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Jonker PB, Sadullozoda M, Cognet G, Saab JJA, Sokol KH, Wu VX, Kumari D, Sheehan C, Ozgurses ME, Agovino D, Croley G, Patel SA, Bock-Hughes A, Macleod KF, Shah H, Coloff JL, Lien EC, Muir A. Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.10.642426. [PMID: 40161789 PMCID: PMC11952453 DOI: 10.1101/2025.03.10.642426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors perturb cellular metabolic activity, which imposes metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cell metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. As a consequence of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturatedenriched fat sources.
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Affiliation(s)
- Patrick B. Jonker
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Mumina Sadullozoda
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Guillaume Cognet
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Juan J. Apiz Saab
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Kelly H. Sokol
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, Michigan, USA, 49503
| | - Violet X. Wu
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Deepa Kumari
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Colin Sheehan
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Mete E. Ozgurses
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA, 60612
| | - Darby Agovino
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Grace Croley
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Smit A. Patel
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Althea Bock-Hughes
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Kay F. Macleod
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Hardik Shah
- Metabolomics Platform, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA, 60637
| | - Jonathan L. Coloff
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA, 60612
| | - Evan C. Lien
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, Michigan, USA, 49503
| | - Alexander Muir
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
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Sun R, Zhang Y, Zhao X, Tang T, Cao Y, Yang L, Tian Y, Zhang Z, Zhang P, Xu F. Temporal and Spatial Metabolic Shifts Revealing the Transition from Ulcerative Colitis to Colitis-Associated Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412551. [PMID: 39840505 PMCID: PMC11923922 DOI: 10.1002/advs.202412551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/17/2024] [Indexed: 01/23/2025]
Abstract
Patients with ulcerative colitis (UC) have a higher risk of developing colorectal cancer (CRC), however, the metabolic shifts during the UC-to-CRC transition remain elusive. In this study, an AOM-DSS-induced three-stage colitis-associated colorectal cancer (CAC) model is constructed and targeted metabolomics analysis and pathway enrichment are performed, uncovering the metabolic changes in this transition. Spatial metabolic trajectories in the "normal-to-normal adjacent tissue (NAT)-to-tumor" transition, and temporal metabolic trajectories in the "colitis-to-dysplasia-to-carcinoma" transition are identified through K-means clustering of 74 spatially and 77 temporally differential metabolites, respectively. The findings reveal two distinct metabolic profile categories during the inflammation-to-cancer progression: those with consistent changes, either increasing (e.g., kynurenic acid, xanthurenic acid) or decreasing (e.g., long-chain fatty acids, LCFAs), and those enriched at specific disease stages (e.g., serotonin). Further analysis of metabolites with consistent temporal trends identifies eicosapentaenoic acid (EPA) as a key metabolite, potentially exerting anti-inflammatory and anti-cancer effects by inhibiting insulin-like growth factor binding protein 5 (IGFBP5). This study reveals novel metabolic mechanisms underlying the transition from UC to CAC and suggests potential targets to delay the progression.
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Affiliation(s)
- Ruiqi Sun
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Yuanyuan Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Xian Zhao
- Department of Pharmacy, Drum Tower Hospital, China Pharmaceutical University, Nanjing, 210008, P. R. China
| | - Tian Tang
- School of Pharmacy, Air Force Medical University, Xi'an, 710032, P. R. China
| | - Yuepeng Cao
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, 210009, P. R. China
| | - Liu Yang
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, 210009, P. R. China
| | - Yuan Tian
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Zunjian Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Pei Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Fengguo Xu
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, P. R. China
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Xie R, Luo Y, Bao B, Wu X, Guo J, Wang J, Qu X, Che X, Zheng C. The Role of Fatty Acid Metabolism, the Related Potential Biomarkers, and Targeted Therapeutic Strategies in Gastrointestinal Cancers. Drug Dev Res 2024; 85:e70014. [PMID: 39527665 DOI: 10.1002/ddr.70014] [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: 05/17/2024] [Revised: 10/12/2024] [Accepted: 10/13/2024] [Indexed: 11/16/2024]
Abstract
Gastrointestinal cancer has emerged as a significant global health concern due to its high incidence and mortality, limited effectiveness of early detection, suboptimal treatment outcomes, and poor prognosis. Metabolic reprogramming is a prominent feature of cancer, and fatty acid metabolism assumes a pivotal role in bridging glucose metabolism and lipid metabolism. Fatty acids play important roles in cellular structural composition, energy supply, signal transduction, and other lipid-related processes. Changes in the levels of fatty acid metabolite may indicate the malignant transformation of gastrointestinal cells, which have an impact on the prognosis of patients and can be used as a marker to monitor the efficacy of anticancer therapy. Therefore, targeting key enzymes involved in fatty acid metabolism, either as monotherapy or in combination with other agents, is a promising strategy for anticancer treatment. This article reviews the potential mechanisms of fatty acid metabolism disorders in the occurrence and development of gastrointestinal tumors, and summarizes the related potential biomarkers and anticancer strategies.
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Affiliation(s)
- Ruixi Xie
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ying Luo
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bowen Bao
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xinshu Wu
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jia Guo
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jin Wang
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaofang Che
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chunlei Zheng
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Department of Oncology, Shanghai Electric Power Hospital, Shanghai, China
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Kiyasu Y, Zuo X, Liu Y, Yao JC, Shureiqi I. EPA, DHA, and resolvin effects on cancer risk: The underexplored mechanisms. Prostaglandins Other Lipid Mediat 2024; 174:106854. [PMID: 38825147 DOI: 10.1016/j.prostaglandins.2024.106854] [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: 02/29/2024] [Revised: 05/23/2024] [Accepted: 05/29/2024] [Indexed: 06/04/2024]
Abstract
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplements have exhibited inconsistent effects on cancer risk, and their potential efficacy as cancer preventive agents has been increasingly questioned, especially in recent large randomized clinical trials. The role of host factors that govern EPA and DHA metabolism in relation to their impact on carcinogenesis remains understudied. Resolvins, the products of EPA and DHA oxidative metabolism, demonstrate intriguing antitumorigenic effects through mechanisms such as promoting macrophage phagocytosis of cell debris and inhibiting the production of proinflammatory chemokines and cytokines by tumor-associated macrophages (TAMs), which are crucial for cancer progression. However, clinical studies have not yet shown a significant increase in target tissue levels of resolvins with EPA and DHA supplementation. 15-Lipoxygenase-1 (ALOX15), a key enzyme in EPA and DHA oxidative metabolism, is often lost in various major human cancers, including precancerous and advanced colorectal cancers. Further research is needed to elucidate whether the loss of ALOX15 expression in colorectal precancerous and cancerous cells affects EPA and DHA oxidative metabolism, the formation of resolvins, and subsequently carcinogenesis. The findings from these studies could aid in the development of novel and effective chemoprevention interventions to reduce cancer risk.
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Affiliation(s)
- Yoshiyuki Kiyasu
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Xiangsheng Zuo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yi Liu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - James C Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Imad Shureiqi
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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Sun G, Li YN, Davies JR, Block RC, Kothapalli KS, Brenna JT, Hull MA. Fatty acid desaturase insertion-deletion polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid eicosapentaenoic acid: a secondary analysis of the seAFOod polyp prevention trial. Am J Clin Nutr 2024; 120:360-368. [PMID: 38879016 PMCID: PMC11347814 DOI: 10.1016/j.ajcnut.2024.06.004] [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: 02/08/2024] [Revised: 05/10/2024] [Accepted: 06/11/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND A fatty acid desaturase (FADS) insertion-deletion (Indel) polymorphism (rs66698963) influences the expression of FADS1, which controls the synthesis of n-6 highly unsaturated fatty acid (HUFA) arachidonic acid (AA). The anti-inflammatory activity of the n-3 HUFA eicosapentaenoic acid (EPA) may be explained by competition with AA for proinflammatory lipid mediator synthesis. A precision medicine approach based on stratification by FADS Indel genotype could identify individuals, who benefit from greatest disease risk reduction by n-3 HUFAs. OBJECTIVES We tested the hypothesis that the FADS insertion (I) allele predicts colorectal polyp risk reduction in a secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2000 mg daily and aspirin 300 mg daily for 12 mo (ISRCTN05926847). METHODS Participant Indel genotype was determined by polymerase chain reaction (PCR) blind to trial outcomes. Colorectal polyp outcomes were included in negative binomial (polyp number) and logistic (polyp detection rate [PDR; percentage with one or more polyps]) regression models comparing each active intervention with its placebo. Presence of ≥1 Indel I allele and an interaction term (I allele × active intervention) were covariates. RESULTS In 528 participants with colonoscopy and FADS Indel data, EPA use irrespective of Indel genotype, was not associated with reduced colorectal polyp number (incidence rate ratio [IRR]: 0.92; 95% confidence interval: 0.74, 1.16), mirroring original seAFOod trial analysis. However, the presence of ≥1 I allele identified EPA users with a significant reduction in colorectal polyp number (IRR: 0.50 [0.28, 0.90]), unlike aspirin, for which there was no interaction. Similar findings were obtained for the PDR. CONCLUSIONS The FADS Indel I allele identified individuals, who displayed colorectal polyp prevention by EPA with a similar effect size to aspirin. Assessment of rs66698963 as a biomarker of therapeutic response to n-3 HUFAs in other populations and healthcare settings is warranted. The seAFOod polyp prevention trial and STOP-ADENOMA study were registered at International Standard Randomised Controlled Trial Number registry as ISRCTN05926847.
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Affiliation(s)
- Ge Sun
- Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Yan Ning Li
- Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, TX, United States; Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United States
| | - John R Davies
- Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Robert C Block
- Department of Public Health Sciences, University of Rochester, Rochester, NY, United States; Cardiovascular Division of the Department of Medicine, University of Rochester, Rochester, NY, United States; Center for Community Health and Prevention, University of Rochester, Rochester, NY, United States
| | - Kumar Sd Kothapalli
- Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, TX, United States; Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United States
| | - J Thomas Brenna
- Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, TX, United States; Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, United States
| | - Mark A Hull
- Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
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Silverman AL, Bouchiba H, Aelvoet A, MacDonald J, Dekker E, Zayadi A, Le J, Feagan B, Jairath V, Ma C, Samadder J. Endoscopic scoring indices for assessing disease severity in familial adenomatous polyposis: Systematic review. Endosc Int Open 2024; 12:E799-E809. [PMID: 38904059 PMCID: PMC11188755 DOI: 10.1055/a-2330-8037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/03/2024] [Indexed: 06/22/2024] Open
Abstract
Background and study aims There is limited consensus on the optimal method for measuring disease severity in familial adenomatous polyposis (FAP). We aimed to systematically review the operating properties of existing endoscopic severity indices for FAP. Methods We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2023 to identify randomized controlled trials (RCTs) that utilized endoscopic outcomes or studies that evaluated the operating properties of endoscopic disease severity indices in FAP. Results A total of 134 studies were included. We evaluated scoring indices and component items of scoring indices, such as polyp count, polyp size, and histology. Partial validation was observed for polyp count and size. The most commonly reported scoring index was the Spigelman classification system, which was used for assessing the severity of duodenal involvement. A single study reported almost perfect interobserver and intra-observer agreement for this system. The InSIGHT polyposis staging system, which was used for assessing colorectal polyp burden, has been partially validated. It showed substantial interobserver reliability; however, the intra-observer reliability was not assessed. Novel criteria for high-risk gastric polyps have been developed and assessed for interobserver reliability. However, these criteria showed a poor level of agreement. Other scoring indices assessing the anal transition zone, duodenal, and colorectal polyps have not undergone validation. Conclusions There are no fully validated endoscopic disease severity indices for FAP. Development and validation of a reliable and responsive endoscopic disease severity instrument will be informative for clinical care and RCTs of pharmacological therapies for FAP.
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Affiliation(s)
| | - Hicham Bouchiba
- Department of Gastroenterology and Hepatology, Cancer Center, University of Amsterdam, Amsterdam, Netherlands
| | - Arthur Aelvoet
- Department of Gastroenterology and Hepatology, Cancer Center, University of Amsterdam, Amsterdam, Netherlands
| | | | - Evelien Dekker
- Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, Netherlands
| | | | - Jessica Le
- Alimentiv, Alimentiv Inc, London, Canada
| | - Brian Feagan
- Alimentiv, Alimentiv Inc, London, Canada
- Division of Gastroenterology and Department of Epidemiology and Biostatistics, Western University, London, Canada
| | - Vipul Jairath
- Alimentiv, Alimentiv Inc, London, Canada
- Division of Gastroenterology and Department of Epidemiology and Biostatistics, Western University, London, Canada
| | - Christopher Ma
- Alimentiv, Alimentiv Inc, London, Canada
- Division of Gastroenterology & Hepatology, Departments of Medicine and Community Health Sciences, University of Calgary Cumming School of Medicine, Calgary, Canada
| | - Jewel Samadder
- Gastroenterology and Hepatology, Mayo Clinic Scottsdale, Scottsdale, United States
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Zuo X, Kiyasu Y, Liu Y, Deguchi Y, Liu F, Moussalli M, Tan L, Wei B, Wei D, Yang P, Shureiqi I. Colorectal ALOX15 as a host factor determinant of EPA and DHA effects on colorectal carcinogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.02.592224. [PMID: 38746303 PMCID: PMC11092629 DOI: 10.1101/2024.05.02.592224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids (ω-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1β, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC. Significance Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1β, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.
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Gilad O, Muller C, Kupfer SS. Chemoprevention in Inherited Colorectal Cancer Syndromes. Clin Colon Rectal Surg 2024; 37:172-179. [PMID: 38606042 PMCID: PMC11006448 DOI: 10.1055/s-0043-1770384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024]
Abstract
Cancer prevention in hereditary gastrointestinal predisposition syndromes relies primarily on intensive screening (e.g., colonoscopy) or prophylactic surgery (e.g., colectomy). The use of chemopreventive agents as an adjunct to these measures has long been studied both in the general population and in hereditary cancer patients, in whom the risk of malignancy, and therefore the potential risk reduction, is considerably greater. However, to date only few compounds have been found to be effective, safe, and tolerable for widespread use. Furthermore, many of the studies involving these rare syndromes suffer from small sample sizes, heterogeneous patient cohorts, short follow-up duration, and lack of standardized endpoints, creating challenges to draw generalizable conclusion regarding efficacy. The following review summarizes the current data on various chemopreventive compounds used in Lynch syndrome and familial adenomatous polyposis in addition to several agents that are currently being investigated.
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Affiliation(s)
- Ophir Gilad
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
| | - Charles Muller
- Division of Gastroenterology and Hepatology, Northwestern University, Chicago, Illinois
| | - Sonia S. Kupfer
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
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Erazo-Oliveras A, Muñoz-Vega M, Salinas ML, Wang X, Chapkin RS. Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk. FEBS J 2024; 291:1299-1352. [PMID: 36282100 PMCID: PMC10126207 DOI: 10.1111/febs.16665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.
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Affiliation(s)
- Alfredo Erazo-Oliveras
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Michael L. Salinas
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
- Center for Environmental Health Research; Texas A&M University; College Station, Texas, 77843; USA
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Poylin VY, Shaffer VO, Felder SI, Goldstein LE, Goldberg JE, Kalady MF, Lightner AL, Feingold DL, Paquette IM. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Inherited Adenomatous Polyposis Syndromes. Dis Colon Rectum 2024; 67:213-227. [PMID: 37682806 DOI: 10.1097/dcr.0000000000003072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/10/2023]
Affiliation(s)
- Vitaliy Y Poylin
- Division of Gastrointestinal and Oncologic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Virginia O Shaffer
- Department of Surgery, Emory University College of Medicine, Atlanta, Georgia
| | - Seth I Felder
- Department of Surgery, Moffit Cancer Center, Tampa, Florida
| | - Lindsey E Goldstein
- Division of General Surgery, North Florida/South Georgia Veteran's Health System, Gainesville, Florida
| | - Joel E Goldberg
- Division of General and Gastrointestinal Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Matthew F Kalady
- Division of Colon and Rectal Surgery, Ohio State University, Columbus, Ohio
| | - Amy L Lightner
- Department of Colorectal Surgery, Scripps Clinic, San Diego, California
| | - Daniel L Feingold
- Division of Colorectal Surgery, Rutgers University, New Brunswick, New Jersey
| | - Ian M Paquette
- Division of Colon and Rectal Surgery, University of Cincinnati, Cincinnati, Ohio
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11
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Pettersen CHH, Samdal H, Sætrom P, Wibe A, Hermansen E, Schønberg SA. The Salmon Oil OmeGo Reduces Viability of Colorectal Cancer Cells and Potentiates the Anti-Cancer Effect of 5-FU. Mar Drugs 2023; 21:636. [PMID: 38132957 PMCID: PMC10744414 DOI: 10.3390/md21120636] [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: 10/19/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 12/23/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancer types worldwide. Chemotherapy is toxic to normal cells, and combinatory treatment with natural well-tolerated products is being explored. Some omega-3 polyunsaturated fatty acids (n-3 PUFAs) and marine fish oils have anti-cancer effects on CRC cells. The salmon oil OmeGo (Hofseth BioCare) contains a spectrum of fatty acids, including the n-3 PUFAs docosahexaenoic acid (DHA) and eicosahexaenoic acid (EPA). We explored a potential anti-cancer effect of OmeGo on the four CRC cell lines DLD-1, HCT-8, LS411N, and LS513, alone and in combination with the chemotherapeutic agent 5-Fluorouracil (5-FU). Screening indicated a time- and dose-dependent effect of OmeGo on the viability of the DLD-1 and LS513 CRC cell lines. Treatment with 5-FU and OmeGo (IC20-IC30) alone indicated a significant reduction in viability. A combinatory treatment with OmeGo and 5-FU resulted in a further reduction in viability in DLD-1 and LS513 cells. Treatment of CRC cells with DHA + EPA in a concentration corresponding to the content in OmeGo alone or combined with 5-FU significantly reduced viability of all four CRC cell lines tested. The lowest concentration of OmeGo reduced viability to a higher degree both alone and in combination with 5-FU compared to the corresponding concentrations of DHA + EPA in three of the cell lines. Results suggest that a combination of OmeGo and 5-FU could have a potential as an alternative anti-cancer therapy for patients with CRC.
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Affiliation(s)
- Caroline H. H. Pettersen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Surgery, St. Olav’s University Hospital, 7006 Trondheim, Norway
- Hofseth BioCare, Kipervikgata 13, 6003 Ålesund, Norway;
| | - Helle Samdal
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Surgery, St. Olav’s University Hospital, 7006 Trondheim, Norway
| | - Pål Sætrom
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Computer Science, Faculty of Information Technology and Electrical Engineering, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
- Bioinformatics Core Facility—BioCore, Norwegian University of Science and Technology (NTNU), 7006 Trondheim, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (NTNU), 7006 Trondheim, Norway
| | - Arne Wibe
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Surgery, St. Olav’s University Hospital, 7006 Trondheim, Norway
| | | | - Svanhild A. Schønberg
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
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12
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Chevalier E, Benamouzig R. Chemoprevention in hereditary digestive neoplasia: A comprehensive review. Therap Adv Gastroenterol 2023; 16:17562848231215585. [PMID: 38050626 PMCID: PMC10693784 DOI: 10.1177/17562848231215585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 10/23/2023] [Indexed: 12/06/2023] Open
Abstract
Hereditary syndromes, such as familial adenomatous polyposis (FAP), MUTYH polyposis or Lynch syndrome, are particularly predisposing to the development of colorectal cancer. These situations have necessitated the development of adapted prevention strategies based largely on reinforced endoscopic surveillance and the search for complementary prevention strategies. This is the case for chemoprevention, which is the long-term administration of chemical agents limiting carcinogenesis, used as primary or secondary prophylaxis. The aim of this review is to present the available literature and the latest advances in chemoprevention in patients with FAP or MUTYH and other polyposis as well as in patients with Lynch syndrome. The main conclusions of the few available guidelines in these situations are also discussed.
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Affiliation(s)
- Eugénie Chevalier
- Department of Gastroenterology and Digestive Oncology, Avicenne Hospital, Bobigny, France
| | - Robert Benamouzig
- Department of Gastroenterology and Digestive Oncology, Avicenne Hospital, AP-HP, Paris Nord la Sorbonne University, 125 Rue de Stalingrad, Bobigny 93000, France
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13
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Hull MA, Ow PL, Ruddock S, Brend T, Smith AF, Marshall H, Song M, Chan AT, Garrett WS, Yilmaz O, Drew DA, Collinson F, Cockbain AJ, Jones R, Loadman PM, Hall PS, Moriarty C, Cairns DA, Toogood GJ. Randomised, placebo-controlled, phase 3 trial of the effect of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases: EPA for Metastasis Trial 2 (EMT2) study protocol. BMJ Open 2023; 13:e077427. [PMID: 38030258 PMCID: PMC10689403 DOI: 10.1136/bmjopen-2023-077427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
INTRODUCTION There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis. METHODS AND ANALYSIS The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6 monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%. ETHICS AND DISSEMINATION Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently. TRIAL REGISTRATION NUMBER NCT03428477.
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Affiliation(s)
- Mark A Hull
- Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Pei Loo Ow
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Sharon Ruddock
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Tim Brend
- Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Alexandra F Smith
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Helen Marshall
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Mingyang Song
- Harvard TH Chan School of Public Health, Boston, Massachusetts, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Wendy S Garrett
- Harvard TH Chan School of Public Health, Boston, Massachusetts, USA
| | - Omer Yilmaz
- Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Boston, Massachusetts, USA
| | - David A Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Fiona Collinson
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | | | - Robert Jones
- Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
| | - Paul M Loadman
- Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
| | - Peter S Hall
- Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK
| | | | - David A Cairns
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Giles J Toogood
- Leeds Institute of Medical Research, University of Leeds, Leeds, UK
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
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14
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Zhang T, Xu Y. Update on Surgical Management of FAP. Clin Colon Rectal Surg 2023; 36:385-390. [PMID: 37795461 PMCID: PMC10547540 DOI: 10.1055/s-0043-1767707] [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: 10/06/2023]
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum. Various genetic variants have been confirmed to be associated with corresponding FAP phenotypes, which play important roles in the diagnosis and surgical treatment of FAP. Generally, proctocolectomy is recommended for FAP patients at the age of 20s. Exceptionally, for patients with attenuated FAP, high-risk of desmoid, chemoprevention therapy, or other circumstances, surgery can be postponed. With the wide application of minimal invasive surgery in colorectal cancer, laparoscopic, robotic surgery, and natural orifice specimen extraction are proved to be feasible for FAP patients, but high-level evidences are needed to confirm their safety and advantages. In the times of precise medicine, the surgical management of FAP should vary with individuals based on genotype, phenotype, and clinical practice. Therefore, in addition to innovation in surgical procedures, investigation in links between genetic features and phenotypes will be helpful to optimize the surgical management of FAP in the future.
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Affiliation(s)
- Tianqi Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
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15
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Halma MTJ, Tuszynski JA, Marik PE. Cancer Metabolism as a Therapeutic Target and Review of Interventions. Nutrients 2023; 15:4245. [PMID: 37836529 PMCID: PMC10574675 DOI: 10.3390/nu15194245] [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: 08/28/2023] [Revised: 09/20/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.
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Affiliation(s)
- Matthew T. J. Halma
- Department of Physics and Astronomy, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- EbMC Squared CIC, Bath BA2 4BL, UK
| | - Jack A. Tuszynski
- Department of Physics, University of Alberta, 11335 Saskatchewan Dr NW, Edmonton, AB T6G 2M9, Canada
- Department of Data Science and Engineering, The Silesian University of Technology, 44-100 Gliwice, Poland
- DIMEAS, Politecnico di Torino, Corso Duca degli Abruzzi 24, I-1029 Turin, Italy
| | - Paul E. Marik
- Frontline COVID-19 Critical Care Alliance, Washington, DC 20036, USA
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16
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Stone JK, Mehta NA, Singh H, El-Matary W, Bernstein CN. Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome. Fam Cancer 2023; 22:413-422. [PMID: 37119510 DOI: 10.1007/s10689-023-00334-3] [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: 01/23/2023] [Accepted: 04/18/2023] [Indexed: 05/01/2023]
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing affected individuals to gastrointestinal (GI) cancers through a high burden of polyposis. Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. Endoscopic therapy of gastric, duodenal, ampullary and rectal pouch polyps is critical to reduce morbidity and cancer related mortality. Management of these lesions is not uniform, and is dependent on their location, size, histology, and risk of malignant potential. Medical therapies targeting pathways that reduce the malignant progression of pre-cancerous lesions have been studied for many years. While studies on the use of aspirin and non-steroidal anti-inflammatories (NSAIDs) in chemoprevention have shown encouraging results in Lynch syndrome and primary colorectal cancer, the potential benefits of these medications have not been duplicated in FAP cohorts. While data remains limited on chemoprevention in FAP, a number of randomized trials are currently underway examining targeted therapies with the potential to slow the progression of the disease. This review aims to provide an in-depth review of the literature on current endoscopic options and chemopreventive therapies targeting FAP. While the endoscopic management has robust data for its use, chemoprevention in FAP is still in its infancy. The complementary use of chemopreventive agents and endoscopic therapy for FAP patients is quickly becoming a growing and exciting area of research.
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Affiliation(s)
- J K Stone
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
| | - N A Mehta
- Center for Interventional and Therapeutic Endoscopy, Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
| | - H Singh
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
| | - W El-Matary
- Section of Pediatric Gastroenterology, Department of Pediatrics, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - C N Bernstein
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
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17
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Kim SH, Park DH, Lim YJ. Impact of Diet on Colorectal Cancer Progression and Prevention: From Nutrients to Neoplasms. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2023; 82:73-83. [PMID: 37621242 DOI: 10.4166/kjg.2023.079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/26/2023]
Abstract
Colorectal cancer (CRC), one of the most common cancers worldwide, continues to increase in incidence and mortality rates. This trend is closely linked to changes in dietary habits, which are major risk factors for colorectal cancer. The increase in the incidence of CRC in countries previously considered low-risk and with low socioeconomic status is most likely due to lifestyle and dietary changes. Understanding the influence of dietary factors on the onset of colorectal cancer is essential for prevention and treatment. This review explores the complex interplay between dietary factors and colorectal cancer, focusing on the key nutrients and dietary habits that influence disease onset and progression. The impact of diet on colorectal microbiota and the influence of diet on early-onset colorectal cancer are also reviewed, reviewing recent research on how dietary interventions affect the treatment and recurrence of colorectal cancer. Finally, the future research directions for developing and applying effective dietary intervention strategies are discussed.
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Affiliation(s)
- Sang Hoon Kim
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Dong Hwan Park
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Yun Jeong Lim
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
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18
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Kyriakidis F, Kogias D, Venou TM, Karlafti E, Paramythiotis D. Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis. Appl Clin Genet 2023; 16:139-153. [PMID: 37600856 PMCID: PMC10439286 DOI: 10.2147/tacg.s372241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 07/31/2023] [Indexed: 08/22/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome marked by extensive colorectal polyposis and a high risk of colorectal cancer (CRC). Having access to screening and enrollment programs can improve survival for patients with FAP by enabling them to undergo surgery before the development of colorectal cancer. Provided that there are a variety of surgical options available to treat colorectal polyps in patients with adenomatous polyposis, the appropriate surgical option for each patient should be considered. The gold-standard treatment to reduce this risk is prophylactic colectomy, typically by the age of 40. However, colectomy is linked to morbidity and constitutes an ineffective way at preventing extra-colonic disease manifestations, such as desmoid disease, thyroid malignancy, duodenal polyposis, and cancer. Moreover, extensive studies have been conducted into the use of chemopreventive agents to prevent disease progression and delay the necessity for a colectomy as well as the onset of extracolonic disease. The ideal chemoprevention agent should demonstrate a biologically plausible mechanism of action and provide safety, easy tolerance over an extended period of time and a lasting and clinically meaningful effect. Although many pharmaceutical and non-pharmaceutical products have been tested through the years, there has not yet been a chemoprevention agent that meets these criteria. Thus, it is necessary to develop new FAP agents that target novel pathways, such as the mTOR pathway. The aim of this article is to review the prior literature on FAP in order to concentrate the current and future perspectives of diagnosis and treatment. In conclusion, we will provide an update on the diagnostic and therapeutic options, surgical or pharmaceutical, while focusing on the potential treatment strategies that could further reduce the risk of CRC.
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Affiliation(s)
- Filippos Kyriakidis
- Second Chemotherapy Department, Theagenio Cancer Hospital of Thessaloniki, Thessaloniki, Greece
| | - Dionysios Kogias
- First Department of Internal Medicine, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Theodora Maria Venou
- Second Chemotherapy Department, Theagenio Cancer Hospital of Thessaloniki, Thessaloniki, Greece
| | - Eleni Karlafti
- Emergency Department, AHEPA General University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
- First Propaedeutic Department of Internal Medicine, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Daniel Paramythiotis
- First Propaedeutic Surgery Department, AHEPA University General Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
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19
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Monahan KJ, Swinyard O, Latchford A. Biology of Precancers and Opportunities for Cancer Interception: Lesson from Colorectal Cancer Susceptibility Syndromes. Cancer Prev Res (Phila) 2023; 16:421-427. [PMID: 37001883 DOI: 10.1158/1940-6207.capr-22-0500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/28/2023] [Accepted: 03/28/2023] [Indexed: 04/04/2023]
Abstract
Hereditary gastrointestinal cancer is associated with molecular and neoplastic precursors which have revealed much about sporadic carcinogenesis. Therefore, an appreciation of constitutional and somatic events linked to these syndromes have provided a useful model for the development of risk models and preventative strategies. In this review, we focus of two of the best characterized syndromes, Lynch syndrome (LS) and familial adenomatous polyposis (FAP). Our understanding of the neoplasia-immune interaction in LS has contributed to the development of immune mediated therapies including cancer preventing vaccines and immunotherapy for cancer precursors. Chemoprevention in LS with aspirin and nonsteroidal anti-inflammatory drugs has also translated into clinical cancer, however the efficacy of such agents in FAP remains elusive when cancer is applied as an endpoint in trials rather than the use of 'indirect' endpoints such as polyp burden, and requires further elucidation of biological mechanisms in FAP. Finally, we review controversies in gastrointestinal surveillance for LS and FAP, including limitations and opportunities of upper and lower gastrointestinal endoscopy in the prevention and early detection of cancer.
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Affiliation(s)
- Kevin J Monahan
- Centre for Familial Intestinal Cancer, St. Marks Hospital & Imperial College, London, United Kingdom
| | - Ottilie Swinyard
- Evolution and Cancer Lab, Centre of Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
- Genomics and Evolutionary Dynamics Lab, Division of Molecular Pathology, Institute of Cancer Research, Sutton, London, United Kingdom
| | - Andrew Latchford
- Centre for Familial Intestinal Cancer, St. Marks Hospital & Imperial College, London, United Kingdom
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20
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Lepore Signorile M, Grossi V, Fasano C, Simone C. Colorectal Cancer Chemoprevention: A Dream Coming True? Int J Mol Sci 2023; 24:7597. [PMID: 37108756 PMCID: PMC10140862 DOI: 10.3390/ijms24087597] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the deadliest forms of cancer worldwide. CRC development occurs mainly through the adenoma-carcinoma sequence, which can last decades, giving the opportunity for primary prevention and early detection. CRC prevention involves different approaches, ranging from fecal occult blood testing and colonoscopy screening to chemoprevention. In this review, we discuss the main findings gathered in the field of CRC chemoprevention, focusing on different target populations and on various precancerous lesions that can be used as efficacy evaluation endpoints for chemoprevention. The ideal chemopreventive agent should be well tolerated and easy to administer, with low side effects. Moreover, it should be readily available at a low cost. These properties are crucial because these compounds are meant to be used for a long time in populations with different CRC risk profiles. Several agents have been investigated so far, some of which are currently used in clinical practice. However, further investigation is needed to devise a comprehensive and effective chemoprevention strategy for CRC.
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Affiliation(s)
- Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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21
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Chen L, Ye L, Hu B. Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine. Biomedicines 2022; 10:3207. [PMID: 36551963 PMCID: PMC9776295 DOI: 10.3390/biomedicines10123207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Hereditary CRC syndromes account for approximately 5-10% of all CRC, with a lifetime risk of CRC that approaches 50-80% in the absence of endoscopic or surgical treatment. Hereditary CRC syndromes can be phenotypically divided into polyposis and non-polyposis syndrome, mainly according to the conditions of polyps. The typical representatives are familial adenomatous polyposis (FAP) and Lynch syndromes (LS), respectively. Over the past few decades, molecular genetics enhanced the discovery of cancer-predisposing genes and revolutionized the field of clinical oncology. Hereditary CRC syndromes have been a key part of this effort, with data showing that pathogenic variants are present in up to 10% of cases. Molecular phenotypes of tumors can not only help identify individuals with genetic susceptibility to CRC but also guide the precision prevention and treatment for the development of CRC. This review emphasizes the molecular basis and prevention strategies for hereditary CRC syndromes.
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Affiliation(s)
| | | | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
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22
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Koseoğlu A, Al-Taie A. The potential chemo-preventive roles of Malus domestica against the risk of colorectal cancer: A suggestive insight into clinical application. Clin Nutr ESPEN 2022; 52:360-364. [PMID: 36513476 DOI: 10.1016/j.clnesp.2022.09.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/28/2022] [Accepted: 09/14/2022] [Indexed: 01/28/2023]
Abstract
Biologically active compounds in fruit-derived ingredients, particularly phytochemicals, have significant potential to modulate and mitigate many pathological processes in the development of disease conditions, including cancer. Colorectal cancer (CRC) remains a major public health issue. Nonetheless, prevention is an important step in lowering the rate of mortality from this cancer. Currently, the link between apple consumption and improved health is becoming remarkably evident and is reported to be beneficial for human health. Phytochemicals, such as flavonoids and other polyphenol compounds extensively available in apple fruits, have well-known positive effects on health outcomes and the potential to combat and prevent the development of CRC, including antioxidant, anti-proliferative, and anti-carcinogenic effects. This review describes the bioactive compounds derived from apple fruits, particularly the polyphenols and flavonoids, their proposed mechanisms responsible for their bioactive properties and health-promoting attributes that could provide potential chemo-preventive effects against the risk of CRC development. The conclusion of the review provides insights into the potential effects of apple-derived bioactive compounds and proposes the need for more clinical studies in large trials for future strategies regarding the valuable effects of apple phytochemicals, which might be therapeutic candidates in the campaign against CRC.
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Affiliation(s)
- Aygül Koseoğlu
- Clinical Pharmacy Department, Faculty of Pharmacy, Medipol University, Istanbul, Turkey
| | - Anmar Al-Taie
- Clinical Pharmacy Department, Faculty of Pharmacy, Istinye University, Istanbul, Turkey.
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23
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Neuhann TM, Haub K, Steinke-Lange V, Morak M, Laner A, Locher M, Holinski-Feder E. Long-term chemoprevention in patients with adenomatous polyposis coli: an observational study. Fam Cancer 2022; 21:463-472. [PMID: 35570229 DOI: 10.1007/s10689-022-00292-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 03/10/2022] [Indexed: 01/07/2023]
Abstract
Prospective short-term studies on effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) point towards a decrease in the number and size of polyps. Effectiveness and safety in the prevention of progression in familial polyposis with NSAIDs in long-term use, which is the prerequisite for therapeutic evaluation in prospective studies, is unknown. The total absolute observation period of 54 patients under sulindac was 399 patient years with a mean of 7.4 (2-19) years per patient. 36 patients (66.7%) showed a fast decrease of polyp burden, 8 (14.8%) were slow responders, and 9 (16.7%) had stable disease; one patient had a slow progression. Upper gastrointestinal (GI) polyp burden remained stable in 47% patients, increased in 31%, and improved in 22%. Advanced adenomas were found in 8 patients only within the first 5 years of chemoprevention, no patient developed desmoid disease, anamnestically evaluated on every follow-up. There were no life-threatening side-effects. Dosage and delivery pattern were essential for effectiveness. This study provides evidence that chemoprevention with sulindac is effective and safe and can, either alone or in combination with other drugs, become a long-term management option in cases of adenomatous polyposis. These results justify further long-term prospective chemoprevention studies to elaborate treatment protocols and guidelines.
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Affiliation(s)
- Teresa M Neuhann
- MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3 - 5, 80335, Munich, Germany.
| | - Katharina Haub
- MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3 - 5, 80335, Munich, Germany
| | - Verena Steinke-Lange
- MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3 - 5, 80335, Munich, Germany
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Kinikum Der Universität München, Munich, Germany
| | - Monika Morak
- MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3 - 5, 80335, Munich, Germany
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Kinikum Der Universität München, Munich, Germany
| | - Andreas Laner
- MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3 - 5, 80335, Munich, Germany
| | - Melanie Locher
- MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3 - 5, 80335, Munich, Germany
| | - Elke Holinski-Feder
- MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3 - 5, 80335, Munich, Germany
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Kinikum Der Universität München, Munich, Germany
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24
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Kiran RP, Kochhar GS, Kariv R, Rex DK, Sugita A, Rubin DT, Navaneethan U, Hull TL, Ko HM, Liu X, Kachnic LA, Strong S, Iacucci M, Bemelman W, Fleshner P, Safyan RA, Kotze PG, D'Hoore A, Faiz O, Lo S, Ashburn JH, Spinelli A, Bernstein CN, Kane SV, Cross RK, Schairer J, McCormick JT, Farraye FA, Chang S, Scherl EJ, Schwartz DA, Bruining DH, Philpott J, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sandborn WJ, Silverberg MS, Pardi DS, Church JM, Shen B. Management of pouch neoplasia: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol 2022; 7:871-893. [PMID: 35798022 DOI: 10.1016/s2468-1253(22)00039-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/18/2022] [Accepted: 01/27/2022] [Indexed: 02/07/2023]
Abstract
Surveillance pouchoscopy is recommended for patients with restorative proctocolectomy with ileal pouch-anal anastomosis in ulcerative colitis or familial adenomatous polyposis, with the surveillance interval depending on the risk of neoplasia. Neoplasia in patients with ileal pouches mainly have a glandular source and less often are of squamous cell origin. Various grades of neoplasia can occur in the prepouch ileum, pouch body, rectal cuff, anal transition zone, anus, or perianal skin. The main treatment modalities are endoscopic polypectomy, endoscopic ablation, endoscopic mucosal resection, endoscopic submucosal dissection, surgical local excision, surgical circumferential resection and re-anastomosis, and pouch excision. The choice of the treatment modality is determined by the grade, location, size, and features of neoplastic lesions, along with patients' risk of neoplasia and comorbidities, and local endoscopic and surgical expertise.
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Affiliation(s)
- Ravi P Kiran
- Division of Colorectal Surgery, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, NY, USA
| | - Gursimran S Kochhar
- Division of Gastroenterology, Hepatology, and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA
| | - Revital Kariv
- Department of Gastroenterology, Tel Aviv Sourasky Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Douglas K Rex
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - Akira Sugita
- Department of Clinical Research and Department of inflammatory Bowel Disease, Yokohama Municipal Citizens Hospital Yokohama, Japan
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA
| | - Udayakumar Navaneethan
- IBD Center and IBD Interventional Unit, Center for Interventional Endoscopy, Orlando Health, Orlando, FL, USA
| | - Tracy L Hull
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Huaibin Mabel Ko
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, NY, USA
| | - Xiuli Liu
- Department of Pathology and Immunology, Washington University, St Louis, MO, USA
| | - Lisa A Kachnic
- Department of Radiation Oncology, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, NY, USA
| | - Scott Strong
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Marietta Iacucci
- Institute of Immunology and Immunotherapy, NIHR Birmingham Biomedical Research Centre, University Hospitals NHS Foundation Trust, University of Birmingham, UK
| | - Willem Bemelman
- Department of Surgery, Academic Medical Center, Amsterdam, Netherlands
| | - Philip Fleshner
- Division of Colorectal Surgery, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Rachael A Safyan
- Division of Hematology and Oncology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Paulo G Kotze
- IBD Outpatients Clinic, Catholic University of Paraná, Curitiba, Brazil
| | - André D'Hoore
- Department of Abdominal Surgery, University Hospital Leuven, Belgium
| | - Omar Faiz
- Department of Surgery, St Mark's Hospital and Academic Institute, Harrow and Department of Surgery and Cancer, Imperial College London, London, UK
| | - Simon Lo
- Pancreatic and Biliary Disease Program, Digestive Diseases, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Jean H Ashburn
- Department of Surgery, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University and IRCCS Humanitas Research Hospital, Division Colon and Rectal Surgery, Rozzano, Milan, Italy
| | - Charles N Bernstein
- University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
| | - Sunanda V Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Raymond K Cross
- Inflammatory Bowel Disease Program, University of Maryland School of Medicine, MD, USA
| | - Jason Schairer
- Department of Gastroenterology, Henry Ford Health System, Detroit, MI, USA
| | - James T McCormick
- Division of Colon and Rectal Surgery, Allegheny Health Network, Pittsburgh, PA, USA
| | - Francis A Farraye
- Division of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL, USA
| | - Shannon Chang
- Inflammatory Bowel Disease Center, NYU Langone Health, NYU Grossman School of Medicine, New York, NY, USA
| | - Ellen J Scherl
- Jill Roberts Center for IBD, Gastroenterology and Hepatology, Weill Cornell Medicine and NewYork Presbyterian Hospital, New York, NY, USA
| | - David A Schwartz
- Department of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jessica Philpott
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
| | - Stuart Bentley-Hibbert
- Department of Radiology, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, NY, USA
| | - Dino Tarabar
- IBD Clinical Center, University Hospital Center Dr Dragiša Mišović, Belgrade, Serbia
| | - Sandra El-Hachem
- Division of Gastroenterology, Hepatology, and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA
| | - William J Sandborn
- Department of Medicine, University of California San Diego, San Diego, CA, USA
| | - Mark S Silverberg
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, Toronto, ON, Canada
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - James M Church
- Division of Colorectal Surgery, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, NY, USA
| | - Bo Shen
- Center for Interventional Inflammatory Bowel Disease, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, NY, USA.
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25
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Heer E, Ruan Y, Mah B, Nguyen T, Lyons H, Poirier A, Boyne DJ, O'Sullivan DE, Heitman SJ, Hilsden RJ, Forbes N, Brenner DR. The efficacy of chemopreventive agents on the incidence of colorectal adenomas: A systematic review and network meta-analysis. Prev Med 2022; 162:107169. [PMID: 35878711 DOI: 10.1016/j.ypmed.2022.107169] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 06/20/2022] [Accepted: 07/17/2022] [Indexed: 10/17/2022]
Abstract
Colorectal cancer (CRC) is the fourth most common cancer and third leading cause of cancer-related death worldwide. Use of chemopreventive agents (CPAs) to reduce the incidence of precursor colorectal adenomas could lower the future burden of CRC. Many classes of potential CPAs have been investigated. To identify the most effective CPAs, we conducted a systematic review and a network meta-analysis (NMA). An electronic search was performed through August 2020 to identify all randomized controlled trials (RCTs) assessing the efficacy of CPAs in reducing the incidence of colorectal adenomas at the time of surveillance colonoscopy among patients who had previously undergone polypectomy during an index colonoscopy. In total, 33 RCTs were included in the NMA, which was conducted under a Bayesian inference framework. Random effects models were used with adjustment for follow-up length and control group event rates to yield relative risks (RRs) and 95% credible intervals (CrIs). Our full network consisted of 13 interventions in addition to a placebo arm. Of 20,925 included patients, 7766 had an adenoma. Compared to placebo, the combination of difluoromethylornithine (DFMO) + Sulindac (RR 0.24, CrI 0.10-0.55) demonstrated a protective effect, while aspirin had a RR of 0.77 (CrI 0.60-1.00), celecoxib 800 mg had a RR of 0.56 (CrI 0.31-1.01) and metformin had a RR of 0.56 (CrI 0.22-1.39). Our results suggest that select CPAs may be efficacious in preventing the development of adenomas. Further studies are needed to identify those patients most likely to benefit and the minimum effective dosages of CPAs.
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Affiliation(s)
- Emily Heer
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Yibing Ruan
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada
| | - Brittany Mah
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Teresa Nguyen
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Hannah Lyons
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada
| | - Abbey Poirier
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada
| | - Devon J Boyne
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Dylan E O'Sullivan
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Steven J Heitman
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Robert J Hilsden
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Nauzer Forbes
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Darren R Brenner
- Forzani & MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, AB, Canada; Department of Cancer Epidemiology and Prevention Research, Cancer Control Alberta, Alberta Health Services, Calgary, AB, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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26
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Fu Y, Xie D, Zhu Y, Zhang X, Yue H, Zhu K, Pi Z, Dai Y. Anti-colorectal cancer effects of seaweed-derived bioactive compounds. Front Med (Lausanne) 2022; 9:988507. [PMID: 36059851 PMCID: PMC9437318 DOI: 10.3389/fmed.2022.988507] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/01/2022] [Indexed: 12/12/2022] Open
Abstract
Seaweeds are classified as Chlorophyta, Rhodophyta, and Phaeophyta. They constitute a number of the most significant repositories of new therapeutic compounds for human use. Seaweed has been proven to possess diverse bioactive properties, which include anticancer properties. The present review focuses on colorectal cancer, which is a primary cause of cancer-related mortality in humans. In addition, it discusses various compounds derived from a series of seaweeds that have been shown to eradicate or slow the progression of cancer. Therapeutic compounds extracted from seaweed have shown activity against colorectal cancer. Furthermore, the mechanisms through which these compounds can induce apoptosis in vitro and in vivo were reviewed. This review emphasizes the potential utility of seaweeds as anticancer agents through the consideration of the capability of compounds present in seaweeds to fight against colorectal cancer.
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Affiliation(s)
- Yunhua Fu
- Changchun University of Chinese Medicine, Changchun, China
| | - Dong Xie
- Changchun University of Chinese Medicine, Changchun, China
| | - Yinghao Zhu
- Changchun University of Chinese Medicine, Changchun, China
| | - Xinyue Zhang
- Jilin Academy of Agricultural Machinery, Changchun, China
| | - Hao Yue
- Changchun University of Chinese Medicine, Changchun, China
| | - Kai Zhu
- Changchun University of Chinese Medicine, Changchun, China
| | - Zifeng Pi
- Changchun University of Chinese Medicine, Changchun, China
- Zifeng Pi
| | - Yulin Dai
- Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Yulin Dai
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27
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Aldoori J, Cockbain AJ, Toogood GJ, Hull MA. Omega-3 polyunsaturated fatty acids: moving towards precision use for prevention and treatment of colorectal cancer. Gut 2022; 71:822-837. [PMID: 35115314 DOI: 10.1136/gutjnl-2021-326362] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022]
Abstract
Data from experimental studies have demonstrated that marine omega-3 polyunsaturated fatty acids (O3FAs) have anti-inflammatory and anticancer properties. In the last decade, large-scale randomised controlled trials of pharmacological delivery of O3FAs and prospective cohort studies of dietary O3FA intake have continued to investigate the relationship between O3FA intake and colorectal cancer (CRC) risk and mortality. Clinical data suggest that O3FAs have differential anti-CRC activity depending on several host factors (including pretreatment blood O3FA level, ethnicity and systemic inflammatory response) and tumour characteristics (including location in the colorectum, histological phenotype (eg, conventional adenoma or serrated polyp) and molecular features (eg, microsatellite instability, cyclooxygenase expression)). Recent data also highlight the need for further investigation of the effect of O3FAs on the gut microbiota as a possible anti-CRC mechanism, when used either alone or in combination with other anti-CRC therapies. Overall, these data point towards a precision approach to using O3FAs for optimal prevention and treatment of CRC based on mechanistic understanding of host, tumour and gut microbiota factors that predict anticancer activity of O3FAs.
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Affiliation(s)
- Joanna Aldoori
- Gastrointestinal & Surgical Sciences, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.,Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Andrew J Cockbain
- Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Giles J Toogood
- Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Mark A Hull
- Gastrointestinal & Surgical Sciences, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
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28
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Kurano M, Sakai E, Yatomi Y. Understanding modulations of lipid mediators in cancer using a murine model of carcinomatous peritonitis. Cancer Med 2022; 11:3491-3507. [PMID: 35315587 PMCID: PMC9487885 DOI: 10.1002/cam4.4699] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/12/2022] [Accepted: 03/14/2022] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies have investigated the possible involvement of eicosanoids, lysophospholipids, and sphingolipids in cancer. We considered that comprehensive measurement of these lipid mediators might provide a better understanding of their involvement in the pathogenesis of cancer. In the present study, we attempted to elucidate the modulations of sphingolipids, lysophospholipids, diacyl‐phospholipids, eicosanoids, and related mediators in cancer by measuring their levels simultaneously by a liquid chromatography‐mass spectrometry method in a mouse model of carcinomatous peritonitis. Methods We investigated the modulations of these lipids in both ascitic fluid and plasma specimens obtained from Balb/c mice injected intraperitoneally with Colon‐26 cells, as well as the modulations of the lipid contents in the cancer cells obtained from the tumor xenografts. Results The results were as follows: the levels of sphingosine 1‐phosphate were increased, while those of lysophosphatidic acid (LysoPA), especially unsaturated long‐chain LysoPA, tended to be increased, in the ascitic fluid. Our findings suggested that ceramides, sphingomyelin, and phosphatidylcholine, their precursors, were supplied by both de novo synthesis and from elsewhere in the body. The levels of lysophosphatidylserine (LysoPS), lysophosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidylethanolamine were also increased in the ascitic fluid, while those of phosphatidylserine (PS), a precursor of LysoPS, were markedly decreased. The levels of arachidonic acid derivatives, especially PGE2‐related metabolites, were increased, while the plasma levels of eicosanoids and related mediators were decreased. Comprehensive statistical analyses mainly identified PS in the ascitic fluid and eicosanoids in the plasma as having highly negative predictive values for cancer. Conclusions The results proposed many unknown associations of lipid mediators with cancer, underscoring the need for further studies. In particular, the PS/LysoPS pathway could be a novel therapeutic target, and plasma eicosanoids could be useful biomarkers for cancer.
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Affiliation(s)
- Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.,Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Eri Sakai
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.,Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
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29
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Aelvoet AS, Buttitta F, Ricciardiello L, Dekker E. Management of familial adenomatous polyposis and MUTYH-associated polyposis; new insights. Best Pract Res Clin Gastroenterol 2022; 58-59:101793. [PMID: 35988966 DOI: 10.1016/j.bpg.2022.101793] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/21/2021] [Accepted: 03/08/2022] [Indexed: 02/07/2023]
Abstract
Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are rare inherited polyposis syndromes with a high colorectal cancer (CRC) risk. Therefore, frequent endoscopic surveillance including polypectomy of relevant premalignant lesions from a young age is warranted in patients. In FAP and less often in MAP, prophylactic colectomy is indicated followed by lifelong endoscopic surveillance of the retained rectum after (sub)total colectomy and ileal pouch after proctocolectomy to prevent CRC. No consensus is reached on the right type and timing of colectomy. As patients with FAP and MAP nowadays have an almost normal life-expectancy due to adequate treatment of colorectal polyposis, challenges in the management of FAP and MAP have shifted towards the treatment of duodenal and gastric adenomas as well as desmoid treatment in FAP. Whereas up until recently upper gastrointestinal surveillance was mostly diagnostic and patients were referred for surgery once duodenal or gastric polyposis was advanced, nowadays endoscopic treatment of premalignant lesions is widely performed. Aiming to reduce polyp burden in the colorectum as well as in the upper gastrointestinal tract, several chemopreventive agents are currently being studied.
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Affiliation(s)
- Arthur S Aelvoet
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands.
| | - Francesco Buttitta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands.
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30
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Aoyama T, Yoshikawa T, Ida S, Cho H, Sakamaki K, Ito Y, Fujitani K, Takiguchi N, Kawashima Y, Nishikawa K, Nunobe S, Hiki N. Effects of perioperative eicosapentaenoic acid‑enriched oral nutritional supplement on the long‑term oncological outcomes after total gastrectomy for gastric cancer. Oncol Lett 2022; 23:151. [PMID: 35836480 PMCID: PMC9258592 DOI: 10.3892/ol.2022.13272] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 02/15/2022] [Indexed: 12/24/2022] Open
Abstract
Basic and clinical reports have suggested that eicosapentaenoic acid (EPA) exhibits anti-tumor activity. The present study evaluated whether perioperative EPA could improve the survival of patients with localized gastric cancer as a key secondary endpoint of a randomized clinical study. The present study was designed as multicenter, open-label, superiority, randomized trial to confirm the preventive effect of EPA on body weight loss after total gastrectomy for gastric cancer. Eligible patients were randomized to either the standard-diet group (EPA-off group) or EPA-on group by a centralized dynamic method. An EPA-enriched supplement (ProSure®) was given to the EPA-on group in addition to their standard diet. This supplement included 600 kcal with 2.2 g/day of EPA. Among the 126 patients who were randomized, 123 patients (EPA-off group, n=60; EPA-on group, n=63) were examined in the survival analyses. All background factors were well balanced between the two groups. The 3-year and 5-year overall survival rates were 74.6 and 67.8%, respectively, in the EPA-off group, and 77.8 and 76.2% in the EPA-on group. There was no significant difference between the EPA-off and EPA-on groups (hazard ratio, 0.77; P=0.424). In the subgroup analysis, the hazard ratio was 0.39 in patients who received neoadjuvant chemotherapy and 0.57 in patients with nodal metastasis. In conclusion, a clear survival benefit of perioperative EPA was not observed in localized gastric cancer. The value of EPA should be further tested in a future study in patients with unfavorable advanced gastric cancer. Clinical trial number: UMIN000006380; date of registration, September 21, 2011.
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Affiliation(s)
- Toru Aoyama
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241‑8515, Japan
| | - Takaki Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241‑8515, Japan
| | - Satoshi Ida
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135‑0063, Japan
| | - Haruhiko Cho
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241‑8515, Japan
| | - Kentaro Sakamaki
- Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama, Kanagawa 232‑0024, Japan
| | - Yuichi Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Aichi 464‑8681, Japan
| | - Kazumasa Fujitani
- Department of Surgery, Osaka General Medical Center, Osaka 558‑8558, Japan
| | - Nobuhiro Takiguchi
- Division of Gastroenterological Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260‑8781, Japan
| | - Yoshiyuki Kawashima
- Department of Gastroenterological Surgery, Saitama Cancer Center, Kitaadachi, Saitama 362‑0806, Japan
| | | | - Soya Nunobe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135‑0063, Japan
| | - Naoki Hiki
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135‑0063, Japan
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31
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Macaron C, Mankaney GN, Haider M, Mouchli M, Hurley K, Burke CA. Chemoprevention Considerations in Patients with Hereditary Colorectal Cancer Syndromes. Gastrointest Endosc Clin N Am 2022; 32:131-146. [PMID: 34798982 DOI: 10.1016/j.giec.2021.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Secondary prevention of colorectal neoplasia with chemoprevention is long-studied area of research and clinical use in patients with the 2 most common hereditary colorectal cancer syndromes including Lynch syndrome and familial adenomatous polyposis. No medication is currently approved for use for the prevention of colorectal polyps or cancer in either the general population or individuals with the hereditary colorectal cancer syndromes. Emerging data in animal models and limited data in humans suggest vaccines may be the next breakthrough for neoplasia prevention in patients with hereditary colorectal cancer. Clinicians must acknowledge chemoprevention is an adjunct and does not supplant endoscopic surveillance.
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Affiliation(s)
- Carole Macaron
- Department of Gastroenterology, Hepatology and Nutrition, Desk A 30, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Gautam N Mankaney
- Department of Gastroenterology and Hepatology, Virginia Mason Franciscan Health, 1100 9th Avenue, Seattle, WA 98101, USA
| | - Mahnur Haider
- John W. Deming Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, #8016, New Orleans, LA 70112, USA
| | - Mohamad Mouchli
- Department of Gastroenterology, Hepatology and Nutrition, Desk A 30, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Karen Hurley
- Center for Behavioral Health, Desk P57, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Carol A Burke
- Department of Gastroenterology, Hepatology and Nutrition, Desk A 30, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Colorectal Surgery, Sanford R. Weiss MD Center for Hereditary Gastrointestinal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH, USA.
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Nana G, Mitra S, Watson H, Young C, Wood HM, Perry SL, Race AD, Quirke P, Toogood GJ, Loadman PM, Hull MA. Luminal Bioavailability of Orally Administered ω-3 PUFAs in the Distal Small Intestine, and Associated Changes to the Ileal Microbiome, in Humans with a Temporary Ileostomy. J Nutr 2021; 151:2142-2152. [PMID: 34036331 PMCID: PMC8349127 DOI: 10.1093/jn/nxab113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/22/2021] [Accepted: 03/29/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Oral administration of purified omega-3 (ω-3) PUFAs is associated with changes to the fecal microbiome. However, it is not known whether this effect is associated with increased PUFA concentrations in the gut. OBJECTIVES We investigated the luminal bioavailability of oral ω-3 PUFAs (daily dose 1 g EPA and 1g DHA free fatty acid equivalents as triglycerides in soft-gel capsules, twice daily) and changes to the gut microbiome, in the ileum. METHODS Ileostomy fluid (IF) and blood were obtained at baseline, after first capsule dosing (median 2 h), and at a similar time after final dosing on day 28, in 11 individuals (median age 63 y) with a temporary ileostomy. Fatty acids were measured by LC-tandem MS. The ileal microbiome was characterized by 16S rRNA PCR and Illumina sequencing. RESULTS There was a mean 6.0 ± 9.8-fold and 6.6 ± 9.6-fold increase in ileal EPA and DHA concentrations (primary outcome), respectively, at 28 d, which was associated with increased RBC ω-3 PUFA content (P ≤ 0.05). The first oral dose did not increase the ileal ω-3 PUFA concentration except in 4 individuals, who displayed high luminal EPA and DHA concentrations, which reduced to concentrations similar to the overall study population at day 28, suggesting physiological adaptation. Bacteroides, Clostridium, and Streptococcus were abundant bacterial genera in the ileum. Ileal microbiome variability over time and between individuals was large, with no consistent change associated with acute ω-3 PUFA dosing. However, high concentrations of EPA and DHA in IF on day 28 were associated with higher abundance of Bacteroides (r2 > 0.86, P < 0.05) and reduced abundance of other genera, including Actinomyces (r2 > 0.94, P < 0.05). CONCLUSIONS Oral administration of ω-3 PUFAs leads to increased luminal ω-3 PUFA concentrations and changes to the microbiome, in the ileum of individuals with a temporary ileostomy. This study is registered on the ISRCTN registry as ISRCTN14530452.
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Affiliation(s)
- Gael Nana
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
- Department of Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Suparna Mitra
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Henry Watson
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
- Department of Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Caroline Young
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Henry M Wood
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Sarah L Perry
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Amanda D Race
- Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom
| | - Philip Quirke
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
| | - Giles J Toogood
- Department of Hepatobiliary Surgery, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Paul M Loadman
- Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom
| | - Mark A Hull
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, United Kingdom
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Murff HJ, Shrubsole MJ, Cai Q, Su T, Dooley JH, Cai SS, Zheng W, Dai Q. N-3 Long Chain Fatty Acids Supplementation, Fatty Acids Desaturase Activity, and Colorectal Cancer Risk: A Randomized Controlled Trial. Nutr Cancer 2021; 74:1388-1398. [PMID: 34291724 PMCID: PMC8782932 DOI: 10.1080/01635581.2021.1955286] [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] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 01/03/2023]
Abstract
INTRODUCTION n-3 long-chain polyunsaturated fatty acids (LCPUFA) have anti-inflammatory effects and may reduce colorectal cancer risk. The purpose of this study was to evaluate the effects of n-3 LCPUFA supplementation on markers of rectal cell proliferation and apoptosis and examine how genetic variation in desaturase enzymes might modify this effect. METHODS We conducted a randomized, double-blind, control six-month trial of 2.5 grams of n-3 LCPUFA per day compared to olive oil. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1). Our primary outcome was change in markers of rectal epithelial proliferation and apoptosis. RESULTS A total of 141 subjects were randomized. We found no difference in apoptosis markers between participants randomized to n-3 LCPUFA compared to olive oil (P = 0.41). N-3 LCPUFA supplementation increased cell proliferation in the lower colonic crypt compared to olive oil (P = 0.03) however baseline indexes of proliferation were different between the groups at randomization. We found no evidence that genotype modified the effect. CONCLUSIONS Our study did not show evidence of a proliferative or pro-apoptotic effect on n-3 LCPUFA supplementation on rectal mucosa regardless of the FADS genotype.ClinicalTrials.gov Identifier: NCT01661764Supplemental data for this article is available online at https://dx.doi.org/10.1080/01635581.2021.1955286.
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Affiliation(s)
- Harvey J. Murff
- Division of General Internal Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center
| | - Martha J. Shrubsole
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN
- Division of Epidemiology, Vanderbilt University Medical Center
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center
| | - Qiuyin Cai
- Division of Epidemiology, Vanderbilt University Medical Center
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center
| | - Timothy Su
- Division of Epidemiology, Vanderbilt University Medical Center
| | | | - Sunny S. Cai
- Tulane University School of Medicine, New Orleans, LA
| | - Wei Zheng
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN
- Division of Epidemiology, Vanderbilt University Medical Center
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center
| | - Qi Dai
- Division of Epidemiology, Vanderbilt University Medical Center
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center
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Aspirin and omega-3 polyunsaturated fatty acid use and their interaction in cardiovascular diseases and colorectal adenomas. Nutr Res Rev 2021; 35:295-307. [PMID: 34253265 DOI: 10.1017/s0954422421000238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Aspirin (acetylsalicylic acid, ASA) is inexpensive and is established in preventing cardiovascular disease (CVD) and colorectal adenomas. Omega-3 (n3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have also shown benefit in preventing CVD. The combination could be an effective preventative measure in patients with such diseases. ASA and n3 PUFA reduced the risk of CVD in ASA-resistant or diabetic patients. EPA- and DHA-deficient patients also benefited the most from n3 PUFA supplementation. Synergistic effects between ASA and EPA and DHA are 'V-shaped' such that optimal ASA efficacy is dependent on EPA and DHA concentrations in blood. In colorectal adenomas, ASA (300 mg/d) and EPA reduced adenoma burden in a location- and subtype-specific manner. Low doses of ASA (75-100 mg/d) were used in CVD prevention; however, ultra-low doses (30 mg/d) can also reduce thrombosis. EPA-to-DHA ratio is also important with regard to efficacy. DHA is more effective in reducing blood pressure and modulating systemic inflammation; however, high-dose EPA can lower CVD events in high-risk individuals. Although current literature has yet to examine ASA and DHA in preventing CVD, such combination warrants further investigation. To increase adherence to ASA and n3 PUFA supplementation, combination dosage form may be required to improve outcomes.
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Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer. Int J Clin Oncol 2021; 26:1353-1419. [PMID: 34185173 PMCID: PMC8286959 DOI: 10.1007/s10147-021-01881-4] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/10/2021] [Indexed: 12/14/2022]
Abstract
Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.
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Noe O, Filipiak L, Royfman R, Campbell A, Lin L, Hamouda D, Stanbery L, Nemunaitis J. Adenomatous polyposis coli in cancer and therapeutic implications. Oncol Rev 2021; 15:534. [PMID: 34267890 PMCID: PMC8256374 DOI: 10.4081/oncol.2021.534] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APCmutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1. In the event of an APC mutation, b-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.
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Affiliation(s)
- Olivia Noe
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Louis Filipiak
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Rachel Royfman
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Austin Campbell
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Leslie Lin
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Danae Hamouda
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Laura Stanbery
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
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Biondi A, Basile F, Vacante M. Familial adenomatous polyposis and changes in the gut microbiota: New insights into colorectal cancer carcinogenesis. World J Gastrointest Oncol 2021; 13:495-508. [PMID: 34163569 PMCID: PMC8204352 DOI: 10.4251/wjgo.v13.i6.495] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/15/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with familial adenomatous polyposis (FAP), an autosomal dominant hereditary colorectal cancer syndrome, have a lifetime risk of developing cancer of nearly 100%. Recent studies have pointed out that the gut microbiota could play a crucial role in the development of colorectal adenomas and the consequent progression to colorectal cancer. Some gut bacteria, such as Fusobacterium nucleatum, Escherichia coli, Clostridium difficile, Peptostreptococcus, and enterotoxigenic Bacteroides fragilis, could be implicated in colorectal carcinogenesis through different mechanisms, including the maintenance of a chronic inflammatory state, production of bioactive tumorigenic metabolites, and DNA damage. Studies using the adenomatous polyposis coliMin/+ mouse model, which resembles FAP in most respects, have shown that specific changes in the intestinal microbial community could influence a multistep progression, the intestinal "adenoma-carcinoma sequence", which involves mucosal barrier injury, low-grade inflammation, activation of the Wnt pathway. Therefore, modulation of gut microbiota might represent a novel therapeutic target for patients with FAP. Administration of probiotics, prebiotics, antibiotics, and nonsteroidal anti-inflammatory drugs could potentially prevent the progression of the adenoma-carcinoma sequence in FAP. The aim of this review was to summarize the best available knowledge on the role of gut microbiota in colorectal carcinogenesis in patients with FAP.
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Affiliation(s)
- Antonio Biondi
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
- Multidisciplinary Research Center for Rare Diseases, University of Catania, Catania 95123, Italy
| | - Francesco Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
- Multidisciplinary Research Center for Rare Diseases, University of Catania, Catania 95123, Italy
| | - Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
- Multidisciplinary Research Center for Rare Diseases, University of Catania, Catania 95123, Italy
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Hall MJ. Updates in chemoprevention research for hereditary gastrointestinal and polyposis syndromes. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2021; 19:30-46. [PMID: 34211259 PMCID: PMC8240460 DOI: 10.1007/s11938-020-00306-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/09/2020] [Indexed: 11/24/2022]
Abstract
PURPOSE OF REVIEW To critically examine recently published research in the area of chemoprevention in hereditary polyposis and gastrointestinal cancers, and to briefly review several ongoing chemoprevention trials testing novel agents in this population. RECENT FINDINGS Four recent chemoprevention trials in patients with familial adenomatous polyposis (FAP) were identified and reviewed. In the FAPEST trial, the combination of erlotinib+sulindac (compared to placebo) met its primary outcome of decreased duodenal polyp burden. A secondary analysis of lower gastrointestinal tract outcomes also demonstrated significant benefits. Two randomized trials in FAP patients examining combination regimens (celecoxib+DFMO and sulindac+DFMO) failed to meet their primary endpoints. Benefits of further research into these combinations was suggested by efficacy signals seen in secondary and post-hoc analyses. Finally, a randomized trial found curcumin (vs placebo) to have no benefit in reducing colorectal polyp count or size in patients with FAP. SUMMARY Progress in developing new and more effective preventive options for patients with hereditary gastrointestinal syndromes continues to be made through the efforts of investigators conducting chemoprevention research.
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Zhou E, Rifkin S. Colorectal Cancer and Diet: Risk Versus Prevention, Is Diet an Intervention? Gastroenterol Clin North Am 2021; 50:101-111. [PMID: 33518157 DOI: 10.1016/j.gtc.2020.10.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer is the third most common cause of cancer in men and women in the world. Epidemiologic research approximates that half of colon cancer risk is preventable by modifiable risk factors, including diet. This article reviews prior studies involving certain food items and their relation to colorectal cancer, to elucidate whether diet can be a potential intervention.
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Affiliation(s)
- Elinor Zhou
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 431, Baltimore, MD, USA.
| | - Samara Rifkin
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, 1150 West Medical Center Drive, 6520 MSRB1, Ann Arbor, MI, USA
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Park JJ, Kim BC, Hong SP, Seo Y, Lee HS, Park YS, Na SY, Park SC, Park J, Kim JH, Moon CM, Huh KC, Park SJ, Cheon JH, Kim WH, Kim TI. The Effect of Metformin in Treatment of Adenomas in Patients with Familial Adenomatous Polyposis. Cancer Prev Res (Phila) 2021; 14:563-572. [PMID: 33509804 DOI: 10.1158/1940-6207.capr-20-0580] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/04/2021] [Accepted: 01/20/2021] [Indexed: 11/16/2022]
Abstract
Familial adenomatous polyposis (FAP) is a hereditary disease characterized by the development of numerous colorectal adenomas in young adults. Metformin, an oral diabetic drug, has been shown to have antineoplastic effects and a favorable safety profile. We performed a randomized, double-blind, controlled trial to evaluate the efficacy of metformin on the regression of colorectal and duodenal adenoma in patients with FAP. Thirty-four FAP patients were randomly assigned in a 1:2:2 ratio to receive placebo, 500 mg metformin, or 1,500 mg metformin per day orally for 7 months. The number and size of polyps and the global polyp burden were evaluated before and after the intervention. This study was terminated early based on the results of the interim analysis. No significant differences were determined in the percentage change of colorectal and duodenal polyp number over the course of treatment among the three treatment arms (P = 0.627 and P = 1.000, respectively). We found no significant differences in the percentage change of colorectal or duodenal polyp size among the three groups (P = 0.214 and P = 0.803, respectively). The overall polyp burdens of the colorectum and duodenum were not significantly changed by metformin treatment at either dosage. Colon polyps removed from the metformin-treated patients showed significantly lower mTOR signal (p-S6) expression than those from patients in the placebo arm. In conclusion, 7 months of treatment with 500 mg or 1,500 mg metformin did not reduce the mean number or size of polyps in the colorectum or duodenum in FAP patients (ClinicalTrials.gov ID: NCT01725490). PREVENTION RELEVANCE: A 7-month metformin treatment (500 mg or 1,500 mg) did not reduce the number or size of polyps in the colorectum or duodenum of FAP patients as compared to placebo. These results do not support the use of metformin to promote regression of intestinal adenomas in FAP patients.
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Affiliation(s)
- Jae Jun Park
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Cancer Prevention Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byung Chang Kim
- Center for Colorectal Cancer, Center for Cancer Prevention & Detection, Division of Cancer Epidemiology and Management, Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi-do, Korea
| | - Sung Pil Hong
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yoojeong Seo
- Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Sun Lee
- Biostatics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea
| | - Young Sook Park
- Department of Internal Medicine, Nowon Eulji University Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Soo-Young Na
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Sung Chul Park
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Jongha Park
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Jae Hak Kim
- Division of Gastroenterology, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea
| | - Chang Mo Moon
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Kyu Chan Huh
- Department of Internal Medicine, Konyang University College of Medicine, Konyang University Hospital, Daejeon, Korea
| | - Soo Jung Park
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Won Ho Kim
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Il Kim
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. .,Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Cancer Prevention Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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Kemp Bohan PM, Mankaney G, Vreeland TJ, Chick RC, Hale DF, Cindass JL, Hickerson AT, Ensley DC, Sohn V, Clifton GT, Peoples GE, Burke CA. Chemoprevention in familial adenomatous polyposis: past, present and future. Fam Cancer 2021; 20:23-33. [PMID: 32507936 PMCID: PMC7276278 DOI: 10.1007/s10689-020-00189-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/18/2020] [Indexed: 01/05/2023]
Abstract
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.
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Affiliation(s)
- Phillip M Kemp Bohan
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA.
| | - Gautam Mankaney
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
| | - Timothy J Vreeland
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Robert C Chick
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Diane F Hale
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Jessica L Cindass
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Annelies T Hickerson
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Daniel C Ensley
- Department of Urology, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Vance Sohn
- Department of Surgery, Madigan Army Medical Center, Joint Base Lewis-McChord, Tacoma, WA, USA
| | - G Travis Clifton
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | | | - Carol A Burke
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
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Tu M, Wang W, Zhang G, Hammock BD. ω-3 Polyunsaturated Fatty Acids on Colonic Inflammation and Colon Cancer: Roles of Lipid-Metabolizing Enzymes Involved. Nutrients 2020; 12:nu12113301. [PMID: 33126566 PMCID: PMC7693568 DOI: 10.3390/nu12113301] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/22/2020] [Accepted: 10/24/2020] [Indexed: 02/06/2023] Open
Abstract
Substantial human and animal studies support the beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) on colonic inflammation and colorectal cancer (CRC). However, there are inconsistent results, which have shown that ω-3 PUFAs have no effect or even detrimental effects, making it difficult to effectively implement ω-3 PUFAs for disease prevention. A better understanding of the molecular mechanisms for the anti-inflammatory and anticancer effects of ω-3 PUFAs will help to clarify their potential health-promoting effects, provide a scientific base for cautions for their use, and establish dietary recommendations. In this review, we summarize recent studies of ω-3 PUFAs on colonic inflammation and CRC and discuss the potential roles of ω-3 PUFA-metabolizing enzymes, notably the cytochrome P450 monooxygenases, in mediating the actions of ω-3 PUFAs.
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Affiliation(s)
- Maolin Tu
- Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA; (M.T.); (G.Z.)
- Department of Food Science and Technology, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
| | - Weicang Wang
- Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA;
| | - Guodong Zhang
- Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA; (M.T.); (G.Z.)
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA 01002, USA
| | - Bruce D. Hammock
- Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA;
- Correspondence: ; Tel.: +1-530-752-7519
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43
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Volpato M, Ingram N, Perry SL, Spencer J, Race AD, Marshall C, Hutchinson JM, Nicolaou A, Loadman PM, Coletta PL, Hull MA. Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid. Cancer Chemother Pharmacol 2020; 87:173-184. [PMID: 33040178 PMCID: PMC7870614 DOI: 10.1007/s00280-020-04157-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/24/2020] [Indexed: 01/05/2023]
Abstract
Purpose The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA. Methods A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models. Results Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours. Conclusion Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies. Electronic supplementary material The online version of this article (10.1007/s00280-020-04157-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Milene Volpato
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK.
| | - Nicola Ingram
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Sarah L Perry
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Jade Spencer
- Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK
| | - Amanda D Race
- Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK
| | - Catriona Marshall
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - John M Hutchinson
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Anna Nicolaou
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.,Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, M13 9PT, UK
| | - Paul M Loadman
- Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK
| | - P Louise Coletta
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Mark A Hull
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
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Bhatt DL, Hull MA, Song M, Van Hulle C, Carlsson C, Chapman MJ, Toth PP. Beyond cardiovascular medicine: potential future uses of icosapent ethyl. Eur Heart J Suppl 2020; 22:J54-J64. [PMID: 33061868 PMCID: PMC7537800 DOI: 10.1093/eurheartj/suaa119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The REDUCE-IT trial demonstrated that icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), reduced cardiovascular events in an at-risk population by a substantial degree. While the cardiovascular protective properties of this compound are now proven, several other potential uses are being actively explored in clinical studies. These areas of investigation include cancer, inflammatory bowel disease, infections, Alzheimer's disease, dementia, and depression. The next decade promises to deepen our understanding of the beneficial effects that EPA may offer beyond cardiovascular risk reduction.
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Affiliation(s)
- Deepak L Bhatt
- Brigham and Women’s Hospital, Heart & Vascular Center and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Mark A Hull
- Division of Gastrointestinal and Surgical Sciences, Leeds Institute of Medical Research, St James’s University Hospital, University of Leeds, Leeds, LS9 7TF, UK
| | - Mingyang Song
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA
- Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital and Harvard Medical School, 100 Cambridge Street, Boston, MA 02114, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, 50 Fruit Street, Boston, MA 02114, USA
| | - Carol Van Hulle
- University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - Cindy Carlsson
- William S. Middleton Memorial Veterans Hospital, Madison VA Geriatric Research, Education and Clinical Center (GRECC), 2500 Overlook Terrace, Madison, WI 53705, USA
- Division of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Wisconsin Alzheimer’s Disease Research Center (ADRC), 600 Highland Ave, J5/1 Mezzanine, Madison, WI 53792, USA
- Wisconsin Alzheimer’s Institute (WAI), 610 Walnut St Suite 957, Madison, WI 53726, USA
| | - M John Chapman
- Sorbonne University, 21, Rue de l'Ecole de Medicine, 75006 Paris, France
- Endocrinology-Metabolism Division, Pitie-Salpetriere University Hospital, 47-83, Boulevard de lopital, 75651 Paris Cedex, France
| | - Peter P Toth
- CGH Medical Center, 101 East Miller Road, Sterling, IL 61081, USA
- Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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45
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Hao Y, Wang Y, Qi M, He X, Zhu Y, Hong J. Risk Factors for Recurrent Colorectal Polyps. Gut Liver 2020; 14:399-411. [PMID: 31547641 PMCID: PMC7366149 DOI: 10.5009/gnl19097] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/22/2019] [Accepted: 06/05/2019] [Indexed: 12/12/2022] Open
Abstract
The recurrence of colorectal polyps is caused by various factors and leads to the carcinogenesis of colorectal cancer, which ranks third in incidence and fourth in mortality among cancers worldwide. The potential risk factors for colorectal polyp recurrence have been demonstrated in multiple trials. However, an article that pools and summarizes the various results is needed. This review enumerates and analyzes some risk factors in terms of patient characteristics, procedural operations, polyp characteristics, and dietary aspects to propose some effective prophylactic measures. This review aimed to provide a reference for clinical application and guide patients to prevent colorectal polyp recurrence in a more effective manner.
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Affiliation(s)
- Yuanzhen Hao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Joint Programme of Nanchang University and Queen Mary University of London, Nanchang, China
| | - Yining Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Joint Programme of Nanchang University and Queen Mary University of London, Nanchang, China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shangha
| | - Miao Qi
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Joint Programme of Nanchang University and Queen Mary University of London, Nanchang, China
| | - Xin He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ying Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Junbo Hong
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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46
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Establishment of a multicomponent dietary bioactive human equivalent dose to delete damaged Lgr5+ stem cells using a mouse colon tumor initiation model. Eur J Cancer Prev 2020; 28:383-389. [PMID: 30234553 DOI: 10.1097/cej.0000000000000465] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Multicomponent therapy has gained interest for its potential to synergize and subsequently lower the effective dose of each constituent required to reduce colon cancer risk. We have previously showed that rapidly cycling Lgr5 stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk. In the present study, we quantified the dose-dependent synergistic properties of dietary n-3 polyunsaturated fatty acids (PUFA) and curcumin (Cur) to promote targeted apoptotic deletion of damaged colonic Lgr5 stem cells. For this purpose, both heterogeneous bulk colonocytes and Lgr5 stem cells were isolated from Lgr5-EGFP-IRES-CreER knock-in mice injected with azoxymethane (AOM). Isolated cells were analyzed for DNA damage (γH2AX), apoptosis (cleaved caspase-3), and targeted apoptosis (both γH2AX and cleaved caspase-3) at 12 h post-AOM injection. Comparison of the percentage of targeted apoptosis in Lgr5 stem cells (GFP) across a broad bioactive dose-range revealed an ED50 of 16.0 mg/day n-3 PUFA + 15.9 mg/day Cur. This corresponded to a human equivalent dose of 3.0 g n-3 PUFA + 3.0 g Cur. In summary, our results provide evidence that a low dose (n-3 PUFA + Cur) combination diet reduces AOM-induced DNA damage in Lgr5 stem cells and enhances targeted apoptosis of DNA-damaged cells, implying that a lower human equivalent dose can be utilized in future human clinical trials.
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Yurko-Mauro K, Van Elswyk M, Teo L. A Scoping Review of Interactions between Omega-3 Long-Chain Polyunsaturated Fatty Acids and Genetic Variation in Relation to Cancer Risk. Nutrients 2020; 12:E1647. [PMID: 32498320 PMCID: PMC7352171 DOI: 10.3390/nu12061647] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
This scoping review examines the interaction of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and genetic variants of various types of cancers. A comprehensive search was performed to identify controlled and observational studies conducted through August 2017. Eighteen unique studies were included: breast cancer (n = 2), gastric cancer (n = 1), exocrine pancreatic cancer (n = 1), chronic lymphocytic leukemia (n = 1), prostate cancer (n = 7) and colorectal cancer (n = 6). An additional 13 studies that focused on fish intake or at-risk populations were summarized to increase readers' understanding of the topic based on this review, DHA and EPA interact with certain genetic variants to decrease breast, colorectal and prostate cancer risk, although data was limited and identified polymorphisms were heterogeneous. The evidence to date demonstrates that omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) may decrease cancer risk by affecting genetic variants of inflammatory pathways, oxidative stress and tumor apoptosis. Collectively, data supports the notion that once a genetic variant is identified, the benefits of a targeted, personalized therapeutic regimen that includes DHA and/or EPA should be considered.
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Affiliation(s)
| | | | - Lynn Teo
- Teo Research Consulting, Silver Spring, MD, 20910, USA;
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48
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Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut 2020; 69:411-444. [PMID: 31780574 PMCID: PMC7034349 DOI: 10.1136/gutjnl-2019-319915] [Citation(s) in RCA: 276] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/25/2019] [Accepted: 11/05/2019] [Indexed: 12/12/2022]
Abstract
Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.
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Affiliation(s)
- Kevin J Monahan
- Family Cancer Clinic, St Mark's Hospital, London, UK
- Faculty of Medicine, Imperial College, London, UK
| | - Nicola Bradshaw
- Clinical Genetics, West of Scotland Genetics Services, Glasgow, Glasgow, UK
| | - Sunil Dolwani
- Gastroenterology, Cardiff and Vale NHS Trust, Cardiff, UK
| | - Bianca Desouza
- Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - James E East
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Mohammad Ilyas
- Faculty of Medicine & Health Sciences, Nottingham University, Nottingham, UK
| | - Asha Kaur
- Head of Policy and Campaigns, Bowel Cancer UK, London, UK
| | - Fiona Lalloo
- Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
| | | | - Matthew D Rutter
- Gastroenterology, University Hospital of North Tees, Stockton-on-Tees, UK
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - Ian Tomlinson
- Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Birmingham, UK
- Cancer Research Centre, University of Edinburgh, Edinburgh, UK
| | - Huw J W Thomas
- Family Cancer Clinic, St Mark's Hospital, London, UK
- Faculty of Medicine, Imperial College, London, UK
| | - James Hill
- Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
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49
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Abstract
The preventability estimate for colorectal cancer (CRC) is approximately 50%, highlighting the huge potential for altering modifiable lifestyle factors (including diet and body fatness) in order to reduce risk of this common malignancy. There is strong evidence that dietary factors (including intake of wholegrains, fibre, red and processed meat and alcohol) affect CRC risk. The lack of positive intervention trials and limited mechanistic understanding likely explain limited public health impact of epidemiological observations, to date. An alternative strategy for nutritional prevention of CRC is use of supplements that provide higher individual nutrient exposure than obtained through the diet (chemoprevention). There are positive data for calcium and/or vitamin D and the n-3 fatty acid EPA from polyp prevention trials using colorectal adenoma as a CRC risk biomarker. Although CRC is an obesity-related malignancy, there remains a paucity of observational data supporting intentional weight loss for CRC risk reduction. Some types of obesity surgeries (Roux-en-Y gastric bypass) might actually increase subsequent CRC risk due to alteration of local intestinal factors. There is intense interest in nutritional therapy of patients after diagnosis of CRC, in order to impact on recurrence and overall survival (now often termed cancer interception). In conclusion, nutritional prevention of CRC continues to hold much promise. Increased mechanistic understanding of the role of individual nutrients (linked to intestinal microbiota), as well as a precision medicine approach to CRC chemoprevention and interception based on both tumour and host factors, should enable translation of nutritional interventions into effective CRC risk reduction measures.
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50
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Kurokawa Y, Fujii G, Tomono S, Miyamoto S, Hamoya T, Takahashi M, Narita T, Komiya M, Kobayashi M, Higami Y, Mutoh M. The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice. J Clin Med 2020; 9:jcm9010270. [PMID: 31963747 PMCID: PMC7019572 DOI: 10.3390/jcm9010270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 01/14/2020] [Accepted: 01/15/2020] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer is the fourth leading cause of cancer death worldwide, and it is important to establish effective methods for preventing colorectal cancer. One effective prevention strategy could be the use of antioxidants. However, the role of the direct antioxidative function of antioxidants against carcinogenesis has not been clarified. Thus, we aimed to determine whether the direct removal of reactive oxygen species by a hydroxyl radical scavenger, NZ-419, could inhibit colorectal carcinogenesis. NZ-419 is a creatinine metabolite that has been shown to be safe and to inhibit the progression of chronic kidney disease in rats, and it is now under clinical development. In the present study, we demonstrated that NZ-419 eliminated reactive oxygen species production in HCT116 cells after H2O2 stimulation and suppressed H2O2-induced Nrf2 promoter transcriptional activity. The administration of 500 ppm NZ-419 to Apc-mutant Min mice for 8 weeks resulted in a decrease in the number of polyps in the middle segment of the small intestine to 62.4% of the value in the untreated control (p < 0.05 vs. control group). As expected, NZ-419 treatment affected the levels of reactive carbonyl species, which are oxidative stress markers in the serum of Min mice. Suppression of the mRNA levels of the proliferation-associated factor c-Myc was observed in intestinal polyps of Min mice after NZ-419 treatment, with a weak suppression of epithelial cell proliferation assessed by proliferation cell nuclear antigen (PCNA) staining in the intestinal polyps. This study demonstrated that NZ-419 suppress the development of intestinal polyps in Min mice, suggesting the utility of radical scavenger/antioxidants as a cancer chemopreventive agent.
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Affiliation(s)
- Yurie Kurokawa
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo 104-0045, Japan; (Y.K.); (S.M.); (T.H.); (M.T.); (T.N.); (M.K.)
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (M.K.); (Y.H.)
| | - Gen Fujii
- Central Radioisotope Division, National Cancer Center Research, Tokyo 104-0045, Japan;
| | - Susumu Tomono
- Department of Microbiology and Immunology, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Shingo Miyamoto
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo 104-0045, Japan; (Y.K.); (S.M.); (T.H.); (M.T.); (T.N.); (M.K.)
- Department of Cancer Cell Research, Sasaki Institute, Sasaki Foundation, Tokyo 101-0062, Japan
| | - Takahiro Hamoya
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo 104-0045, Japan; (Y.K.); (S.M.); (T.H.); (M.T.); (T.N.); (M.K.)
| | - Maiko Takahashi
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo 104-0045, Japan; (Y.K.); (S.M.); (T.H.); (M.T.); (T.N.); (M.K.)
| | - Takumi Narita
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo 104-0045, Japan; (Y.K.); (S.M.); (T.H.); (M.T.); (T.N.); (M.K.)
| | - Masami Komiya
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo 104-0045, Japan; (Y.K.); (S.M.); (T.H.); (M.T.); (T.N.); (M.K.)
| | - Masaki Kobayashi
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (M.K.); (Y.H.)
- Translational Research Center, Research Institute of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan
| | - Yoshikazu Higami
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan; (M.K.); (Y.H.)
- Translational Research Center, Research Institute of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan
| | - Michihiro Mutoh
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo 104-0045, Japan; (Y.K.); (S.M.); (T.H.); (M.T.); (T.N.); (M.K.)
- Translational Research Center, Research Institute of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan
- Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo 104-0045, Japan
- Correspondence: ; Tel.: +81-03-3542-2511 (ext. 3337)
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