-cancer link are becoming increasingly clear and provide multiple opportunities for primary to tertiary prevention. Several obesity-related host factors can influence tumor initiation, progression and/or response to therapy, and these have been implicated as key contributors to the complex effects of obesity on cancer incidence and outcomes. These host factors include insulin, insulin-like growth factor-I, leptin, adiponectin, steroid hormones, cytokines, and inflammation-related molecules. Each of these host factors is considered in the context of energy balance and as potential targets for cancer prevention. The possibility of prevention at the systems level, including energy restriction, dietary composition, and exercise is considered as is the importance of the newly emerging field of stem cell research as a model for studying energy balance and cancer prevention.
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Aleksandrova K, Boeing H, Jenab M, Bueno-de-Mesquita HB, Jansen E, van Duijnhoven FJB, Rinaldi S, Fedirko V, Romieu I, Riboli E, Gunter MJ, Westphal S, Overvad K, Tjønneland A, Halkjær J, Racine A, Boutron-Ruault MC, Clavel-Chapelon F, Kaaks R, Lukanova A, Trichopoulou A, Lagiou P, Trichopoulos D, Mattiello A, Pala V, Palli D, Tumino R, Vineis P, Buckland G, Sánchez MJ, Amiano P, Huerta JM, Barricarte A, Menéndez V, Peeters PH, Söderberg S, Palmqvist R, Allen NE, Crowe FL, Khaw KT, Wareham N, Pischon T. Leptin and soluble leptin receptor in risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Cancer Res 2012; 72:5328-37. [PMID: 22926557 DOI: 10.1158/0008-5472.can-12-0465] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P(trend) = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P(trend) = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P(trend) = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P(trend) = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis.
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Affiliation(s)
- Krasimira Aleksandrova
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
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Ho GYF, Wang T, Gunter MJ, Strickler HD, Cushman M, Kaplan RC, Wassertheil-Smoller S, Xue X, Rajpathak SN, Chlebowski RT, Vitolins MZ, Scherer PE, Rohan TE. Adipokines linking obesity with colorectal cancer risk in postmenopausal women. Cancer Res 2012; 72:3029-37. [PMID: 22511581 PMCID: PMC3790260 DOI: 10.1158/0008-5472.can-11-2771] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines-adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HR(Q4-Q1)), 1.84; 95% CI, 1.17-2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.
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Affiliation(s)
- Gloria Y F Ho
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
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Healy LA, Howard JM, Ryan AM, Beddy P, Mehigan B, Stephens R, Reynolds JV. Metabolic syndrome and leptin are associated with adverse pathological features in male colorectal cancer patients. Colorectal Dis 2012; 14:157-65. [PMID: 21689278 DOI: 10.1111/j.1463-1318.2011.02562.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIM Metabolic syndrome (MetS) describes a clustering of factors including central obesity, hypertension and raised plasma glucose, triglycerides and high-density lipoprotein (HDL) cholesterol. Central obesity is associated with a risk for colorectal cancer, but the impact of MetS on colorectal cancer biology and outcomes is unclear. METHOD A prospective observational study of colorectal cancer patients was carried out in an Irish population. Patients underwent metabolic and anthropometric assessment before treatment, including measurement of serum hormones and adipokines and CT measurement of visceral fat. MetS was defined according to the International Diabetes Federation definition(3) . RESULTS One-hundred and thirty consecutive colorectal cancer patients (66 men and 64 women) were recruited. MetS was diagnosed in 38% patients compared with the population norms reported at 21%(21) . Male patients had a significantly greater visceral fat area compared with female patients. MetS was associated with node-positive disease (P = 0.026), percentage nodal involvement (P = 0.033) and extramural vascular invasion (P = 0.049) in male patients but no significant association was observed in female patients. HDL cholesterol was also significantly associated with a more advanced pathological stage (P = 0.014) and node-positive disease (P = 0.028). Leptin was associated with nodal status (P = 0.036), microvascular invasion (P = 0.054), advanced pathological stage (P = 0.046) and more advanced Dukes stage (P = 0.042). CONCLUSION We report a high prevalence of MetS and visceral obesity in a colorectal cancer population. MetS and plasma leptin are associated with a more aggressive tumour phenotype in male patients only.
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Affiliation(s)
- L A Healy
- Department of Clinical Nutrition, St James's Hospital and Trinity College Dublin, Ireland.
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Abstract
The increasing incidence of obesity and its co-morbid conditions poses a great challenge to global health. In addition to cardiovascular disease and diabetes, epidemiological data demonstrate a link between obesity and multiple types of cancer. The molecular mechanisms underlying how obesity causes an increased risk of cancer are poorly understood. Obesity disrupts the dynamic role of the adipocyte in energy homeostasis, resulting in inflammation and alteration of adipokine (for example, leptin and adiponectin) signalling. Additionally, obesity causes secondary changes that are related to insulin signalling and lipid deregulation that may also foster cancer development. Understanding these molecular links may provide an avenue for preventive and therapeutic strategies to reduce cancer risk and mortality in an increasingly obese population.
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Affiliation(s)
- Melin J Khandekar
- Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
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Notarnicola M, Miccolis A, Tutino V, Lorusso D, Caruso MG. Low levels of lipogenic enzymes in peritumoral adipose tissue of colorectal cancer patients. Lipids 2011; 47:59-63. [PMID: 22090062 DOI: 10.1007/s11745-011-3630-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Accepted: 11/02/2011] [Indexed: 12/21/2022]
Abstract
Lipoprotein lipase (LPL) is the crucial enzyme for intravascular catabolism of triglyceride-rich lipoproteins. Fatty acid synthase (FAS) is a key anabolic enzyme that catalyzes the terminal steps in the novo biosynthesis of 18:2n-6. The involvement of both LPL and FAS in tumor biology has been widely demonstrated in different studies and to verify whether there are regional differences in the expression of these enzymes in visceral adipose tissue from patients with colorectal cancer might be representative of events which sustain tumor growth. The objective of this study was to evaluate LPL and FAS activity and expression of their genes in adipose tissue adjacent to neoplasia and distant from it from patients operated for colorectal cancer. LPL enzymatic activity was evaluated by a fluorescent method and FAS activity by a radiometer assay. Reverse-transcription and real-time PCR were used to detect mRNA levels of two enzymes. Our findings show a significant reduction in both LPL and FAS gene expression and activity levels in adipose tissue adjacent to tumor lesion compared to those detected in paired tissue distant from neoplasia. These results underline the influence of tumor microenvironment on lipid metabolism in adipose tissue, demonstrating a tumor-induced impairment in the formation and lipid storing capacity of adipose tissue in patients with colorectal cancer.
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Affiliation(s)
- Maria Notarnicola
- Laboratory of Biochemistry, National Institute for Digestive Diseases "S. de Bellis", Via Turi, 27, 70013, Castellana Grotte, Bari, Italy.
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Hillon P, Guiu B, Vincent J, Petit JM. Obesity, type 2 diabetes and risk of digestive cancer. ACTA ACUST UNITED AC 2011; 34:529-33. [PMID: 20864282 DOI: 10.1016/j.gcb.2010.07.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Revised: 06/26/2010] [Accepted: 07/31/2010] [Indexed: 01/08/2023]
Abstract
The frequency of obesity has been increasing worldwide for 20 years. Many epidemiological studies support a correlation between obesity and increased risk of cancer, particularly digestive cancers in both genders, and gynaecological cancer in women. Currently, about 5% of cancers could be directly related to overweight. Carcinogenesis mechanisms induced by obesity involve insulin resistance, adipokine and angiogenic factor secretions, and inflammation. Experimental and clinical evidence suggest that insulin resistance plays a major role in carcinogenesis. Insulin and non-protein banded IGF-1, whose levels are increased in type 2 diabetes, stimulate cellular growth and inhibit apoptosis. Abnormalities in adipokine secretion by the central adipose tissue play a role at different stages of obesity-induced carcinogenesis. Excess of leptin and PAI-1, associated with a decrease in adiponectin secretion in obese people, contributes to carcinogenesis through cellular growth and angiogenesis stimulation. Remodelling of the extracellular matrix due to metalloproteinase stimulation by PAI-1 is also able to promote cell migration. Obesity not only increases cancer frequency, but is also liable to modify the prognosis and the response to antiangiogenic therapy of digestive cancers. This data suggests the need for clinicians to take into account overweight in cancer risk evaluation and to consider obesity and metabolic disorders as confounding factors in designing therapeutic studies.
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Affiliation(s)
- P Hillon
- Université de Bourgogne, CHU de Dijon, rue de l'église, Dijon, France.
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Uchiyama T, Takahashi H, Sugiyama M, Sakai E, Endo H, Hosono K, Yoneda K, Yoneda M, Inamori M, Nagashima Y, Inayama Y, Wada K, Nakajima A. Leptin receptor is involved in STAT3 activation in human colorectal adenoma. Cancer Sci 2010; 102:367-72. [DOI: 10.1111/j.1349-7006.2010.01803.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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