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Cote AL, Munger CJ, Ringel AE. Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions. Cell Rep 2025; 44:115234. [PMID: 39862435 DOI: 10.1016/j.celrep.2025.115234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/24/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.
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Affiliation(s)
- Andrea L Cote
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Chad J Munger
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Alison E Ringel
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
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May L, Hu B, Jerajani P, Jagdeesh A, Alhawiti O, Cai L, Semenova N, Guo C, Isbell M, Deng X, Faber A, Pillappa R, Bandyopadhyay D, Wang XY, Neuwelt A, Koblinski J, Bos PD, Li H, Martin R, Landry JW. The Innate Immune System and the TRAIL-Bcl-XL Axis Mediate a Sex Bias in Lung Cancer and Confer a Therapeutic Vulnerability in Females. Cancer Res 2024; 84:4140-4155. [PMID: 39312191 PMCID: PMC11649478 DOI: 10.1158/0008-5472.can-24-0585] [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: 02/21/2024] [Revised: 06/21/2024] [Accepted: 09/18/2024] [Indexed: 10/25/2024]
Abstract
There is a significant sex bias in lung cancer, with males showing increased mortality compared with females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex bias in humanized mice, with male patient-derived xenograft lung tumors being more progressive and deadlier than female patient-derived xenograft lung tumors, we identified mouse tumor models of lung cancer with the same sex bias. This sex bias was not observed in models of breast, colon, melanoma, and renal cancers. In vivo, the sex bias in growth and lethality required intact ovaries, functional innate NK cells and monocytes/macrophages, and the activating receptor NKG2D. Ex vivo cell culture models were sensitized to the anticancer effects of NKG2D-mediated NK cell and macrophage killing through the TRAIL-Bcl-XL axis when cultured with serum from female mice with intact ovaries. In both flank and orthotopic models, the Bcl-XL inhibitor navitoclax (ABT-263) improved tumor growth control in female mice and required NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and TRAIL pathway agonists could be used as a personalized therapy to improve outcomes in women with lung cancer. Significance: Lung cancers in females are more susceptible to killing through a TRAIL-Bcl-XL axis, indicating that targeting this axis therapeutically could represent a personalized approach to treat female patients with lung cancer.
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Affiliation(s)
- Lauren May
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
| | - Bin Hu
- VCU OVPRI, Virginia Commonwealth University, VCU Massey Comprehensive Cancer Center, Richmond, VA, 23298
| | - Preksha Jerajani
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
| | - Akash Jagdeesh
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
| | - Ohud Alhawiti
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
| | - Lillian Cai
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
| | - Nina Semenova
- Department of Pharmaceutical Science, Hampton University, Hampton VA, 23668
| | - Chunqing Guo
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
| | - Madison Isbell
- Department of Microbiology and Immunology, VCU School of Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA, 23298
| | - Xiaoyan Deng
- Department of Biostatistics, School of Population Health, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298
| | - Anthony Faber
- Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, VCU School of Dentistry, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298
| | - Raghavendra Pillappa
- Department of Pathology, VCU School of Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA, 23298
| | - Dipankar Bandyopadhyay
- Department of Biostatistics, School of Population Health, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
| | - Alexander Neuwelt
- Department of Internal Medicine, Division of Hematology, Oncology, and Palliative Care, Virginia Commonwealth University, Richmond, VA, 23298
- Staff Physician, Department of Internal Medicine, Division of Hematology and Oncology, Richmond VA Medical Center, Richmond, VA, 23249
| | - Jennifer Koblinski
- VCU OVPRI, Virginia Commonwealth University, VCU Massey Comprehensive Cancer Center, Richmond, VA, 23298
| | - Paula D. Bos
- Department of Pathology, VCU School of Medicine, VCU Massey Comprehensive Cancer, Richmond, VA, 23298
| | - Howard Li
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401
| | - Rebecca Martin
- Department of Microbiology and Immunology, VCU School of Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA, 23298
| | - Joseph W. Landry
- Department of Human and Molecular Genetics, VCU School of Medicine, VCU Institute of Molecular Medicine, VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA
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Ead AS, Wirkus J, Matsukuma K, Mackenzie GG. A high-fat diet induces changes in mesenteric adipose tissue accelerating early-stage pancreatic carcinogenesis in mice. J Nutr Biochem 2024; 131:109690. [PMID: 38876394 DOI: 10.1016/j.jnutbio.2024.109690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 06/01/2024] [Accepted: 06/09/2024] [Indexed: 06/16/2024]
Abstract
Increased adiposity is a significant risk factor for pancreatic cancer development. Multiple preclinical studies have documented that high-fat, high calorie diets, rich in omega-6 fatty acids (FA) accelerate pancreatic cancer development. However, the effect of a high-fat, low sucrose diet (HFD), on pancreatic carcinogenesis remains unclear. We evaluated the impact of a HFD on early-stage pancreatic carcinogenesis in the clinically relevant KrasLSL-G12D/+; Ptf1aCre/+ (KC) genetically engineered mouse model, and characterized the role of the mesenteric adipose tissue (MAT). Cohorts of male and female KC mice were randomly assigned to a control diet (CD) or a HFD, matched for FA composition (9:1 of omega-6 FA: omega-3 FA), and fed their diets for 8 weeks. After 8 weeks on a HFD, KC mice had significantly higher body weight, fat mass, and serum leptin compared to CD-fed KC mice. Furthermore, a HFD accelerated pancreatic acinar-to-ductal metaplasia (ADM) and proliferation, associated with increased activation of ERK and STAT3, and macrophage infiltration in the pancreas, compared to CD-fed KC mice. Metabolomics analysis of the MAT revealed sex differences between diet groups. In females, a HFD altered metabolites related to FA (α-linolenic acid and linoleic acid) and amino acid metabolism (alanine, aspartate, glutamate). In males, a HFD significantly affected pathways related to alanine, aspartate, glutamate, linoleic acid, and the citric acid cycle. A HFD accelerates early pancreatic ADM through multifaceted mechanisms, including effects at the tumor and surrounding MAT. The sex-dependent changes in MAT metabolites could explain some of the sex differences in HFD-induced pancreatic ADM.
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Affiliation(s)
- Aya S Ead
- Department of Nutrition, University of California, Davis, California, USA
| | - Joanna Wirkus
- Department of Nutrition, University of California, Davis, California, USA
| | - Karen Matsukuma
- Department of Pathology and Laboratory Medicine, Davis Medical Center, University of California, Sacramento, California, USA; University of California Davis Comprehensive Cancer Center, University of California, Sacramento, California, USA
| | - Gerardo G Mackenzie
- Department of Nutrition, University of California, Davis, California, USA; University of California Davis Comprehensive Cancer Center, University of California, Sacramento, California, USA.
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Nathan K, E M, Jabaris S SL, Visweswaraiah NK. Effect of abrupt and gradual calorie restriction regimens on biochemical and behavioral markers in obese mice model. Nutr Health 2024; 30:499-511. [PMID: 36650659 DOI: 10.1177/02601060221131726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Background: Although Calorie Restriction (CR) is primarily considered in obesity management, behavioral studies of CR and its methodology of implementation are not well-defined. Objective: The study aimed to determine the efficacy of the extensively researched method of CR-abrupt calorie restriction (ACR) and a newly proposed gradual calorie restriction (GCR) in terms of body weight, behavioral and biochemical parameters in the obese animal model-C57BL/6J mice. Design: Male obese mice were subjected to GCR regimen for 14 weeks which was compared and evaluated for anxiety-like behavior and stress levels with ACR. Plasma corticosterone was measured before initiation of CR and every three weeks following GCR and ACR, whereas plasma insulin was measured twice-after obesity induction and post 14 weeks of CR. The behavioral assessments were conducted before inducing CR and every three weeks following ACR and GCR. Results: A significant anxiety-like behavior and an increase in plasma corticosterone were observed in mice on GCR during the critical initial six weeks of CR (p < 0.05). Both groups showed a decrease in plasma glucose levels; however, the GCR group showed a significant reduction (p < 0.01). There was a significant decrease in social interaction in both groups with an increase in the latency period and a decrease in time spent with the stranger animal during the social interaction test (p < 0.05). Conclusion: The mice on GCR regimen demonstrated lesser anxiety-like behavior and low plasma corticosterone levels compared to those on ACR. This gives us a new avenue in CR research to evaluate the methodologies of implementing CR.
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Affiliation(s)
- Kousalya Nathan
- Department of Biochemistry, Chettinad Academy of Research and Education, Kanchipuram District, Tamil Nadu, India
| | - Malligai E
- Department of Biochemistry, Chettinad Academy of Research and Education, Kanchipuram District, Tamil Nadu, India
| | - Sugin Lal Jabaris S
- Department of Pharmacology, Siddha Central Research Institute, Central Council for Research in Siddha, Anna Govt. Hospital Campus, Chennai, India
| | - Naveen K Visweswaraiah
- Australian Research Council for Complementary and Integrative Medicine (ARCCIM), Faculty of Health, University of Technology, Sydney, Australia
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Sun Q, Tian Q, Bravo Iniguez A, Sun X, Zhang H, Deavila J, Du M, Zhu MJ. AMPK Deficiency Increases DNA Methylation and Aggravates Colorectal Tumorigenesis in AOM/DSS Mice. Genes (Basel) 2024; 15:835. [PMID: 39062614 PMCID: PMC11276171 DOI: 10.3390/genes15070835] [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: 05/26/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of Mlh1 in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC.
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Affiliation(s)
- Qi Sun
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Qiyu Tian
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Alejandro Bravo Iniguez
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Xiaofei Sun
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
| | - Hui Zhang
- Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA;
| | - Jeanene Deavila
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA; (J.D.); (M.D.)
| | - Min Du
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA; (J.D.); (M.D.)
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA; (Q.S.); (Q.T.); (A.B.I.); (X.S.)
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Beaudry AG, Law ML, Gilley-Connor KR, Buley H, Dungan CM, Nascimento CMC, Vichaya EG, Wiggs MP. Diet-induced obesity does not exacerbate cachexia in male mice bearing Lewis-lung carcinoma tumors. Am J Physiol Regul Integr Comp Physiol 2024; 326:R254-R265. [PMID: 38252513 DOI: 10.1152/ajpregu.00208.2023] [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: 08/27/2023] [Revised: 01/11/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024]
Abstract
Cachexia is a muscle-wasting syndrome commonly observed in patients with cancer, which can significantly worsen clinical outcomes. Because of a global rise in obesity, the coexistence of cachexia in obese individuals poses unique challenges, with the impact of excessive adiposity on cachexia severity and underlying pathophysiology not well defined. Understanding the interplay between cachexia and obesity is crucial for improving diagnosis and treatment strategies for these patients; therefore, the present study examined differences in cachexia between lean and obese mice bearing Lewis lung carcinoma (LLC) tumors. Nine-week-old, male C57Bl6J mice were placed on either a chow or a high-fat diet (HFD) for 9 wk. After the diet intervention, mice were inoculated with LLC or vehicle. Markers of cachexia, such as body and muscle loss, were noted in both chow and HFD groups with tumors. Tumor weight of HFD animals was greater than that of chow. LLC tumors reduced gastrocnemius, plantaris, and soleus mass, regardless of diet. The tibialis anterior and plantaris mass and cross-sectional area of type IIb/x fibers in the gastrocnemius were not different between HFD-chow, HFD-tumor, and chow-tumor. Using RNA sequencing (RNA-seq) of the plantaris muscle from chow-tumor and HFD-tumor groups, we identified ∼400 differentially expressed genes. Bioinformatic analysis identified changes in lipid metabolism, mitochondria, bioenergetics, and proteasome degradation. Atrophy was not greater despite larger tumor burden in animals fed an HFD, and RNA-seq data suggests that partial protection is mediated through differences in mitochondrial function and protein degradation, which may serve as future mechanistic targets.NEW & NOTEWORTHY This study provides timely information on the interaction between obesity and cancer cachexia. Lean and obese animals show signs of cachexia with reduced body weight, adipose tissue, and gastrocnemius muscle mass. There was not significant wasting in the tibialis anterior, plantaris, or fast twitch fibers in the gastrocnemius muscle of obese animals with tumors. RNA-seq analysis reveals that obese tumor bearing animals had differential expression of mitochondria- and degradation-related genes, which may direct future studies in mechanistic research.
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Affiliation(s)
- Anna G Beaudry
- Department of Health, Human Performance, and Recreation, Baylor University, Waco, Texas, United States
| | - Michelle L Law
- Department of Human Sciences and Design, Baylor University, Waco, Texas, United States
| | - Kayla R Gilley-Connor
- Department of Psychology and Neuroscience, Baylor University, Waco, Texas, United States
| | - Hailey Buley
- Department of Psychology and Neuroscience, Baylor University, Waco, Texas, United States
| | - Cory M Dungan
- Department of Health, Human Performance, and Recreation, Baylor University, Waco, Texas, United States
| | | | - Elisabeth G Vichaya
- Department of Psychology and Neuroscience, Baylor University, Waco, Texas, United States
| | - Michael P Wiggs
- Department of Health, Human Performance, and Recreation, Baylor University, Waco, Texas, United States
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Tung YT, Chen YL, Fan TY, Fong TH, Chiu WC. Effects of dietary adjustment of n-3: n-6 fatty-acid ratio to 1:2 on anti-inflammatory and insulin-signaling pathways in ovariectomized mice with high fat diet-induced obesity. Heliyon 2023; 9:e20451. [PMID: 37817999 PMCID: PMC10560786 DOI: 10.1016/j.heliyon.2023.e20451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 09/09/2023] [Accepted: 09/26/2023] [Indexed: 10/12/2023] Open
Abstract
Estrogen deficiency increases the secretion of inflammatory mediators and can lead to obesity. Consequently, estrogen deficiency can cause metabolic syndrome, particularly insulin resistance during menopause. Both fish oil and perilla oil contain n-3 fatty acids, which may regulate several inflammatory cytokines. Additionally, adjusting the dietary n-3:n-6 fatty-acid ratio to 1:2 may help treat or prevent chronic diseases. Therefore, we investigated the effect of anti-inflammatory and insulin-signaling pathways, not solely in relation to the (n-3:n-6 fatty-acid ratio at 1:2), but also considering the origin of n-3 fatty acids found in fish oil and perilla oil, in a mouse model of estrogen deficiency induced by ovariectomy and obesity induced by a high-fat diet (HFD). Female C57BL/6J mice were divided into five groups: sham mice on a normal diet; ovariectomized (OVX) mice on a normal diet (OC); OVX mice on a HFD plus lard oil (OL), fish oil (OF), or perilla oil (OP). The dietary n-3:n-6 ratio in the OF and OP groups was adjusted to 1:2. The results showed OF group exhibited significantly lower abdominal adipose tissue weight, fewer liver lipid droplets, and smaller uterine adipocytes, compared with the OL group. Compared with the OL group, the OF and OP groups exhibited higher oral glucose tolerance and lower serum alanine aminotransferase activity, triacylglycerol levels, and total cholesterol levels. Hepatic JAK2, STAT3, and SOCS3 mRNA expression and p-NF-κB p65 and IL-6 levels were significantly lower in the OF and OP groups than in the OL group. Only the OF group exhibited an increase in PI3K and Akt mRNA expression, decrease in GLUT2 mRNA expression, and considerable elevation of p-Akt. Both fish and perilla oil reduced inflammatory signaling markers. However, only fish oil improved insulin signaling (PI3K, Akt, and GLUT2). Our data suggest that fish oil can alleviate insulin signaling through activating the PI3K-Akt-GLUT2 cascade signaling pathway.
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Affiliation(s)
- Yu-Tang Tung
- Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 402, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Ya-Ling Chen
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
- Cell Therapy Center, Chang Gung Memorial Hospital, New Taipei City 333, Taiwan
| | - Tzu-Yu Fan
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
- Cell Therapy Center, Chang Gung Memorial Hospital, New Taipei City 333, Taiwan
| | - Tsorng-Harn Fong
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taiwan
| | - Wan-Chun Chiu
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
- Research Center of Geriatric Nutrition, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
- Department of Nutrition, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
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May L, Shows K, Nana-Sinkam P, Li H, Landry JW. Sex Differences in Lung Cancer. Cancers (Basel) 2023; 15:3111. [PMID: 37370722 PMCID: PMC10296433 DOI: 10.3390/cancers15123111] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Sex disparities in the incidence and mortality of lung cancer have been observed since cancer statistics have been recorded. Social and economic differences contribute to sex disparities in lung cancer incidence and mortality, but evidence suggests that there are also underlying biological differences that contribute to the disparity. This review summarizes biological differences which could contribute to the sex disparity. Sex hormones and other biologically active molecules, tumor cell genetic differences, and differences in the immune system and its response to lung cancer are highlighted. How some of these differences contribute to disparities in the response to therapies, including cytotoxic, targeted, and immuno-therapies, is also discussed. We end the study with a discussion of our perceived future directions to identify the key biological differences which could contribute to sex disparities in lung cancer and how these differences could be therapeutically leveraged to personalize lung cancer treatment to the individual sexes.
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Affiliation(s)
- Lauren May
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, VCU School of Medicine, Richmond, VA 23298, USA;
| | - Kathryn Shows
- Department of Biology, Virginia State University, Petersburg, VA 23806, USA;
| | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Disease and Critical Care Medicine, VCU School of Medicine, Richmond, VA 23298, USA; (P.N.-S.); (H.L.)
| | - Howard Li
- Department of Internal Medicine, Division of Pulmonary Disease and Critical Care Medicine, VCU School of Medicine, Richmond, VA 23298, USA; (P.N.-S.); (H.L.)
| | - Joseph W. Landry
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, VCU School of Medicine, Richmond, VA 23298, USA;
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9
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Visniauskas B, Reverte V, Abshire CM, Ogola BO, Rosales CB, Galeas-Pena M, Sure VN, Sakamuri SSVP, Harris NR, Kilanowski-Doroh I, Mcnally AB, Horton AC, Zimmerman M, Katakam PVG, Lindsey SH, Prieto MC. High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet. Am J Physiol Heart Circ Physiol 2023; 324:H762-H775. [PMID: 36930656 PMCID: PMC10151046 DOI: 10.1152/ajpheart.00638.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/02/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.
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Affiliation(s)
- Bruna Visniauskas
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Tulane Center for Sex-Based Biology and Medicine, New Orleans, Louisiana, United States
| | - Virginia Reverte
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Caleb M Abshire
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Benard O Ogola
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Carla B Rosales
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Michelle Galeas-Pena
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Venkata N Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Siva S V P Sakamuri
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Nicholas R Harris
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Isabella Kilanowski-Doroh
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Alexandra B Mcnally
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Alec C Horton
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Margaret Zimmerman
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Prasad V G Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Sarah H Lindsey
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Tulane Center for Sex-Based Biology and Medicine, New Orleans, Louisiana, United States
- Tulane Hypertension and Renal Center of Excellence, New Orleans, Louisiana, United States
| | - Minolfa C Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Tulane Center for Sex-Based Biology and Medicine, New Orleans, Louisiana, United States
- Tulane Hypertension and Renal Center of Excellence, New Orleans, Louisiana, United States
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10
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Petrecca S, Quail DF. Mouse Models of Obesity to Study the Tumor-Immune Microenvironment. Methods Mol Biol 2023; 2614:121-138. [PMID: 36587123 DOI: 10.1007/978-1-0716-2914-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Obesity is associated with chronic, low-grade systemic inflammation and leads to changes in the immune microenvironment of various tissues. As a result, obesity is associated with increased risk of cancer and a worse prognosis in patients. Given the prevalence of obesity worldwide, understanding the fundamental biology governing the relationship between obesity and cancer is critical. In this chapter, we describe preclinical models of obesity that can be combined with standard tumor models and techniques to study the tumor-immune microenvironment. We also discuss important considerations when planning experiments involving these models.
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Affiliation(s)
- Sarah Petrecca
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada.,Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada
| | - Daniela F Quail
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada. .,Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada. .,Department of Physiology, Faculty of Medicine, McGill University, Montreal, QC, Canada.
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11
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The Complex of Phycobiliproteins, Fucoxanthin, and Krill Oil Ameliorates Obesity through Modulation of Lipid Metabolism and Antioxidants in Obese Rats. Nutrients 2022; 14:nu14224815. [PMID: 36432501 PMCID: PMC9693846 DOI: 10.3390/nu14224815] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/05/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Phycobiliproteins, fucoxanthin, and krill oil are natural marine products with excellent activities. In the study, we prepared the complex of phycobiliproteins, fucoxanthin, and krill oil (PFK) and assessed the anti-obesity, lipid-lowering, and antioxidant activities in high-fat diet rats. The results showed that the rats significantly and safely reduced body weight gain and regulated serum biochemical parameters at 50 mg/kg phycobiliproteins, 10 mg/kg fucoxanthin, and 100 mg/kg krill oil. Furthermore, the molecular mechanism study suggested that the complex of PFK confined the enzyme activities of lipid synthesis and enhanced antioxidant activity to improve obesity indirectly. The conclusions demonstrated that the complex of PFK has potent anti-obesity and hypolipidemic effects which have potential use as a natural and healthy food and medicine for anti-obesity and lowering blood lipids in the future.
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12
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Pérez-Matute P, López IP, Íñiguez M, Recio-Fernández E, Torrens R, Piñeiro-Hermida S, Alfaro-Arnedo E, Chau L, Walz C, Hoeflich A, Oteo JA, Pichel JG. IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet. Front Endocrinol (Lausanne) 2022; 13:1033208. [PMID: 36353242 PMCID: PMC9638844 DOI: 10.3389/fendo.2022.1033208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE We aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice. METHODS UBC-CreERT2, Igf1rfl/fl mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized Igf1r deletion with tamoxifen. Animals were analyzed at two different ages: i) 13-weeks old young mice, and ii) 12-months old middle-aged mice. In addition, the effects of 10 weeks-long high-fat diet (HFD) were investigated in middle-aged mice. RESULTS Young IGF1R-deficient mice were insulin-resistant, with high IGF1, growth hormone (GH) and IGFBP3, as well as low IGFBP2 circulating levels. Males also presented increased triglycerides in liver. In contrast, middle-aged mice did not clearly show all of these alterations, suggesting possible compensatory effects. Middle-aged IGF1R-deficient male mice were able to counteract the negative effects induced by aging and HFD in adiposity, inflammation and glucose metabolism. A metabolic sexual dimorphism dependent on IGF1R was observed, especially in middle-aged mice. CONCLUSIONS These results demonstrate that IGF1R is involved in metabolic homeostasis, with effects modulated by diet-induced obesity and aging in a sex dependent manner. Thus, IGF1R deficiency in mice is proposed as a useful tool to understand metabolic alterations observed in patients with IGF1R gene deletions.
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Affiliation(s)
- Patricia Pérez-Matute
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
- *Correspondence: Patricia Pérez-Matute,
| | - Icíar P. López
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - María Íñiguez
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
| | - Emma Recio-Fernández
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
| | - Raquel Torrens
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - Sergio Piñeiro-Hermida
- Miguel Servet Foundation-Navarra's Health Research Institute (IDISNA), Navarrabiomed Biomedical Research Center, Oncoimmunology Group, Pamplona, Spain
| | - Elvira Alfaro-Arnedo
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - Luong Chau
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Christina Walz
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Andreas Hoeflich
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - José A. Oteo
- Infectious Diseases, Microbiota and Metabolism Unit, Infectious Diseases Department, Center for Biomedical Research of La Rioja (CIBIR) -Hospital Universitario San Pedro, Logroño, Spain
| | - José G. Pichel
- Lung Cancer and Respiratory Diseases Unit. Fundación Rioja Salud, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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13
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Wu X, Ueland PM, Roper J, Koh GY, Liang X, Crott JW, Yilmaz ÖH, Bronson RT, Mason JB. Combined Supplementation with Vitamin B-6 and Curcumin is Superior to Either Agent Alone in Suppressing Obesity-Promoted Colorectal Tumorigenesis in Mice. J Nutr 2021; 151:3678-3688. [PMID: 34590119 DOI: 10.1093/jn/nxab320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/26/2021] [Accepted: 08/30/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation. OBJECTIVES We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis. METHODS Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids. RESULTS HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans. CONCLUSIONS In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.
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Affiliation(s)
- Xian Wu
- Vitamins & Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Per M Ueland
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Jatin Roper
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Gar Yee Koh
- Vitamins & Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Xu Liang
- The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA, USA
| | - Jimmy W Crott
- Vitamins & Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Ömer H Yilmaz
- The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA, USA
| | | | - Joel B Mason
- Vitamins & Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
- Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA
- Division of Clinical Nutrition, Tufts Medical Center, Boston, MA, USA
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14
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Gaculenko A, Gregoric G, Popp V, Seyler L, Ringer M, Kachler K, Wu Z, Kisel W, Hofbauer C, Hofbauer LC, Uder M, Schett G, Bäuerle T, Bozec A. Systemic PPARγ Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents. J Bone Miner Res 2021; 36:2440-2452. [PMID: 34378824 DOI: 10.1002/jbmr.4422] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/26/2021] [Accepted: 08/04/2021] [Indexed: 12/13/2022]
Abstract
Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPARγ) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Anastasia Gaculenko
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Institute of Radiology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Gasper Gregoric
- Institute of Radiology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Vanessa Popp
- Institute of Radiology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Lisa Seyler
- Institute of Radiology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Mark Ringer
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katerina Kachler
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Zhengquan Wu
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Wadim Kisel
- University Center for Traumatology, Orthopedics and Plastic Surgery OUPC, Technische Universität Dresden, Dresden, Germany
| | - Christine Hofbauer
- National Center for Tumor Diseases (NCT), Partner Site Dresden/University Cancer Center (UCC), Technische Universität Dresden, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III and University Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Michael Uder
- Institute of Radiology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Tobias Bäuerle
- Institute of Radiology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
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15
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Choi IY, Choi YJ, Shin DW, Han KD, Jeon KH, Jeong SM, Yoo JE. Association between obesity and the risk of gastric cancer in premenopausal and postmenopausal women: A nationwide cohort study. J Gastroenterol Hepatol 2021; 36:2834-2840. [PMID: 34033134 DOI: 10.1111/jgh.15558] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 03/26/2021] [Accepted: 05/23/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Obesity was suggested to increase the incidence of gastric cancer (GC) in women, but results from previous studies were inconsistent. We investigated the relationship between obesity and the risk of GC according to menopausal status. METHODS We enrolled 1 418 180 premenopausal and 4 854 187 postmenopausal women aged ≥ 40 years using the Korean National Health Insurance System Cohort (2009-2014). We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for GC incidence according to body mass index (BMI) and waist circumference (WC) using the Cox proportional hazards models. RESULTS During the mean follow-up period of 7.2 years, 42 441 women were newly diagnosed with GC. Compared with the group with BMI 18.5-22.9 kg/m2 , the adjusted HRs (95% CIs) for GC in the groups with BMI < 18.5, 23-24.9, 25-29.9, and ≥ 30 kg/m2 were 1.12 (0.95-1.33), 0.96 (0.89-1.04), 1.02 (0.94-1.11), and 0.99 (0.83-1.18), respectively, for premenopausal women and 1.07 (1.00-1.14), 1.01 (0.99-1.04), 1.03 (1.00-1.05), and 1.11 (1.10-1.16), respectively, for postmenopausal women. Compared with the group with WC 65-74.9 cm, the adjusted HRs (95% CIs) for GC for the groups with WC < 65, 75-84.9, 85-94.9, and ≥ 90 cm were 1.00 (0.88-1.15), 1.03 (0.96-1.11), 1.10 (0.99-1.22), and 1.02 (0.81-1.27), respectively, for premenopausal women and 1.01 (0.94-1.09), 1.01 (0.99-1.04), 1.09 (1.06-1.13), and 1.14 (1.09-1.19), respectively, for postmenopausal women. CONCLUSIONS We found a positive association between the highest BMI and WC category and risk of GC in postmenopausal women; however, such an association was not evident in premenopausal women.
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Affiliation(s)
- In Young Choi
- Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Jin Choi
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Wook Shin
- Department of Family Medicine/Supportive Care Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyung Do Han
- Department of Biostatistics, Soongsil University, Seoul, Korea
| | - Keun Hye Jeon
- Department of Family Medicine, CHA Gumi Medical Center, CHA University, Gumi, Korea
| | - Su-Min Jeong
- Department of Family Medicine/Supportive Care Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Eun Yoo
- Department of Family Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
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16
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Ullah R, Rauf N, Nabi G, Yi S, Yu-Dong Z, Fu J. Mechanistic insight into high-fat diet-induced metabolic inflammation in the arcuate nucleus of the hypothalamus. Biomed Pharmacother 2021; 142:112012. [PMID: 34388531 DOI: 10.1016/j.biopha.2021.112012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/31/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022] Open
Abstract
A high-fat diet (HFD) is linked with cytokines production by non-neuronal cells within the hypothalamus, which mediates metabolic inflammation. These cytokines then activate different inflammatory mediators in the arcuate nucleus of the hypothalamus (ARC), a primary hypothalamic area accommodating proopiomelanocortin (POMC) and agouti-related peptide (AGRP) neurons, first-order neurons that sense and integrate peripheral metabolic signals and then respond accordingly. These mediators, such as inhibitor of κB kinase-β (IKKβ), suppression of cytokine signaling 3 (SOCS3), c-Jun N-terminal kinases (JNKs), protein kinase C (PKC), etc., cause insulin and leptin resistance in POMC and AGRP neurons and support obesity and related metabolic complications. On the other hand, inhibition of these mediators has been shown to counteract the impaired metabolism. Therefore, it is important to discuss the contribution of neuronal and non-neuronal cells in HFD-induced hypothalamic inflammation. Furthermore, understanding few other questions, such as the diets causing hypothalamic inflammation, the gender disparity in response to HFD feeding, and how hypothalamic inflammation affects ARC neurons to cause impaired metabolism, will be helpful for the development of therapeutic approaches to prevent or treat HFD-induced obesity.
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Affiliation(s)
- Rahim Ullah
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
| | - Naveed Rauf
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Ghulam Nabi
- Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Shen Yi
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Zhou Yu-Dong
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Junfen Fu
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; National Children's Regional Medical Center, Hangzhou 310052, China.
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17
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Shetty A, Suresh PS. A synergy of estradiol with leptin modulates the long non-coding RNA NEAT1/ mmu-miR-204-5p/IGF1 axis in the uterus of high-fat-diet-induced obese ovariectomized mice. J Steroid Biochem Mol Biol 2021; 209:105843. [PMID: 33588025 DOI: 10.1016/j.jsbmb.2021.105843] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/06/2021] [Accepted: 02/09/2021] [Indexed: 02/06/2023]
Abstract
Obesity increases the risk of developing cancers for both males and females. This study investigated potential crosstalk between estradiol and leptin signaling pathways within the endometrium of high-fat-diet-induced obese ovariectomized mice to gain insight into possible links between obesity and endometrial cancer. We administered 17-β estradiol (0.2 μg/mouse subcutaneously) and/or recombinant mouse leptin (1 μg/g Bwt intraperitoneally.,) for 20 h to high-fat-diet-induced obese ovariectomized mice. The uterine tissues of experimental animals after treatments were studied by histological, immunohistochemical, quantitative real-time PCR (gene/miRNAs), and methylation-specific PCR analyses. Quantitative real-time PCR analysis revealed significantly increased expression of Cyclin d1, Esr1, Igf1, Igfbp2, Vegf, Oct4, and Pgr after estradiol and leptin co-treatment. Methylation-specific PCR results indicated that the hormonal dependent transcriptional regulation of Vegf, Igf1, and Pgr is independent of promoter methylation. The decreased expression of mmu- miR-204-5p after estradiol and leptin treatments correlated with the increased expression of long non-coding RNA Neat1. Insilico analysis confirmed the interaction of Neat1 and mmu- miR-204-5p and gene targets of mmu-miR-204-5p, including Igf1 were analyzed in this study. Immunohistochemical analyses revealed subcellular localization and increased expression of ESR, VEGF, phospho-Estrogen Receptor-α (pTyr537), and LEPR proteins following estradiol and leptin exposure. Overall, the data from our in vivo studies suggest the regulation of Neat1-mmu-miR-204-5p- Igf1 axis and associated gene expression changes in uterine tissue after estradiol and leptin co-treatment. In humans, long-term exposure to estradiol and leptin can alter endometrial homeostasis through the NEAT1-miR-204-5p-Igf1 axis and favor carcinogenic pathways, which provide mechanistic insight into the obesity-associated endometrial cancer.
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Affiliation(s)
- Abhishek Shetty
- Department of Biosciences, Mangalore University, Mangalagangothri, Mangalore, 574 199, Karnataka, India
| | - Padmanaban S Suresh
- School of Biotechnology, National Institute of Technology, Calicut, 673601, Kerala, India.
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18
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Abstract
Obesity is epidemiologically linked to 13 forms of cancer. The local and systemic obese environment is complex and likely affect tumors through multiple avenues. This includes modulation of cancer cell phenotypes and the composition of the tumor microenvironment. A molecular understanding of how obesity links to cancer holds promise for identifying candidate genes for targeted therapy for obese cancer patient. Herein, we review both the cell-autonomous and non-cell-autonomous mechanisms linking obesity and cancer as well as provide an overview of the mouse model systems applied to study this.
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Affiliation(s)
- Xiao-Zheng Liu
- Department of Biomedicine, University of Bergen, N-5020 Bergen, Norway
| | - Line Pedersen
- Department of Biomedicine, University of Bergen, N-5020 Bergen, Norway
| | - Nils Halberg
- Department of Biomedicine, University of Bergen, N-5020 Bergen, Norway
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19
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Obesity Potentiates Esophageal Squamous Cell Carcinoma Growth and Invasion by AMPK-YAP Pathway. J Immunol Res 2020; 2020:6765474. [PMID: 33381605 PMCID: PMC7748896 DOI: 10.1155/2020/6765474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 10/01/2020] [Accepted: 11/30/2020] [Indexed: 01/05/2023] Open
Abstract
Obesity could increase the risk of esophageal squamous cell carcinoma (ESCC) and affect its growth and progression, but the mechanical links are unclear. The objective of the study was to explore the impact of obesity on ESCC growth and progression utilizing in vivo trials and cell experiments in vitro. Diet-induced obese and lean nude mice were inoculated with TE-1 cells, then studied for 4 weeks. Serum glucose, insulin, leptin, and visfatin levels were assayed. Sera of nude mice were obtained and then utilized to culture TE-1. MTT, migration and invasion assays, RT-PCR, and Western blotting were used to analyze endocrine effect of obesity on cell proliferation, migration, invasion, and related genes expression of TE-1. Obese nude mice bore larger tumor xenografts than lean animals, and were hyperglycemic and hyperinsulinemic with an elevated level of leptin and visfatin in sera, and also were accompanied by a fatty liver. As for the subcutaneous tumor xenograft model, tumors were more aggressive in obese nude mice than lean animals. Tumor weight correlated positively with mouse body weight, liver weight of mice, serum glucose, HOMA-IR, leptin, and visfatin. Obesity prompted significant TE-1 cell proliferation, migration, and invasion by endocrine mechanisms and impacted target genes. The expression of AMPK and p-AMPK protein decreased significantly (P < 0.05); MMP9, total YAP, p-YAP, and nonphosphorylated YAP protein increased significantly (P < 0.05) in the cells cultured with conditioned media and xenograft tumor from the obese group; the mRNA expression of AMPK decreased significantly (P < 0.05); YAP and MMP9 mRNA expression increased significantly (P < 0.05) in the cells exposed to conditioned media from the obese group. In conclusion, the altered adipokine milieu and metabolites in the context of obesity may promote ESCC growth in vivo; affect proliferation, migration, and invasion of ESCC cells in vitro; and regulate MMP9 and AMPK-YAP signaling pathway through complex effects including the endocrine effect.
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Bader J, Carson M, Enos R, Velazquez K, Sougiannis A, Singh U, Becker W, Nagarkatti M, Fan D, Murphy A. High-fat diet-fed ovariectomized mice are susceptible to accelerated subcutaneous tumor growth potentially through adipose tissue inflammation, local insulin-like growth factor release, and tumor associated macrophages. Oncotarget 2020; 11:4554-4569. [PMID: 33346251 PMCID: PMC7733624 DOI: 10.18632/oncotarget.27832] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 11/03/2020] [Indexed: 12/20/2022] Open
Abstract
Background: The association between obesity and colorectal cancer (CRC) risk has been well established. This relationship appears to be more significant in men than in women, which may be attributable to sex hormones. However, controlled animal studies to substantiate these claims and the mechanisms involved are lacking. Materials and Methods: MC38 murine colon adenocarcinoma cells were injected subcutaneously into high-fat diet (HFD) fed male, female and ovariectomized (OVX) female C57BL/6 mice. Results: HFD increased tumor growth (main effect) that was consistent with metabolic perturbations (P < 0.01). HFD OVX mice exhibited the most significant tumor growth compared to HFD male and female mice (p < 0.05) and this was associated with increased subcutaneous adipose tissue (p < 0.05). Further, the subcutaneous adipose tissue depots within HFD OVX mice exhibited more severe macrophage associated inflammation compared to female (P < 0.01), but not male mice. Conditioned media from subcutaneous adipose tissue of HFD OVX contained higher IGF-1 levels compared to male (P < 0.01), but not female mice. Finally, HFD OVX mice had increased M2-like gene expression in their tumor-associated macrophages (TAMs) compared to female mice (P < 0.01). Conclusions: This work provides evidences suggesting adiposity, adipose specific IGF-1, macrophage associated adipose inflammation, and TAMs as potential mechanisms driving obesity-enhanced CRC in females lacking ovarian hormones.
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Affiliation(s)
- Jackie Bader
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Meredith Carson
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Reilly Enos
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Kandy Velazquez
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Alexander Sougiannis
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Udai Singh
- Department of Medicine, University of Virginia Health Systems, Charlottesville, VA 22908, USA
| | - William Becker
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Daping Fan
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
| | - Angela Murphy
- Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
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Abstract
Elevated circulating insulin levels are frequently observed in the setting of obesity and early type 2 diabetes, as a result of insensitivity of metabolic tissues to the effects of insulin. Higher levels of circulating insulin have been associated with increased cancer risk and progression in epidemiology studies. Elevated circulating insulin is believed to be a major factor linking obesity, diabetes and cancer. With the development of targeted cancer therapies, insulin signalling has emerged as a mechanism of therapeutic resistance. Although metabolic tissues become insensitive to insulin in the setting of obesity, a number of mechanisms allow cancer cells to maintain their ability to respond to insulin. Significant progress has been made in the past decade in understanding the insulin receptor and its signalling pathways in cancer, and a number of lessons have been learnt from therapeutic failures. These discoveries have led to numerous clinical trials that have aimed to reduce the levels of circulating insulin and to abrogate insulin signalling in cancer cells. With the rising prevalence of obesity and diabetes worldwide, and the realization that hyperinsulinaemia may contribute to therapeutic failures, it is essential to understand how insulin and insulin receptor signalling promote cancer progression.
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Affiliation(s)
- Emily J Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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22
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IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer's Disease. Cells 2020; 9:cells9071605. [PMID: 32630818 PMCID: PMC7407279 DOI: 10.3390/cells9071605] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.
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Abstract
Despite great advances in treatment, cancer remains a leading cause of death worldwide. Diet can greatly impact health, while caloric restriction and fasting have putative benefits for disease prevention and longevity. Strong epidemiological associations exist between obesity and cancer, whereas healthy diets can reduce cancer risk. However, less is known about how diet might impact cancer once it has been diagnosed and particularly how diet can impact cancer treatment. In the present review, we discuss the links between obesity, diet, and cancer. We explore potential mechanisms by which diet can improve cancer outcomes, including through hormonal, metabolic, and immune/inflammatory effects, and present the limited clinical research that has been published in this arena. Though data are sparse, diet intervention may reduce toxicity, improve chemotherapy efficacy, and lower the risk of long-term complications in cancer patients. Thus, it is important that we understand and expand the science of this important but complex adjunctive cancer treatment strategy.
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Affiliation(s)
- Steven D Mittelman
- Division of Pediatric Endocrinology, University of California, Los Angeles (UCLA), Children's Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA;
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24
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Pellizzon MA, Ricci MR. Choice of Laboratory Rodent Diet May Confound Data Interpretation and Reproducibility. Curr Dev Nutr 2020; 4:nzaa031. [PMID: 32258990 PMCID: PMC7103427 DOI: 10.1093/cdn/nzaa031] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/21/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
The reproducibility of experimental data is challenged by many factors in both clinical and preclinical research. In preclinical studies, several factors may be responsible, and diet is one variable that is commonly overlooked, especially by those not trained in nutrition. In particular, grain-based diets contain complex ingredients, each of which can provide multiple nutrients, non-nutrients, and contaminants, which may vary from batch to batch. Thus, even when choosing the same grain-based diet used in the past by others, its composition will likely differ. In contrast, purified diets contain refined ingredients that offer the ability to control the composition much more closely and maintain consistency from one batch to the next, while minimizing the presence of non-nutrients and contaminants. In this article, we provide several different examples or scenarios showing how the diet choice can alter data interpretation, potentially affecting reproducibility and knowledge gained within any given field of study.
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25
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Gennari A, Foca F, Zamarchi R, Rocca A, Amadori D, De Censi A, Bologna A, Cavanna L, Gianni L, Scaltriti L, Rossi E, Facchinetti A, Martini V, Bruzzi P, Nanni O. Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial. Breast Cancer Res Treat 2020; 181:61-68. [PMID: 32200486 DOI: 10.1007/s10549-020-05596-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/12/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients. METHODS CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses. RESULTS Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found. CONCLUSION Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26).
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Affiliation(s)
- Alessandra Gennari
- Medical Oncology, Department of Translational Medicine, University of Eastern Piedmont, Via Solaroli 17, 28100, Novara, Italy.
| | - Flavia Foca
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Rita Zamarchi
- Department of Immunology and Oncological Molecular Diagnostics, Veneto Institute of Oncology (IOV) IRCCS, Padua, Italy
| | - Andrea Rocca
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Dino Amadori
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Andrea De Censi
- Division of Medical Oncology, EO Ospedali Galliera, Genoa, Italy
| | - Alessandra Bologna
- Department of Oncology, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
| | - Luigi Cavanna
- Oncology-Hematology Department, Hospital of Piacenza, Piacenza, Italy
| | - Lorenzo Gianni
- Department of Medical Oncology, Ospedale Infermi, Rimini, Italy
| | - Laura Scaltriti
- Oncology Day Hospital Unit, Ospedale Civile Di Guastalla, Guastalla, Italy
| | - Elisabetta Rossi
- Department of Immunology and Oncological Molecular Diagnostics, Veneto Institute of Oncology (IOV) IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Paduva, Paduva, Italy
| | - Antonella Facchinetti
- Department of Immunology and Oncological Molecular Diagnostics, Veneto Institute of Oncology (IOV) IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Paduva, Paduva, Italy
| | - Veronica Martini
- Medical Oncology, Department of Translational Medicine, University of Eastern Piedmont, Via Solaroli 17, 28100, Novara, Italy
| | - Paolo Bruzzi
- Department of Clinical Epidemiology, IRCCS San Martino - IST, Genoa, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Hao Q, Diaz T, Verduzco ADR, Magyar CE, Zhong J, Elshimali Y, Rettig MB, Henning SM, Vadgama JV, Wang P. Arctigenin inhibits prostate tumor growth in high-fat diet fed mice through dual actions on adipose tissue and tumor. Sci Rep 2020; 10:1403. [PMID: 31996731 PMCID: PMC6989655 DOI: 10.1038/s41598-020-58354-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 01/14/2020] [Indexed: 11/09/2022] Open
Abstract
This study investigated the inhibitory effect of arctigenin, a novel anti-inflammatory lignan, on prostate cancer in obese conditions both in vitro and in vivo. In vitro obese models were established by co-culture of mouse adipocytes 3T3-L1 with androgen-sensitive LNCaP human prostate cancer cells, or by culturing LNCaP cells in adipocytes-conditioned medium. Arctigenin significantly inhibited LNCaP proliferation, along with decreased androgen receptor (AR) and increased Nkx3.1 cellular expression. Male severe combined immunodeficiency mice were subcutaneously implanted with human prostate cancer LAPC-4 xenograft tumors for in vivo study. Mice were fed high-fat (HF) diet and orally given arctigenin at 50 mg/kg body weight daily or vehicle control for 6 weeks. Tumor bearing HF control mice showed a significant increase in serum free fatty acids (FFAs) and decrease in subcutaneous/peritoneal fat depots compared to non-tumor bearing control mice. Arctigenin intervention significantly reduced tumor growth by 45%, associated with decreased circulating FFAs and adipokines/cytokines including IGF-1, VEGF, and MCP-1, along with decreased AR, Ki67, and microvessel density and increased Nkx3.1 expression in tumors. These results indicate the strong ability of arctigenin to co-target obesity and tumor itself in inhibition of prostate tumor growth at a lower concentration compared to most phytochemicals.
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Affiliation(s)
- Qiongyu Hao
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, 90059, USA
- David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Tanya Diaz
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, 90059, USA
| | - Alejandro Del Rio Verduzco
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, 90059, USA
| | - Clara E Magyar
- Department of Pathology, University of California, Los Angeles, CA, 90095, USA
| | - Jin Zhong
- VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA
- University of California, Riverside, CA, 92521, USA
| | - Yahya Elshimali
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, 90059, USA
| | - Matthew B Rettig
- Departments of Medicine and Urology, University of California, Los Angeles, CA, 90095, USA
| | - Susanne M Henning
- Center for Human Nutrition, University of California, Los Angeles, CA, 90095, USA
| | - Jaydutt V Vadgama
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, 90059, USA
- David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Piwen Wang
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, 90059, USA.
- Center for Human Nutrition, University of California, Los Angeles, CA, 90095, USA.
- David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
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Wang Y, Nasiri AR, Damsky WE, Perry CJ, Zhang XM, Rabin-Court A, Pollak MN, Shulman GI, Perry RJ. Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer. Cell Rep 2019; 24:47-55. [PMID: 29972790 DOI: 10.1016/j.celrep.2018.06.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 05/07/2018] [Accepted: 06/01/2018] [Indexed: 10/28/2022] Open
Abstract
Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu.
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Affiliation(s)
- Yongliang Wang
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Ali R Nasiri
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - William E Damsky
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Curtis J Perry
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Xian-Man Zhang
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Aviva Rabin-Court
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Michael N Pollak
- Department of Oncology, McGill University, Montreal, Quebec H3T 1E2, Canada; Department of Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada; Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
| | - Gerald I Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Rachel J Perry
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
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Gorres-Martens BK, Field TJ, Schmidt ER, Munger KA. Exercise prevents HFD- and OVX-induced type 2 diabetes risk factors by decreasing fat storage and improving fuel utilization. Physiol Rep 2019; 6:e13783. [PMID: 29981201 PMCID: PMC6035332 DOI: 10.14814/phy2.13783] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 06/11/2018] [Accepted: 06/14/2018] [Indexed: 11/24/2022] Open
Abstract
Previous studies suggest that the loss of estrogens increase one's risk for type 2 diabetes (T2D), and combining the loss of estrogens with a high-fat diet (HFD) poses an even greater risk for T2D. The extent to which exercise can ameliorate the deleterious effects of estrogen loss combined with a HFD and the molecular mechanisms accounting for the whole body changes is currently unknown. Therefore, we fed female Wistar rats a standard diet or a HFD for 10 weeks. The rats fed the HFD were either ovariectomized (OVX) or their ovaries remained intact. A subset of the HFD/OVX rats also underwent exercise training on a motor-driven treadmill. Exercise significantly reduced the total body weight gain, periuterine white adipose tissue (WAT) weight, hyperglycemia, and hyperinsulinemia. Additionally, the ability to store fat, as measured by lipoprotein lipase (LPL) in the WAT, was increased in the HFD/OVX group; however, exercise reduced the LPL levels. Furthermore, the combination of the HFD with OVX decreased the WAT citrate synthase protein level, which was increased with exercise. These data suggest that even during the combined HFD/OVX physiological state, exercise can decrease several risk factors associated with T2D, decrease fat storage, and increase fuel utilization.
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Affiliation(s)
| | - Tyler J Field
- Exercise and Sport Sciences Department, Augustana University, Sioux Falls, South Dakota
| | - Emma R Schmidt
- Exercise and Sport Sciences Department, Augustana University, Sioux Falls, South Dakota
| | - Karen A Munger
- Research & Development, Sioux Falls VA Health Care System, Sioux Falls, South Dakota
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29
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Hermano E, Goldberg R, Rubinstein AM, Sonnenblick A, Maly B, Nahmias D, Li JP, Bakker MAH, van der Vlag J, Vlodavsky I, Peretz T, Elkin M. Heparanase Accelerates Obesity-Associated Breast Cancer Progression. Cancer Res 2019; 79:5342-5354. [PMID: 31481501 DOI: 10.1158/0008-5472.can-18-4058] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 06/06/2019] [Accepted: 08/26/2019] [Indexed: 11/16/2022]
Abstract
Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages-key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients. SIGNIFICANCE: This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.
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Affiliation(s)
- Esther Hermano
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Rachel Goldberg
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ariel M Rubinstein
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Amir Sonnenblick
- Oncology Division, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Bella Maly
- Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Daniela Nahmias
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Jin-Ping Li
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Marinka A H Bakker
- Nephrology Research Laboratory, Department of Nephrology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
| | - Johan van der Vlag
- Nephrology Research Laboratory, Department of Nephrology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
| | - Israel Vlodavsky
- Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Tamar Peretz
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
- Hebrew University Medical School, Jerusalem, Israel
| | - Michael Elkin
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
- Hebrew University Medical School, Jerusalem, Israel
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30
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Abstract
Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells' dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.
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Diabetes Mellitus and Colon Carcinogenesis: Expectation for Inhibition of Colon Carcinogenesis by Oral Hypoglycemic Drugs. GASTROINTESTINAL DISORDERS 2019. [DOI: 10.3390/gidisord1020023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The global deaths due to colorectal cancer and diabetes mellitus have increased by 57% and 90%, respectively. The relationship between various cancers and diabetes mellitus has been shown in multiple epidemiological studies. Hence, better management of diabetes mellitus is expected to reduce the risk of various cancers. This review focuses on colorectal cancer and aims to summarize recent findings on the antitumor effects of various oral hypoglycemic drugs on colorectal cancer and their estimated mechanisms. Of the seven classes of oral hypoglycemic agents, only metformin was found to have suppressive effects on colorectal cancer in both clinical and basic research. Clinical and basic researches on suppressing effects of glinides, dipeptidyl peptidase-4 inhibitors, thiazolidinedione, α-glucosidase inhibitors, and sodium glucose cotransporter-2 inhibitors against colon carcinogenesis have been insufficient and have not arrived at any conclusion. Therefore, further research regarding these agents is warranted. In addition, the suppressive effects of these agents in healthy subjects without diabetes should also be investigated.
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Rabin-Court A, Rodrigues MR, Zhang XM, Perry RJ. Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation. PLoS One 2019; 14:e0218126. [PMID: 31188872 PMCID: PMC6561592 DOI: 10.1371/journal.pone.0218126] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 05/27/2019] [Indexed: 12/17/2022] Open
Abstract
Obesity is associated with increased incidence and worse prognosis of more than one dozen tumor types; however, the molecular mechanisms for this association remain under debate. We hypothesized that insulin, which is elevated in obesity-driven insulin resistance, would increase tumor glucose oxidation in obesity-associated tumors. To test this hypothesis, we applied and validated a stable isotope method to measure the ratio of pyruvate dehydrogenase flux to citrate synthase flux (VPDH/VCS, i.e. the percent of total mitochondrial oxidation fueled by glucose) in tumor cells. Using this method, we found that three tumor cell lines associated with obesity (colon cancer [MC38], breast cancer [4T1], and prostate cancer [TRAMP-C3] cells) increase VPDH/VCS in response to physiologic concentrations of insulin. In contrast, three tumor cell lines that are not associated with obesity (melanoma [YUMM1.7], B cell lymphoma [BCL1 clone 5B1b], and small cell lung cancer [NCI-H69] cells) exhibited no oxidative response to insulin. The observed increase in glucose oxidation in response to insulin correlated with a dose-dependent increase in cell division in obesity-associated tumor cell lines when grown in insulin, whereas no alteration in cell division was seen in tumor types not associated with obesity. These data reveal that a shift in substrate preference in the setting of physiologic insulin may comprise a metabolic signature of obesity-associated tumors that differs from that of those not associated with obesity.
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Affiliation(s)
- Aviva Rabin-Court
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Marcos R. Rodrigues
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Xian-Man Zhang
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Rachel J. Perry
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail:
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Tsai CF, Chen JH, Wu CT, Chang PC, Wang SL, Yeh WL. Induction of osteoclast-like cell formation by leptin-induced soluble intercellular adhesion molecule secreted from cancer cells. Ther Adv Med Oncol 2019; 11:1758835919846806. [PMID: 31205504 PMCID: PMC6535721 DOI: 10.1177/1758835919846806] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 03/13/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Leptin is considered a tumorigenic adipokine, suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported as proportional to cancer stage and considered as a potential diagnosis biomarker. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years. Material and methods: The expression of ICAM-1 and its regulatory signaling were examined by Western blot or flow cytometry. The effect of soluble ICAM-1 on osteoclast formation was investigated by tartrate-resistance acid phosphatase staining of RAW cells and tumor-induced osteolysis in vivo. Results: In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with the receptor activator of nuclear factor kappa-B ligand (RANKL) in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis in vivo. Conclusion: These findings suggest that soluble ICAM-1 produced under leptin treatment enhances osteoclast formation and is involved in tumor-induced osteolysis. Leptin plays an important role in physiology in health and diseases. Leptin affects immune responses that may induce inflammation and carcinogenesis. Leptin is also considered as a tumorigenic adipokine suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported to be proportional to cancer stage and considered as a potential diagnosis biomarker. It has been reported that soluble ICAM-1 allows tumor cells to escape from immune recognition and stimulates angiogenesis and tumor growth. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years. In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with receptor activator of nuclear factor-kappa B ligand in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis in vivo. These findings suggest that soluble ICAM-1 produced under leptin treatment is possibly involved in lung and breast cancer bone metastasis.
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Affiliation(s)
- Cheng-Fang Tsai
- Department of Biotechnology, Asia University, Taichung, China
| | - Jia-Hong Chen
- Department of General Surgery, Buddhist Tzu Chi Medical Foundation, Taichung, China
| | - Chen-Teng Wu
- Department of Surgery, China Medical University Hospital, Taichung, China
| | - Pei-Chun Chang
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, China
| | - Shu-Lin Wang
- Institute of New Drug Development, China Medical University, Taichung, China
| | - Wei-Lan Yeh
- Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Road, Taichung, 40402 China
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Wu X, Koh GY, Huang Y, Crott JW, Bronson RT, Mason JB. The Combination of Curcumin and Salsalate is Superior to Either Agent Alone in Suppressing Pro‐Cancerous Molecular Pathways and Colorectal Tumorigenesis in Obese Mice. Mol Nutr Food Res 2019; 63:e1801097. [DOI: 10.1002/mnfr.201801097] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 12/10/2018] [Indexed: 01/14/2023]
Affiliation(s)
- Xian Wu
- Vitamins & Carcinogenesis Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA 02111
| | - Gar Yee Koh
- Vitamins & Carcinogenesis Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA 02111
| | - Yueyi Huang
- Vitamins & Carcinogenesis Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA 02111
- Friedman School of Nutrition Science and Policy Tufts University Boston MA 02111
| | - Jimmy W. Crott
- Vitamins & Carcinogenesis Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA 02111
| | | | - Joel B. Mason
- Vitamins & Carcinogenesis Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Boston MA 02111
- Friedman School of Nutrition Science and Policy Tufts University Boston MA 02111
- Division of Gastroenterology Tufts Medical Center Boston MA 02111
- Division of Clinical Nutrition Tufts Medical Center Boston MA 02111
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35
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Canter RJ, Le CT, Beerthuijzen JM, Murphy WJ. Obesity as an immune-modifying factor in cancer immunotherapy. J Leukoc Biol 2018; 104:487-497. [PMID: 29762866 PMCID: PMC6113103 DOI: 10.1002/jlb.5ri1017-401rr] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 04/17/2018] [Accepted: 04/18/2018] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy has achieved breakthrough status in many advanced stage malignancies and is rapidly becoming the fourth arm of cancer treatment. Although cancer immunotherapy has generated significant excitement because of the potential for complete and sometimes durable responses, there is also the potential for severe and occasionally life-threatening toxicities, including cytokine release syndrome and severe autoimmunity. A large body of work also points to a "metainflammatory" state in obesity associated with impairment of immune responses. Because immune checkpoint blockade (and other cancer immunotherapies) have altered the landscape of immunotherapy in cancer, it is important to understand how immune responses are shaped by obesity and how obesity may modify both immunotherapy responses and potential toxicities.
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Affiliation(s)
- Robert J. Canter
- University of California, Davis, School of Medicine, Department of Surgery, Division of Surgical Oncology, Sacramento, CA 95817
| | - Catherine T Le
- University of California, Davis, School of Medicine, Departments of Dermatology and Internal Medicine, Sacramento, CA 95817
| | - Johanna M.T. Beerthuijzen
- University of California, Davis, School of Medicine, Departments of Dermatology and Internal Medicine, Sacramento, CA 95817
| | - William J. Murphy
- University of California, Davis, School of Medicine, Departments of Dermatology and Internal Medicine, Sacramento, CA 95817
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36
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Guan F, Tabrizian T, Novaj A, Nakanishi M, Rosenberg DW, Huffman DM. Dietary Walnuts Protect Against Obesity-Driven Intestinal Stem Cell Decline and Tumorigenesis. Front Nutr 2018; 5:37. [PMID: 29904634 PMCID: PMC5990619 DOI: 10.3389/fnut.2018.00037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 04/23/2018] [Indexed: 12/12/2022] Open
Abstract
Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer. Therefore, the purpose of this study was to determine if walnuts could preserve intestinal homeostasis, and attenuate tumorigenesis and growth in the context of obesity and a high calorie diet. To this end, we studied effects of walnuts on these parameters under different dietary conditions in wildtype mice, two independent Apc models (Apc1638N/+ and ApcΔ14), and in MC38 colon cancer cells in vivo, respectively. Walnuts did not alter the metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet (LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts (HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore, walnuts reduced tumor multiplicity in Apc1638N/+ male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; P = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; P = 0.07), and preferentially limited tumor growth in ApcΔ14 male mice (P = 0.019) fed a high-calorie western-style diet. In summary, these data demonstrate that walnuts confer significant protection against intestinal tumorigenesis and growth and preserve ISC function in the context of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence connecting walnuts as a potentially effective dietary strategy to break the obesity-colon cancer link.
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Affiliation(s)
- Fangxia Guan
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.,Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States.,School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Tahmineh Tabrizian
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.,Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Ardijana Novaj
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.,Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Masako Nakanishi
- School of Medicine, University of Connecticut Health, Farmington, CT, United States
| | - Daniel W Rosenberg
- School of Medicine, University of Connecticut Health, Farmington, CT, United States
| | - Derek M Huffman
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.,Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States.,Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, United States
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37
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Muller YL, Skelton G, Piaggi P, Chen P, Nair A, Kobes S, Hsueh WC, Knowler WC, Hanson RL, Baier LJ, Bogardus C. Identification and functional analysis of a novel G310D variant in the insulin-like growth factor 1 receptor (IGF1R) gene associated with type 2 diabetes in American Indians. Diabetes Metab Res Rev 2018; 34:e2994. [PMID: 29470850 DOI: 10.1002/dmrr.2994] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/06/2018] [Accepted: 02/12/2018] [Indexed: 12/31/2022]
Abstract
AIMS Insulin-like growth factor 1 receptor (IGF1R) is involved in cell growth and glucose homeostasis. In the current study, the IGF1R locus was analysed as a candidate gene for type 2 diabetes (T2D) in American Indians. MATERIALS AND METHODS Whole genome sequence data from 335 American Indians identified 3 novel missense variants in IGF1R. The associations of IGF1R variants with T2D, age of T2D onset and birth weight were analysed in a population-based sample of 7701 American Indians. RESULTS A novel glycine-to-aspartic acid substitution (G310D) in IGF1R was identified, which associated with T2D in a sex-specific manner (Psex interaction = 0.02). In women, the aspartic acid (D) allele (frequency = 0.034) was associated with increased risk for T2D (n = 4292, P = 2.0 × 10-5 adjusted for age, birth year, and the first 5 genetic principal components; odds ratio [OR] = 2.23 [1.54-3.23] per risk allele) and an earlier age of T2D onset (n = 4292, P = 2 × 10-4 , hazard rate ratio = 1.45 [1.20-1.75], Psex interaction = 0.05). Female carriers of the D-allele also had lower birth weight (n = 1313, β = -163 g, P = .006, Psex interaction = 0.008). Among 85 siblings discordant for G310D, carriers of the D-allele had shorter stature as compared with carriers of the G-allele (β = -1.6 cm, P = .001, within family model). The G310D variant was functionally studied in vitro, where the D-allele had a 22% increase (P = .0005) in FOXO1-induced transcriptional activity, due to decreased activation of the PI3K/AKT pathway mediated through reduced IGF1R activity. CONCLUSION A unique G310D variant in IGF1R, which occurs in 6% American Indians, may impair IGF1R signalling pathways, thereby increasing the risk of T2D.
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Affiliation(s)
- Yunhua L Muller
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Graham Skelton
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Paolo Piaggi
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Peng Chen
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Anup Nair
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Sayuko Kobes
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Wen-Chi Hsueh
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - William C Knowler
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Robert L Hanson
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Leslie J Baier
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
| | - Clifton Bogardus
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA
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38
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Aguilar EG, Murphy WJ. Obesity induced T cell dysfunction and implications for cancer immunotherapy. Curr Opin Immunol 2018; 51:181-186. [PMID: 29655021 DOI: 10.1016/j.coi.2018.03.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 02/09/2018] [Accepted: 03/13/2018] [Indexed: 12/12/2022]
Abstract
Obesity has been shown to increase risk for a number of different disorders, including cancer. In addition, obesity is also associated with immune dysfunction, which could contribute to its strong association with other comorbidities. Recently, the immune system has been found to be heavily regulated by changes in metabolism. In particular, T cells are able to respond to intrinsic metabolic regulatory mechanisms, as well as extrinsic factors such as the changes in metabolite availability. The dysfunctional metabolic environment created by obesity could therefore have a direct impact on T cell responses. In this review, we highlight recent findings in the fields of T cell biology and obesity, with a focus on mechanisms driving T cell dysfunction and potential implications for immunotherapeutic treatment of cancer.
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Affiliation(s)
- Ethan G Aguilar
- Department of Dermatology, UC Davis School of Medicine, Sacramento, CA 95816, USA
| | - William J Murphy
- Department of Dermatology, UC Davis School of Medicine, Sacramento, CA 95816, USA; Department of Internal Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
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Sundaram S, Yan L. Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice. Oncotarget 2018; 7:65669-65675. [PMID: 27582541 PMCID: PMC5323183 DOI: 10.18632/oncotarget.11598] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/11/2016] [Indexed: 01/29/2023] Open
Abstract
The objective of this study was to determine whether a reduction in energy intake ameliorated the high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma in mice. Male C57BL/6 mice were fed the AIN93G diet, a high-fat diet or a high-fat diet with a 5% restriction of the intake. Energy restriction reduced body adiposity and body weight, but maintained growth similar to mice fed the AIN93G diet. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of metastases formed in lungs. Restricted feeding reduced the number of metastases by 23%, metastatic cross-sectional area by 32% and volume by 45% compared to the high-fat diet. The high-fat diet elevated plasma concentrations of proinflammatory cytokines (monocyte chemotactic protein-1, plasminogen activator inhibitor-1, leptin), angiogenic factors (vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1) and insulin. Restricted feeding significantly reduced the high-fat diet-induced elevations in plasma concentrations of proinflammatory cytokines, angiogenic factors and insulin. These results demonstrated that a reduction in diet intake by 5% reduced high-fat diet-enhanced metastasis, which may be associated with the mitigation of adiposity and down-regulation of cancer-promoting proinflammatory cytokines and angiogenic factors.
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Affiliation(s)
- Sneha Sundaram
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA
| | - Lin Yan
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA
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40
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O'Neill AM, Gillaspie EA, Burrington CM, Lynch DT, Dauchy RT, Blask DE, Tirrell PC, Reis BA, Horsman MJ, Greene MW. Development and Characterization of a Novel Congenic Rat Strain for Obesity and Cancer Research. Nutr Cancer 2018; 70:278-287. [PMID: 29313726 DOI: 10.1080/01635581.2018.1412483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The association between a Western Diet and colon cancer suggests that dietary factors and/or obesity may contribute to cancer progression. Our objective was to develop a new animal model of obesity and the associated pathophysiology to investigate human cancer independent of dietary components that induce obesity. A novel congenic rat strain was established by introducing the fa allele from the Zucker rat into the Rowett Nude rat to generate a "fatty nude rat". The obese phenotype was first characterized in the new model. To then examine the utility of this model, lean and obese rats were implanted with HT-29 human colon cancer xenografts and tumor growth monitored. Fatty nude rats were visibly obese and did not develop fasting hyperglycemia. Compared to lean rats, fatty nude rats developed fasting hyperinsulinemia, glucose intolerance, and insulin resistance. Colon cancer tumor growth rate and final weight were increased (P < 0.05) in fatty nude compared to lean rats. Final tumor weight was associated with p38 kinase phosphorylation (P < 0.01) in fatty nude rats. We have established a novel model of obesity and pre-type 2 diabetes that can be used to investigate human cancer and therapeutics in the context of obesity and its associated pathophysiology.
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Affiliation(s)
- Ann Marie O'Neill
- a Department of Biology , Auburn University Montgomery , Montgomery , Alabama , USA.,b Department of Nutrition, Auburn University , Auburn , Alabama , USA
| | - Erin A Gillaspie
- c Department of Thoracic Surgery , School of Medicine, Vanderbilt University , Nashville , Tennessee , USA
| | | | - Darin T Lynch
- d Bassett Research Institute , Cooperstown , New York , USA
| | - Robert T Dauchy
- e Department of Structural & Cellular Biology , Tulane University School of Medicine and Tulane Cancer Center , Tulane , Los Angeles , USA
| | - David E Blask
- e Department of Structural & Cellular Biology , Tulane University School of Medicine and Tulane Cancer Center , Tulane , Los Angeles , USA
| | - Paul C Tirrell
- f Department of Internal Medicine , Bassett Medical Center , Cooperstown , New York , USA
| | - Brian A Reis
- d Bassett Research Institute , Cooperstown , New York , USA
| | | | - Michael W Greene
- b Department of Nutrition, Auburn University , Auburn , Alabama , USA.,d Bassett Research Institute , Cooperstown , New York , USA.,g Boshell Metabolic Diseases and Diabetes Program, Auburn University , Auburn , Alabama , USA
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Chakraborty D, Benham V, Bullard B, Kearney T, Hsia HC, Gibbon D, Demireva EY, Lunt SY, Bernard JJ. Fibroblast growth factor receptor is a mechanistic link between visceral adiposity and cancer. Oncogene 2017; 36:6668-6679. [PMID: 28783178 PMCID: PMC5709202 DOI: 10.1038/onc.2017.278] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/19/2017] [Accepted: 07/03/2017] [Indexed: 02/07/2023]
Abstract
Epidemiological evidence implicates excess adipose tissue in increasing cancer risk. Despite a steeply rising global prevalence of obesity, how adiposity contributes to transformation (stage a non-tumorigenic cell undergoes to become malignant) is unknown. To determine the factors in adipose tissue that stimulate transformation, we used a novel ex vivo system of visceral adipose tissue (VAT)-condition medium-stimulated epithelial cell growth in soft agar. To extend this system in vivo, we used a murine lipectomy model of ultraviolet light B-induced, VAT-promoted skin tumor formation. We found that VAT from mice and obese human donors stimulated growth in soft agar of non-tumorigenic epithelial cells. The difference in VAT activity was associated with fibroblast growth factor-2 (FGF2) levels. Moreover, human and mouse VAT failed to stimulate growth in soft of agar in cells deficient in FGFR-1 (FGF2 receptor). We also demonstrated that circulating levels of FGF2 were associated with non-melanoma tumor formation in vivo. These data implicate FGF2 as a major factor VAT releases to transform epithelial cells-a novel, potential pathway of VAT-enhanced tumorigenesis. Strategies designed to deplete VAT stores of FGF2 or inhibit FGFR-1 in abdominally obese individuals may be important cancer prevention strategies as well as adjuvant therapies for improving outcomes.
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Affiliation(s)
- D Chakraborty
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - V Benham
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - B Bullard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - T Kearney
- Division of Surgical Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - H C Hsia
- Section of Plastic Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - D Gibbon
- Summit Medical4 Group, Livingston, NJ, USA
| | - E Y Demireva
- Office for the Vice President for Research and Graduate Studies, Michigan State University, East Lansing, MI, USA
| | - S Y Lunt
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - J J Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
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Magkos F, Sullivan S, Fitch M, Smith G, Fabbrini E, Mittendorfer B, Hellerstein M, Klein S. Effect of Weight Gain and Weight Loss on In Vivo Colonocyte Proliferation Rate in People with Obesity. Obesity (Silver Spring) 2017; 25 Suppl 2:S81-S86. [PMID: 29086514 PMCID: PMC5679222 DOI: 10.1002/oby.21983] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 07/29/2017] [Accepted: 08/09/2017] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate the effects of diet-induced changes in energy balance and body weight on in vivo colonocyte fractional proliferation rates (FPR) in people with obesity. METHODS In vivo colonocyte FPR was assessed in 31 men and women with obesity (BMI: 35.4 ± 4.0 kg/m2 , age: 52.6 ± 8.9 years) before and after diet-induced weight loss, weight gain, or weight maintenance. Subjects ingested aliquots of 2 H2 O (heavy water) daily for 4 to 7 days, followed by flexible sigmoidoscopy with colon biopsies to assess the incorporation of 2 H into the DNA of dividing colonocytes. RESULTS Colonocyte FPR averaged 12.7% ± 3.8% per day and correlated directly with intra-abdominal adipose tissue (IAAT) volume (r = 0.364, P = 0.044). Colonocyte FPR decreased in the weight loss group, did not change in the weight maintenance group, and increased in the weight gain group. The change in colonocyte FPR correlated directly with the percent change in body weight (r = 0.409, P = 0.028) and IAAT volume (r = 0.598, P = 0.001). CONCLUSIONS A high-calorie diet and weight gain increase, whereas a low-calorie diet and weight loss decrease, in vivo colonocyte proliferation rate in people with obesity. These results suggest that changes in energy balance influence the risk of developing colon cancer in people with obesity by regulating colonic mucosal growth rates.
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Affiliation(s)
- Faidon Magkos
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore & Clinical Nutrition Research Centre, A*STAR, Singapore
| | - Shelby Sullivan
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO
| | - Mark Fitch
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA
| | - Gordon Smith
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO
| | - Elisa Fabbrini
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO
| | - Bettina Mittendorfer
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO
| | - Marc Hellerstein
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA
| | - Samuel Klein
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO
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Goldberg R, Sonnenblick A, Hermano E, Hamburger T, Meirovitz A, Peretz T, Elkin M. Heparanase augments insulin receptor signaling in breast carcinoma. Oncotarget 2017; 8:19403-19412. [PMID: 28038446 PMCID: PMC5386693 DOI: 10.18632/oncotarget.14292] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 12/01/2016] [Indexed: 01/09/2023] Open
Abstract
Recently, growing interest in the potential link between metabolic disorders (i.e., diabetes, obesity, metabolic syndrome) and breast cancer has mounted, including studies which indicate that diabetic/hyperinsulinemic women have a significantly higher risk of bearing breast tumors that are more aggressive and associated with higher death rates. Insulin signaling is regarded as a major contributor to this phenomenon; much less is known about the role of heparan sulfate-degrading enzyme heparanase in the link between metabolic disorders and cancer.In the present study we analyzed clinical samples of breast carcinoma derived from diabetic/non-diabetic patients, and investigated effects of heparanase on insulin signaling in breast carcinoma cell lines, as well as insulin-driven growth of breast tumor cells.We demonstrate that heparanase activity leads to enhanced insulin signaling and activation of downstream tumor-promoting pathways in breast carcinoma cells. In agreement, heparanase enhances insulin-induced proliferation of breast tumor cells in vitro. Moreover, analyzing clinical data from diabetic breast carcinoma patients, we found that concurrent presence of both diabetic state and heparanase in tumor tissue (as opposed to either condition alone) was associated with more aggressive phenotype of breast tumors in the patient cohort analyzed in our study (two-sided Fisher's exact test; p=0.04). Our findings highlight the emerging role of heparanase in powering effect of hyperinsulinemic state on breast tumorigenesis and imply that heparanase targeting, which is now under intensive development/clinical testing, could be particularly efficient in a growing fraction of breast carcinoma patients suffering from metabolic disorders.
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Affiliation(s)
- Rachel Goldberg
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Amir Sonnenblick
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Esther Hermano
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Tamar Hamburger
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Amichay Meirovitz
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Tamar Peretz
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Michael Elkin
- Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
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Matsushita N, Hassanein MT, Martinez-Clemente M, Lazaro R, French SW, Xie W, Lai K, Karin M, Tsukamoto H. Gender difference in NASH susceptibility: Roles of hepatocyte Ikkβ and Sult1e1. PLoS One 2017; 12:e0181052. [PMID: 28797077 PMCID: PMC5552280 DOI: 10.1371/journal.pone.0181052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 06/26/2017] [Indexed: 12/22/2022] Open
Abstract
Myeloid cell and hepatocyte IKKβ may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of non-alcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKKβ deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKKβ deficiency (IkbkbΔhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male IkbkbΔhep mice having worst NASH and lowest plasma estradiol levels. LXRα is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbΔhep mice with NASH, and a Sult1e1 promoter activity is increased by LXRα and its ligand and augmented by expression of a S32A mutant of IκBα. These results demonstrate striking gender differences in regulation by IKKβ of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKβ is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients.
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Affiliation(s)
- Noriko Matsushita
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Mohamed T. Hassanein
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Marcos Martinez-Clemente
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Raul Lazaro
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Samuel W. French
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Wen Xie
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States of America
| | - Keane Lai
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Michael Karin
- Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, California, United States of America
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
- Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
- * E-mail:
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Li HJ, Fu JK, Che XM, Fan L, Zhang Y, Bai E. Obesity accelerates murine gastric cancer growth by modulating the Sirt1/YAP pathway. Oncol Lett 2017; 14:4151-4157. [PMID: 28943922 PMCID: PMC5592852 DOI: 10.3892/ol.2017.6715] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 05/11/2017] [Indexed: 11/05/2022] Open
Abstract
A previous study from our group using an in vivo model demonstrated that diet induced-obesity increases the risk of gastric cancer and may prompt its growth. However, the molecular mechanisms underlying this association remain unclear and require further investigation. The aim of the present study was to investigate the potential molecular mechanisms through which obesity affects gastric cancer growth. In a subcutaneous mouse model, tumors were significantly larger in obese mice compared with non-obese and lean mice. In addition, markedly increased levels of Sirt1 and YAP protein were observed in the nucleus of cells from subcutaneous tumors from obese mice compared with those from lean mice. Murine forestomach carcinoma (MFC) cells treated with 5% sera from obese mice exhibited significantly increased expression of Sirt1 and YAP compared with MFC cells treated with sera from lean mice. In addition, a positive correlation was observed between Sirt1 expression and YAP expression, and between Sirt1 expression and serum visfatin levels in mice. These results suggested that diet-induced obesity could promote murine gastric cancer growth by modulating the Sirt1/YAP signaling pathway.
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Affiliation(s)
- Hai-Jun Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jun-Ke Fu
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiang-Ming Che
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lin Fan
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yong Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - E Bai
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Dorfman MD, Krull JE, Douglass JD, Fasnacht R, Lara-Lince F, Meek TH, Shi X, Damian V, Nguyen HT, Matsen ME, Morton GJ, Thaler JP. Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice. Nat Commun 2017; 8:14556. [PMID: 28223698 PMCID: PMC5322503 DOI: 10.1038/ncomms14556] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 01/12/2017] [Indexed: 02/06/2023] Open
Abstract
Female mice are less susceptible to the negative metabolic consequences of high-fat diet feeding than male mice, for reasons that are incompletely understood. Here we identify sex-specific differences in hypothalamic microglial activation via the CX3CL1-CX3CR1 pathway that mediate the resistance of female mice to diet-induced obesity. Female mice fed a high-fat diet maintain CX3CL1-CX3CR1 levels while male mice show reductions in both ligand and receptor expression. Female Cx3cr1 knockout mice develop 'male-like' hypothalamic microglial accumulation and activation, accompanied by a marked increase in their susceptibility to diet-induced obesity. Conversely, increasing brain CX3CL1 levels in male mice through central pharmacological administration or virally mediated hypothalamic overexpression converts them to a 'female-like' metabolic phenotype with reduced microglial activation and body-weight gain. These data implicate sex differences in microglial activation in the modulation of energy homeostasis and identify CX3CR1 signalling as a potential therapeutic target for the treatment of obesity.
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Affiliation(s)
- Mauricio D. Dorfman
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Jordan E. Krull
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - John D. Douglass
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Rachael Fasnacht
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Fernando Lara-Lince
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Thomas H. Meek
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Xiaogang Shi
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Vincent Damian
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Hong T. Nguyen
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Miles E. Matsen
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Gregory J. Morton
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
| | - Joshua P. Thaler
- UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA
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Role of Nampt and Visceral Adiposity in Esophagogastric Junction Adenocarcinoma. J Immunol Res 2017; 2017:3970605. [PMID: 28168205 PMCID: PMC5266808 DOI: 10.1155/2017/3970605] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/22/2016] [Indexed: 12/20/2022] Open
Abstract
Nampt including eNampt and iNampt may contribute to mediating obesity-associated cancers. This study investigated the role of Nampt in esophagogastric junction adenocarcinoma (EGA), a cancer strongly correlated with obesity. Visceral adiposity was defined by waist circumference or VFA. eNampt in sera were measured by enzyme-linked immunosorbent assay. iNampt expression in EGA was determined by PCR, western blot, and immunohistochemistry. Sera eNampt were significantly elevated in these overweight and obese patients, especially for viscerally obese patients, and positively correlated with BMI, waist circumference, VFA, and also primary tumor, regional lymph nodes, and TNM stage (P < 0.05). iNampt expression in both the mRNA and protein levels was upregulated in EGAs (P < 0.05). iNampt staining was found primarily in the cytoplasm and nuclei and significantly associated with tumor, lymph nodes, and TNM stage and also correlated positively with serum eNampt, BMI, total fat area, VFA, superficial fat area, and waist circumference (P < 0.05). iNampt, eNampt, tumor, lymph nodes, and TNM stage correlated to the survival of EGAs, and iNampt expression and TNM stage affected the prognosis independently (P < 0.05). This study highlighted the association of eNampt/iNampt with visceral obesity and a potential impact on the biology of EGA.
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Ding J, Li C, Tang J, Yi C, Liu JY, Qiu M. Higher Expression of Proteins in IGF/IR Axes in Colorectal Cancer is Associated with Type 2 Diabetes Mellitus. Pathol Oncol Res 2016; 22:773-9. [PMID: 27138191 DOI: 10.1007/s12253-016-0065-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 04/26/2016] [Indexed: 02/05/2023]
Abstract
Preexisting type 2 diabetes mellitus (preDM) increases occurrence and mortality of colorectal cancer (CRC). Insulin growth factor (IGF)/insulin receptor (IR) axes play an important role in the development of both diabetes and CRC. We aimed to explore the characteristics of proteins expression in IGF/IR axes in CRC tissues with preDM. Two hundred fifty CRC patients in West China hospital were included in analysis. Among them, 125 patients had history of diabetes matched by 125 CRC without diabetes at a 1:1 ratio. Immunohistochemical staining was used to detect the expression of proteins in IGF/IR axis. More positive expression of IGF-1, IGF-1R and IR were found in CRC group with diabetes than in non-diabetes group. No difference was detected in the expression of IR substrate-1, IR substrate-2, IGF-2, IGF binding protein 3, and mammalian target of rapamycin between two groups. Multivariate analysis showed that diabetes history was associated with all of the expression of IGF-1, IGF-1R and IR, and higher T staging and lymph node metastasis were respectively independent factors of IGF-1 and IGF-1R expression in CRC patients. Besides, IGF-1 expression was positively associated with IGF-1R and IR expression in all CRC tissues, and the association of IGF-1 and IR expression seemed to be closer in diabetes group than in non-diabetes group. Higher expression of IGF-1, IGF-1R and IR proteins in CRC was associated with diabetes, suggesting IGF-1/IR signaling may play a special part in development of CRC in patients with diabetes.
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Affiliation(s)
- Jing Ding
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan Province, 610041, China
| | - Cong Li
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan Province, 610041, China
| | - Jie Tang
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan Province, 610041, China
| | - Cheng Yi
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan Province, 610041, China
| | - Ji-Yan Liu
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan Province, 610041, China
| | - Meng Qiu
- Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan Province, 610041, China.
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Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode. Breast Cancer Res 2016; 18:29. [PMID: 26956474 PMCID: PMC4782371 DOI: 10.1186/s13058-016-0689-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 02/19/2016] [Indexed: 01/08/2023] Open
Abstract
Background Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown. Methods The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland. Results Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity. Conclusions Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0689-1) contains supplementary material, which is available to authorized users.
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Ben-Shmuel S, Rostoker R, Scheinman EJ, LeRoith D. Metabolic Syndrome, Type 2 Diabetes, and Cancer: Epidemiology and Potential Mechanisms. Handb Exp Pharmacol 2016; 233:355-372. [PMID: 25903410 DOI: 10.1007/164_2015_12] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Obesity is associated with multiple metabolic disorders that drive cardiovascular disease, T2D and cancer. The doubling in the number of obese adults over the past 3 decades led to the recognition of obesity as a "disease". With over 42 million children obese or overweight, this epidemic is rapidly growing worldwide. Obesity and T2D are both associated together and independently with an increased risk for cancer and a worse prognosis. Accumulating evidence from epidemiological studies revealed potential factors that may explain the association between obesity-linked metabolic disorders and cancer risk. Studies based on the insulin resistance MKR mice, highlighted the roe of the insulin receptor and its downstream signaling proteins in mediating hyperinsulinemia's mitogenic effects. Hypercholesterolemia was also shown to promote the formation of larger tumors and enhancement in metastasis. Furthermore, the conversion of cholesterol into 27-Hydroxycholesterol was found to link high fat diet-induced hypercholesterolemia with cancer pathophysiology. Alteration in circulating adipokines and cytokines are commonly found in obesity and T2D. Adipokines are involved in tumor growth through multiple mechanisms including mTOR, VEGF and cyclins. In addition, adipose tissues are known to recruit and alter macrophage phenotype; these macrophages can promote cancer progression by secreting inflammatory cytokines such as TNF-α and IL-6. Better characterization on the above factors and their downstream effects is required in order to translate the current knowledge into the clinic, but more importantly is to understand which are the key factors that drive cancer in each patient. Until we reach this point, policies and activities toward healthy diets and physical activities remain the best medicine.
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Affiliation(s)
- Sarit Ben-Shmuel
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Ran Rostoker
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Eyal J Scheinman
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Derek LeRoith
- Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel.
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