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1
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Baima G, Ribaldone DG, Romano F, Aimetti M, Romandini M. The Gum-Gut Axis: Periodontitis and the Risk of Gastrointestinal Cancers. Cancers (Basel) 2023; 15:4594. [PMID: 37760563 PMCID: PMC10526746 DOI: 10.3390/cancers15184594] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/01/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Periodontitis has been linked to an increased risk of various chronic non-communicable diseases, including gastrointestinal cancers. Indeed, dysbiosis of the oral microbiome and immune-inflammatory pathways related to periodontitis may impact the pathophysiology of the gastrointestinal tract and its accessory organs through the so-called "gum-gut axis". In addition to the hematogenous spread of periodontal pathogens and inflammatory cytokines, recent research suggests that oral pathobionts may translocate to the gastrointestinal tract through saliva, possibly impacting neoplastic processes in the gastrointestinal, liver, and pancreatic systems. The exact mechanisms by which oral pathogens contribute to the development of digestive tract cancers are not fully understood but may involve dysbiosis of the gut microbiome, chronic inflammation, and immune modulation/evasion, mainly through the interaction with T-helper and monocytic cells. Specifically, keystone periodontal pathogens, including Porphyromonas gingivalis and Fusobacterium nucleatum, are known to interact with the molecular hallmarks of gastrointestinal cancers, inducing genomic mutations, and promote a permissive immune microenvironment by impairing anti-tumor checkpoints. The evidence gathered here suggests a possible role of periodontitis and oral dysbiosis in the carcinogenesis of the enteral tract. The "gum-gut axis" may therefore represent a promising target for the development of strategies for the prevention and treatment of gastrointestinal cancers.
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Affiliation(s)
- Giacomo Baima
- Department of Surgical Sciences, University of Turin, 10125 Torino, Italy; (G.B.); (F.R.); (M.A.)
| | | | - Federica Romano
- Department of Surgical Sciences, University of Turin, 10125 Torino, Italy; (G.B.); (F.R.); (M.A.)
| | - Mario Aimetti
- Department of Surgical Sciences, University of Turin, 10125 Torino, Italy; (G.B.); (F.R.); (M.A.)
| | - Mario Romandini
- Department of Periodontology, Faculty of Dentistry, University of Oslo, 0313 Oslo, Norway
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2
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Xie WJ, Li J. Obesity and cancer stem cells: Roles in cancer initiation, progression and therapy resistance. World J Stem Cells 2023; 15:120-135. [PMID: 37181008 PMCID: PMC10173809 DOI: 10.4252/wjsc.v15.i4.120] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/28/2023] [Accepted: 03/16/2023] [Indexed: 04/26/2023] Open
Abstract
Obesity, the global pandemic since industrialization, is the number one lifestyle-related risk factor for premature death, which increases the incidence and mortality of various diseases and conditions, including cancer. In recent years, the theory of cancer stem cells (CSCs), which have the capacity for self-renewal, metastasis and treatment resistance, has been bolstered by increasing evidence. However, research on how obesity affects CSCs to facilitate cancer initiation, progression and therapy resistance is still in its infancy, although evidence has already begun to accumulate. Regarding the ever-increasing burden of obesity and obesity-related cancer, it is pertinent to summarize evidence about the effects of obesity on CSCs, as elucidating these effects will contribute to the improvement in the management of obesity-related cancers. In this review, we discuss the association between obesity and CSCs, with a particular focus on how obesity promotes cancer initiation, progression and therapy resistance through CSCs and the mechanisms underlying these effects. In addition, the prospect of preventing cancer and targeting the mechanisms linking obesity and CSCs to reduce cancer risk or to improve the survival of patients with cancer is considered.
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Affiliation(s)
- Wen-Jie Xie
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China.
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3
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Zhu CH, Li YX, Xu YC, Wang NN, Yan QJ, Jiang ZQ. Tamarind Xyloglucan Oligosaccharides Attenuate Metabolic Disorders via the Gut-Liver Axis in Mice with High-Fat-Diet-Induced Obesity. Foods 2023; 12:foods12071382. [PMID: 37048202 PMCID: PMC10093524 DOI: 10.3390/foods12071382] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 04/14/2023] Open
Abstract
Functional oligosaccharides exert obesity-reducing effects by acting at various pathological sites responsible for the development of obesity. In this study, tamarind xyloglucan oligosaccharides (TXOS) were used to attenuate metabolic disorders via the gut-liver axis in mice with high-fat-diet (HFD)-induced obesity, as determined through LC/MS-MS and 16S rRNA sequencing technology. A TXOS dose equivalent to 0.39 g/kg/day in humans restored the gut microbiota in obese mice, which was in part supported by the key microflora, particularly Bifidobacterium pseudolongum. Moreover, TXOS reduced the abundance of opportunistic pathogen species, such as Klebsiella variicola and Romboutsia ilealis. The bodyweight and weight gain of TXOS-treated (4.8 g/kg per day) mice began to decrease at the 14th week, decreasing by 12.8% and 23.3%, respectively. Sixteen fatty acids were identified as potential biomarkers in the liver, and B. pseudolongum and caprylic acid were found to tightly regulate each other. This was associated with reduced inflammation in the liver, circulation, and adipose tissue and protection from metabolic disorders. The findings of this study indicate that TXOS can significantly increase the gut microbiota diversity of obese mice and restore the HFD-induced dysbiosis of gut microbiota.
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Affiliation(s)
- Chun-Hua Zhu
- Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yan-Xiao Li
- Key Laboratory of Food Bioengineering (China National Light Industry), College of Engineering, China Agricultural University, Beijing 100083, China
- College of Food Science and Engineering, Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing University of Finance and Economics, Nanjing 210023, China
| | - Yun-Cong Xu
- Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Nan-Nan Wang
- Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Qiao-Juan Yan
- Key Laboratory of Food Bioengineering (China National Light Industry), College of Engineering, China Agricultural University, Beijing 100083, China
| | - Zheng-Qiang Jiang
- Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
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4
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Pourvali K, Monji H. Obesity and intestinal stem cell susceptibility to carcinogenesis. Nutr Metab (Lond) 2021; 18:37. [PMID: 33827616 PMCID: PMC8028194 DOI: 10.1186/s12986-021-00567-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
Background Obesity is a top public health problem associated with an increase in colorectal cancer incidence. Stem cells are the chief cells in tissue homeostasis that self-renew and differentiate into other cells to regenerate the organ. It is speculated that an increase in stem cell pool makes cells susceptible to carcinogenesis. In this review, we looked at the recent investigations linking obesity/high-fat diet-induced obesity to intestinal carcinogenesis with regard to intestinal stem cells and their niche. Findings High-fat diet-induced obesity may rise intestinal carcinogenesis by increased Intestinal stem cells (ISC)/progenitor’s population, stemness, and niche independence through activation of PPAR-δ with fatty acids, hormonal alterations related to obesity, and low-grade inflammation. However, these effects may possibly relate to the interaction between fats and carbohydrates, and not a fatty acid per se. Nonetheless, literature studies are inconsistency in their results, probably due to the differences in the diet components and limitations of genetic models used. Conclusion High-fat diet-induced obesity affects carcinogenesis by changing ISC proliferation and function. However, a well-matched diet and the reliable colorectal cancer models that mimic human carcinogenesis is necessary to clearly elucidate the influence of high-fat diet-induced obesity on ISC behavior.
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Affiliation(s)
- Katayoun Pourvali
- Department of Cellular and Molecular Nutrition, Faculty of Nutrition Science and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, 1981619573, Tehran, Iran
| | - Hadi Monji
- Department of Cellular and Molecular Nutrition, Faculty of Nutrition Science and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, 1981619573, Tehran, Iran.
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5
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Muthusami S, Ramachandran IK, Babu KN, Krishnamoorthy S, Guruswamy A, Queimado L, Chaudhuri G, Ramachandran I. Role of Inflammation in the Development of Colorectal Cancer. Endocr Metab Immune Disord Drug Targets 2020; 21:77-90. [PMID: 32901590 DOI: 10.2174/1871530320666200909092908] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 07/23/2020] [Accepted: 07/29/2020] [Indexed: 11/22/2022]
Abstract
Chronic inflammation can lead to the development of many diseases, including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohnmp's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation, together with genetic and epigenetic changes, have been shown to lead to the development and progression of CRC. Various cell types present in the colon, such as enterocytes, Paneth cells, goblet cells, and macrophages, express receptors for inflammatory cytokines and respond to tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key pro-inflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of pro-inflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy) to alleviate the symptoms or treat inflammation-associated CRC by using monoclonal antibodies or aptamers to block pro-inflammatory molecules, inhibitors of tyrosine kinases in the inflammatory signaling cascade, competitive inhibitors of pro-inflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/pro-inflammatory cytokine gene expression.
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Affiliation(s)
- Sridhar Muthusami
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India
| | | | - Kokelavani Nampalli Babu
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India
| | - Sneha Krishnamoorthy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India
| | - Akash Guruswamy
- University of Missouri- Kansas City, College of Medicine, Kansas City, MO 64110, United States
| | - Lurdes Queimado
- Departments of Otorhinolaryngology - Head and Neck Surgery, Cell Biology, Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
| | - Gautam Chaudhuri
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
| | - Ilangovan Ramachandran
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
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Abstract
Despite great advances in treatment, cancer remains a leading cause of death worldwide. Diet can greatly impact health, while caloric restriction and fasting have putative benefits for disease prevention and longevity. Strong epidemiological associations exist between obesity and cancer, whereas healthy diets can reduce cancer risk. However, less is known about how diet might impact cancer once it has been diagnosed and particularly how diet can impact cancer treatment. In the present review, we discuss the links between obesity, diet, and cancer. We explore potential mechanisms by which diet can improve cancer outcomes, including through hormonal, metabolic, and immune/inflammatory effects, and present the limited clinical research that has been published in this arena. Though data are sparse, diet intervention may reduce toxicity, improve chemotherapy efficacy, and lower the risk of long-term complications in cancer patients. Thus, it is important that we understand and expand the science of this important but complex adjunctive cancer treatment strategy.
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Affiliation(s)
- Steven D Mittelman
- Division of Pediatric Endocrinology, University of California, Los Angeles (UCLA), Children's Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA;
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7
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Chiodi I, Mondello C. Life style factors, tumor cell plasticity and cancer stem cells. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2020; 784:108308. [PMID: 32430096 DOI: 10.1016/j.mrrev.2020.108308] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/15/2022]
Abstract
Cancers are heterogeneous tissues and a layer of heterogeneity is determined by the presence of cells showing stemness traits, known as cancer stem cells (CSCs). Evidence indicates that CSCs are important players in tumor development, progression and relapse. Oncogenic transformation of normal stem cells can give rise to CSCs, but CSCs can also originate from de-differentiation of bulk tumor cells. Thus, factors promoting the increase of normal stem cell pools or stimulating the acquisition of stemness features by tumor cells can have serious consequences on cancer origin and progression. In this review, we will first give an overview of the CSC model of cancer development and we will then discuss the role of life style factors, such as high caloric diet, alcohol drinking and smoking, on the widening of stem cell pools and the induction of CSC features in tumors. Finally, we will discuss some healthy life style factors that can help to prevent cancer.
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Affiliation(s)
- Ilaria Chiodi
- Istituto di Genetica Molecolare L. L. Cavalli-Sforza, CNR, via Abbiategrasso 207, 27100, Pavia, Italy
| | - Chiara Mondello
- Istituto di Genetica Molecolare L. L. Cavalli-Sforza, CNR, via Abbiategrasso 207, 27100, Pavia, Italy.
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8
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Garcia-Villatoro EL, DeLuca JAA, Callaway ES, Allred KF, Davidson LA, Hensel ME, Menon R, Ivanov I, Safe SH, Jayaraman A, Chapkin RS, Allred CD. Effects of high-fat diet and intestinal aryl hydrocarbon receptor deletion on colon carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2020; 318:G451-G463. [PMID: 31905023 PMCID: PMC7137094 DOI: 10.1152/ajpgi.00268.2019] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Consumption of a high-fat diet has been associated with an increased risk of developing colorectal cancer (CRC). However, the effects of the interaction between dietary fat content and the aryl hydrocarbon receptor (AhR) on colorectal carcinogenesis remain unclear. Mainly known for its role in xenobiotic metabolism, AhR has been identified as an important regulator for maintaining intestinal epithelial homeostasis. Although previous research using whole body AhR knockout mice has revealed an increased incidence of colon and cecal tumors, the unique role of AhR activity in intestinal epithelial cells (IECs) and modifying effects of fat content in the diet at different stages of sporadic CRC development are yet to be elucidated. In the present study, we have examined the effects of a high-fat diet on IEC-specific AhR knockout mice in a model of sporadic CRC. Although loss of AhR activity in IECs significantly induced the development of premalignant lesions, in a separate experiment, no significant changes in colon mass incidence were observed. Moreover, consumption of a high-fat diet promoted cell proliferation in crypts at the premalignant colon cancer lesion stage and colon mass multiplicity as well as β-catenin expression and nuclear localization in actively proliferating cells in colon masses. Our data demonstrate the modifying effects of high-fat diet and AhR deletion in IECs on tumor initiation and progression.NEW & NOTEWORTHY Through the use of an intestinal-specific aryl hydrocarbon receptor (AhR) knockout mouse model, this study demonstrates that the expression of AhR in intestinal epithelial cells is required to reduce the formation of premalignant colon cancer lesions. Furthermore, consumption of a high-fat diet and the loss of AhR in intestinal epithelial cells influences the development of colorectal cancer at various stages.
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Affiliation(s)
| | - Jennifer A. A. DeLuca
- 1Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Evelyn S. Callaway
- 2Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Kimberly F. Allred
- 1Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
| | - Laurie A. Davidson
- 1Department of Nutrition and Food Science, Texas A&M University, College Station, Texas,3Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
| | - Martha E. Hensel
- 4Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas
| | - Rani Menon
- 2Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Ivan Ivanov
- 5Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Stephen H. Safe
- 5Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Arul Jayaraman
- 2Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Robert S. Chapkin
- 1Department of Nutrition and Food Science, Texas A&M University, College Station, Texas,3Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
| | - Clinton D. Allred
- 1Department of Nutrition and Food Science, Texas A&M University, College Station, Texas
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9
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The Gut Microbiome and Type 2 Diabetes Mellitus: Discussing a Complex Relationship. Biomedicines 2020; 8:biomedicines8010008. [PMID: 31936158 PMCID: PMC7168169 DOI: 10.3390/biomedicines8010008] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/02/2020] [Accepted: 01/05/2020] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a disease that affects over 9% of the United States population and is closely linked to obesity. While obesity was once thought to stem from a sedentary lifestyle and diets high in fat, recent evidence supports the idea that there is more complexity pertinent to the issue. The human gut microbiome has recently been the focus in terms of influencing disease onset. Evidence has shown that the microbiome may be more closely related to T2DM than what was originally thought. High fat diets typically result in poor microbiome heath, which then shifts the gut into a state of dysbiosis. Dysbiosis can then lead to metabolic deregulation, including increased insulin resistance and inflammation, two key factors in the development of T2DM. The purpose of this review is to discuss how microbiome relates to T2DM onset, especially considering obesity, insulin resistance, and inflammation.
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10
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O'Neill AM, Burrington CM, Gillaspie EA, Lynch DT, Horsman MJ, Greene MW. High-fat Western diet–induced obesity contributes to increased tumor growth in mouse models of human colon cancer. Nutr Res 2016; 36:1325-1334. [PMID: 27866828 DOI: 10.1016/j.nutres.2016.10.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 10/14/2016] [Accepted: 10/17/2016] [Indexed: 12/29/2022]
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11
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Kristo AS, Klimis-Zacas D, Sikalidis AK. Protective Role of Dietary Berries in Cancer. Antioxidants (Basel) 2016; 5:antiox5040037. [PMID: 27775562 PMCID: PMC5187535 DOI: 10.3390/antiox5040037] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/24/2016] [Accepted: 10/11/2016] [Indexed: 12/25/2022] Open
Abstract
Dietary patterns, including regular consumption of particular foods such as berries as well as bioactive compounds, may confer specific molecular and cellular protection in addition to the overall epidemiologically observed benefits of plant food consumption (lower rates of obesity and chronic disease risk), further enhancing health. Mounting evidence reports a variety of health benefits of berry fruits that are usually attributed to their non-nutritive bioactive compounds, mainly phenolic substances such as flavonoids or anthocyanins. Although it is still unclear which particular constituents are responsible for the extended health benefits, it appears that whole berry consumption generally confers some anti-oxidant and anti-inflammatory protection to humans and animals. With regards to cancer, studies have reported beneficial effects of berries or their constituents including attenuation of inflammation, inhibition of angiogenesis, protection from DNA damage, as well as effects on apoptosis or proliferation rates of malignant cells. Berries extend effects on the proliferation rates of both premalignant and malignant cells. Their effect on premalignant cells is important for their ability to cause premalignant lesions to regress both in animals and in humans. The present review focuses primarily on in vivo and human dietary studies of various berry fruits and discusses whether regular dietary intake of berries can prevent cancer initiation and delay progression in humans or ameliorate patients’ cancer status.
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Affiliation(s)
- Aleksandra S Kristo
- Department of Nutrition and Dietetics, Istanbul Yeni Yuzyil University, Yilanli Ayasma Caddesi No. 26, Istanbul 34010, Turkey.
| | | | - Angelos K Sikalidis
- Department of Nutrition and Dietetics, Istanbul Yeni Yuzyil University, Yilanli Ayasma Caddesi No. 26, Istanbul 34010, Turkey.
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12
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Huang L, Shan YJ, He CX, Ren MH, Tian PJ, Song W. Effects of L. paracasei subp. paracasei X12 on cell cycle of colon cancer HT-29 cells and regulation of mTOR signalling pathway. J Funct Foods 2016. [DOI: 10.1016/j.jff.2015.12.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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13
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DeClercq V, McMurray DN, Chapkin RS. Obesity promotes colonic stem cell expansion during cancer initiation. Cancer Lett 2015; 369:336-43. [PMID: 26455770 DOI: 10.1016/j.canlet.2015.10.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 09/29/2015] [Accepted: 10/01/2015] [Indexed: 02/08/2023]
Abstract
There is an urgent need to elucidate the mechanistic links between obesity and colon cancer. Convincing evidence for the role of Lgr5(+) stem cells in colon tumorigenesis has been established; however, the influence of obesity on stem cell maintenance is unknown. We assessed the effects of high fat (HF) feeding on colonic stem cell maintenance during cancer initiation (AOM induced) and the responsiveness of stem cells to adipokine signaling pathways. The number of colonic GFP(+) stem cells was significantly higher in the AOM-injected HF group compared to the LF group. The Lgr5(+) stem cells of the HF fed mice exhibited statistically significant increases in cell proliferation and decreases in apoptosis in response to AOM injection compared to the LF group. Colonic organoid cultures from lean mice treated with an adiponectin receptor agonist exhibited a reduction in Lgr5-GPF(+) stem cell number and an increase in apoptosis; however, this response was diminished in the organoid cultures from obese mice. These results suggest that the responsiveness of colonic stem cells to adiponectin in diet-induced obesity is impaired and may contribute to the stem cell accumulation observed in obesity.
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Affiliation(s)
- V DeClercq
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA
| | - D N McMurray
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University Health Science Center, College Station, TX, USA
| | - R S Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA; Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University Health Science Center, College Station, TX, USA; Department of Nutrition and Food Science, Texas A&M University, College Station, MS 2253, Cater Mattil, TX 77843-2253, USA; Center for Translational Environmental Health Research, Texas A&M University, College Station, TX, USA.
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14
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Chapkin RS, DeClercq V, Kim E, Fuentes NR, Fan YY. Mechanisms by Which Pleiotropic Amphiphilic n-3 PUFA Reduce Colon Cancer Risk. CURRENT COLORECTAL CANCER REPORTS 2014; 10:442-452. [PMID: 25400530 DOI: 10.1007/s11888-014-0241-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer is one of the major causes of cancer-related mortality in both men and women worldwide. Genetic susceptibility and diet are primary determinants of cancer risk and tumor behavior. Experimental, epidemiological, and clinical data substantiate the beneficial role of n-3 polyunsaturated fatty acids (PUFA) in preventing chronic inflammation and colon cancer. From a mechanistic perspective, n-3 PUFA are pleiotropic and multifaceted with respect to their molecular mechanisms of action. For example, this class of dietary lipid uniquely alters membrane structure/ cytoskeletal function, impacting membrane receptor function and downstream signaling cascades, including gene expression profiles and cell phenotype. In addition, n-3 PUFA can synergize with other potential anti-tumor agents, such as fermentable fiber and curcumin. With the rising prevalence of diet-induced obesity, there is also an urgent need to elucidate the link between chronic inflammation in adipose tissue and colon cancer risk in obesity. In this review, we will summarize recent developments linking n-3 PUFA intake, membrane alterations, epigenetic modulation, and effects on obesity-associated colon cancer risk.
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Affiliation(s)
- Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA. Center for Translational Environmental Health Research, Texas A&M University, College Station, TX 77843, USA. Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA. Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843, USA. Faculty of Toxicity, Texas A&M University, College Station, TX 77843, USA
| | - Vanessa DeClercq
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA. Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA
| | - Eunjoo Kim
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA. Molecular & Cellular Medicine, Texas A&M University, College Station, TX 77843, USA
| | - Natividad Roberto Fuentes
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA. Faculty of Toxicity, Texas A&M University, College Station, TX 77843, USA
| | - Yang-Yi Fan
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA. Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA
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15
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Riondino S, Roselli M, Palmirotta R, Della-Morte D, Ferroni P, Guadagni F. Obesity and colorectal cancer: role of adipokines in tumor initiation and progression. World J Gastroenterol 2014; 20:5177-5190. [PMID: 24833848 PMCID: PMC4017033 DOI: 10.3748/wjg.v20.i18.5177] [Citation(s) in RCA: 136] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of "adiposopathy", defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC.
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Sikalidis AK, Fitch MD, Fleming SE. Risk of colonic cancer is not higher in the obese Lep(ob) mouse model compared to lean littermates. Pathol Oncol Res 2013; 19:867-74. [PMID: 23813464 DOI: 10.1007/s12253-013-9656-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 05/29/2013] [Indexed: 01/08/2023]
Abstract
Epidemiological data suggest that obesity increases the risk of colorectal cancer in humans. Given that diet-induced obesity mouse models verified the epidemiological data, the present study aimed to determine whether obese C57BL/6J-Lep(ob) male mice (a different obesity in vivo model) were at greater risk of colonic cancer than their lean male littermates. Risk of colonic tumorigenesis was assessed by numbers of aberrant crypts, aberrant crypt foci and colonic tumors. Proliferation of the colonic epithelia was assessed histochemically following administration of BrdU. Availability of the procarcinogen, azoxymethane (AOM) to target tissues was assessed by quantifying via HPLC plasma AOM concentrations during the 60 min period following AOM injection. When obese and lean mice were injected with azoxymethane (AOM) at doses calculated to provide equivalent AOM levels per kg lean body mass, obese animals had significantly fewer aberrant crypts/colon and fewer aberrant crypt foci/colon than the lean animals. Tumors were identified in the colonic mucosa of lean (4 tumors in 14 mice) but not obese (0 tumors in 15 mice) mice. Colonic cell proliferation was not significantly different for obese and lean mice. Because these results were unexpected, plasma AOM concentrations were measured and were found to be lower in the obese than lean mice. When plasma AOM levels were comparable for the lean and obese mice, the Lep(ob) mice continued to have significantly fewer aberrant crypt foci/colon than the lean mice, but differences were not statistically different for aberrant crypts/colon. Interestingly, obese Lep(ob) mice did not exhibit increased risk of colonic cancer as expected. Instead, Lep(ob) mice exhibited equivalent or lower risk of colon cancer when compared to the lean group. These results taken together with in vivo results from diet-induced obesity studies, imply that leptin may be responsible for the increased risk of colon cancer associated with obesity.
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Affiliation(s)
- Angelos K Sikalidis
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, 94720, USA,
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