|
1
|
Papadimitriou N, Qu C, Harrison TA, Bever AM, Martin RM, Tsilidis KK, Newcomb PA, Thibodeau SN, Newton CC, Um CY, Obón-Santacana M, Moreno V, Brenner H, Mandic M, Chang-Claude J, Hoffmeister M, Pellatt AJ, Schoen RE, Harlid S, Ogino S, Ugai T, Buchanan DD, Lynch BM, Gruber SB, Cao Y, Hsu L, Huyghe JR, Lin Y, Steinfelder RS, Sun W, Van Guelpen B, Zaidi SH, Toland AE, Berndt SI, Huang WY, Aglago EK, Drew DA, French AJ, Georgeson P, Giannakis M, Hullar M, Nowak JA, Thomas CE, Le Marchand L, Cheng I, Gallinger S, Jenkins MA, Gunter MJ, Campbell PT, Peters U, Song M, Phipps AI, Murphy N. Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses. EBioMedicine 2024; 101:105010. [PMID: 38350331 PMCID: PMC10874711 DOI: 10.1016/j.ebiom.2024.105010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 01/25/2024] [Accepted: 01/30/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.
Collapse
Affiliation(s)
- Nikos Papadimitriou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Alaina M Bever
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, USA
| | - Richard M Martin
- MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK; National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; School of Public Health, University of Washington, Seattle, WA, USA
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Christina C Newton
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Caroline Y Um
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Mireia Obón-Santacana
- Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona 08908, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid 28029, Spain
| | - Victor Moreno
- Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona 08908, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid 28029, Spain; Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona 08908, Spain
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marko Mandic
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrew J Pellatt
- Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Tomotaka Ugai
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010, Australia; Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Brigid M Lynch
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Stephen B Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Robert S Steinfelder
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Wei Sun
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Syed H Zaidi
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Amanda E Toland
- Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Elom K Aglago
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - David A Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Amy J French
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Peter Georgeson
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010, Australia
| | - Marios Giannakis
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Meredith Hullar
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Johnathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Claire E Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | | | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Marc J Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Peter T Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| |
Collapse
|
|
2
|
Serrated polyps in patients with ulcerative colitis: Unique clinicopathological and biological characteristics. PLoS One 2023; 18:e0282204. [PMID: 36827302 PMCID: PMC9955668 DOI: 10.1371/journal.pone.0282204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 02/10/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND Serrated polyps have recently been reported in patients with ulcerative colitis (UC); however, their prevalence and detailed characteristics remain unclear. METHODS The prevalence and clinicopathological and biological characteristics of serrated polyps in patients with UC were retrospectively examined in a single tertiary inflammatory bowel disease center in Japan from 2000 to 2020. RESULTS Among 2035 patients with UC who underwent total colonoscopy, 252 neoplasms, including 36 serrated polyps (26 in colitis-affected segments, 10 in colitis-unaffected segments), were identified in 187 patients with UC. The proportion of serrated polyps was 1.8% (36/2035). Serrated polyps in colitis-affected segments were common with extensive colitis (88%), history of persistent active colitis (58%), and long UC duration (12.1 years). Serrated polyps in colitis-affected segments were more common in men (88%). Of the 26 serrated polyps in colitis-affected segments, 15, 6, and 5 were categorized as sessile serrated lesion-like dysplasia, traditional serrated adenoma-like dysplasia, and serrated dysplasia not otherwise specified, respectively. Sessile serrated lesion-like dysplasia was common in the proximal colon (67%) and with BRAF mutation (62%), whereas traditional serrated adenoma-like dysplasia and serrated dysplasia not otherwise specified were common in the distal colon (100% and 80%, respectively) and with KRAS mutations (100% and 75%, respectively). CONCLUSIONS Serrated polyps comprised 14% of the neoplasias in patients with UC. Serrated polyps in colitis-affected segments were common in men with extensive and longstanding colitis, suggesting chronic inflammation in the development of serrated polyps in patients with UC.
Collapse
|
|
3
|
Zhang Z, Bahaji Azami NL, Liu N, Sun M. Research Progress of Intestinal Microecology in the Pathogenesis of Colorectal Adenoma and Carcinogenesis. Technol Cancer Res Treat 2023; 22:15330338221135938. [PMID: 36740990 PMCID: PMC9903042 DOI: 10.1177/15330338221135938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Colorectal adenoma is a precancerous lesion that may progress to colorectal cancer. Patients with colorectal adenoma had a 4-fold higher risk of developing colorectal malignancy than the rest of the population, with approximately 80% of colorectal cancer originating from colorectal adenoma. Therefore, preventing the occurrence and progression of colorectal adenoma is crucial in reducing the risk for colorectal cancer. The human intestinal microecology is a complex system consisting of numerous microbial communities with a sophisticated structure. Interactions among intestinal microorganisms play crucial roles in maintaining normal intestinal structure, digestion, absorption, metabolism, and other functions. The colorectal system is the largest microbial bank or fermentation system in the human body. Studies suggest that intestinal microecological imbalance, one of the most important environmental factors, may play an essential role in the occurrence and development of colorectal adenoma and colorectal cancer. Based on the complexity of studying the gut microbiota ecosystem, its specific role in the occurrence and development of colorectal adenoma is yet to be elucidated. In addition, further studies are expected to provide new insights regarding the prevention and treatment of colorectal adenoma. This article reviews the relationship and mechanism of the diversity of the gut microbiota, the relevant inflammatory response, immune regulation, and metabolic changes in the presence of colorectal adenomas.
Collapse
Affiliation(s)
- Zhipeng Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Nisma Lena Bahaji Azami
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ningning Liu
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Ningning Liu, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Mingyu Sun, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Mingyu Sun
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
4
|
The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma—Recent Findings and Review. Biomedicines 2022; 10:biomedicines10071670. [PMID: 35884974 PMCID: PMC9312930 DOI: 10.3390/biomedicines10071670] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/17/2022] Open
Abstract
The inflammatory process plays a significant role in the development of colon cancer (CRC). Intestinal cytokine networks are critical mediators of tissue homeostasis and inflammation but also impact carcinogenesis at all stages of the disease. Recent studies suggest that inflammation is of greater importance in the serrated pathway than in the adenoma-carcinoma pathway. Interleukins have gained the most attention due to their potential role in CRC pathogenesis and promising results of clinical trials. Malignant transformation is associated with the pro-tumorigenic and anti-tumorigenic cytokines. The harmony between proinflammatory and anti-inflammatory factors is crucial to maintaining homeostasis. Immune cells in the tumor microenvironment modulate immune sensitivity and facilitate cancer escape from immune surveillance. Therefore, clarifying the role of underlying cytokine pathways and the effects of their modulation may be an important step to improve the effectiveness of cancer immunotherapy.
Collapse
|
|
5
|
Li J, You L, Xu Z, Bai H, Fei X, Yang J, Li Q, Qian S, Lin S, Tang M, Wang J, Chen K, Jin M. Healthy lifestyle and the risk of conventional adenomas and serrated polyps: Findings from a large colonoscopy screening population. Int J Cancer 2022; 151:67-76. [PMID: 35191524 DOI: 10.1002/ijc.33974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/28/2022] [Accepted: 02/10/2022] [Indexed: 12/24/2022]
Abstract
Evidence on the link between healthy lifestyle and colorectal cancer (CRC) precursors is limited. Our study aimed to examine and compare the associations of healthy lifestyle with CRC precursors in adenoma (AD) -carcinoma and serrated pathways. A total of 24,480 participants including 6,309 ADs, 1,343 serrated polyps (SPs), and 16,828 polyp-free controls were included. A healthy lifestyle score (HLS) was constructed based on five lifestyle factors including cigarette smoking, alcohol drinking, physical activity, diet, and body weight, and categorized into least, slightly, moderately, and most healthy. Multivariable logistic regressions were used to estimate odds ratio (OR) and 95% confidence interval (CI). Inverse dose-response associations between the HLS and risk of ADs were observed (OR per 1 score increment for ADs: 0.82 [95% CI 0.79 - 0.84]; for SPs: 0.73 [95% CI 0.69 - 0.78]), and the association with SPs was more evident than with ADs (OR 0.90, 95% CI 0.85 - 0.96). Compared with participants with the least healthy lifestyle, those with the most healthy lifestyle had 47% lower risk of ADs (OR 0.53, 95% CI 0.47 - 0.59) and 70% lower risk of SPs (OR 0.30, 95% CI 0.23 - 0.39), respectively. These inverse associations were consistent across lesion stage and anatomic subsite and not modified by any stratification factors. The risk advancement periods for the most vs. the least healthy lifestyle were -9.49 years for ADs and -20.69 years for SPs. Our findings help confirm the preventive role of healthy lifestyle in colorectal carcinogenesis.
Collapse
Affiliation(s)
- Jiayu Li
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liuqing You
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Non-Communicable Disease Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
| | - Zenghao Xu
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Bai
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinglin Fei
- Jiashan Institute of Cancer Prevention and Treatment, Jiashan, China
| | - Jinhua Yang
- Jiashan Institute of Cancer Prevention and Treatment, Jiashan, China
| | - Qilong Li
- Jiashan Institute of Cancer Prevention and Treatment, Jiashan, China
| | - Sangni Qian
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shujuan Lin
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengling Tang
- Department of Public Health, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianbing Wang
- Department of Public Health, National Clinical Research Center for Child Health of Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Chen
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mingjuan Jin
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
6
|
Oplawski M, Dziobek K, Zmarzły N, Grabarek BO, Kiełbasiński R, Kieszkowski P, Januszyk P, Talkowski K, Schweizer M, Kras P, Plewka A, Boroń D. Variances in the Level of COX-2 and iNOS in Different Grades of Endometrial Cancer. Curr Pharm Biotechnol 2020; 21:52-59. [PMID: 31533599 DOI: 10.2174/1389201020666190918104105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/30/2019] [Accepted: 09/01/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Many experimental studies have demonstrated the importance of COX-2 in the tumor angiogenesis. Inducible iNOS is responsible for a high and stable level of nitric oxide and is expressed in response to pro-inflammatory factors. OBJECTIVE The aim of this study was to evaluate the expression of COX-2 and iNOS at the protein level and to assess their potential prognostic significance in patients with endometrial cancer. METHODS The study group consisted of 45 women with endometrial cancer divided according to the degree of histological differentiation i.e. G1, 17; G2, 15; G3, 13. The control group consisted of 15 women without neoplastic changes. The expression of studied proteins was determined immunohistochemically with specific polyclonal antibodies. RESULTS Analysis of the COX-2 expression showed that the optical density of the reaction product in G1 reached 186% in the control group, while the values in G2 and G3 reached 243% and 293%, respectively. In the case of iNOS, the optical density of the reaction product reached the following percentages in the control group: 147% in G1, 243% in G2, and 241% in G3. CONCLUSION Our findings suggest that changes in the expression of COX-2 and iNOS may be potentially useful in predicting the progression of endometrial cancer and treatment effectiveness.
Collapse
Affiliation(s)
- Marcin Oplawski
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland
| | - Konrad Dziobek
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Cracow, Poland
| | - Nikola Zmarzły
- Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland
| | - Beniamin O Grabarek
- Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Cracow, Poland.,Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland
| | - Robert Kiełbasiński
- Department of Obstetrics & Gynaecology Ward, Health Center in Mikołów, Mikołów, Poland
| | | | - Piotr Januszyk
- Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland
| | - Karol Talkowski
- University of Warmia and Mazury in Olsztyn, Department of Psychiatry, Olsztyn, Poland
| | - Michał Schweizer
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Cracow, Poland
| | - Piotr Kras
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland
| | - Andrzej Plewka
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | - Dariusz Boroń
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| |
Collapse
|
|
7
|
Slobodnick A, Krasnokutsky S, Lehmann RA, Keenan RT, Quach J, Francois F, Pillinger MH. Colorectal Cancer Among Gout Patients Undergoing Colonoscopy. J Clin Rheumatol 2019; 25:335-340. [PMID: 31764494 DOI: 10.1097/rhu.0000000000000893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/OBJECTIVE The connection between gout and various cancers remains unclear. We assessed the relationship between gout and colorectal cancer in a population of veterans. METHODS We reviewed the Computerized Patient Record System of the VA New York Harbor Health Care System to assess the 10-year occurrence of colorectal cancer in patients with gout undergoing colonoscopy, versus patients with osteoarthritis but no gout. RESULTS Gout and osteoarthritis subjects were similar in age, ethnicity, body mass index, and smoking history. Among 581 gout and 598 osteoarthritis subjects with documented colonoscopies, the 10-year prevalence of colorectal cancer was significantly lower in gout (0.8%) versus osteoarthritis (3.7%) (p = 0.0008) patients. Differences in colorectal cancer rates remained significant after stratifying for nonsteroidal anti-inflammatory drug use. Among gout subjects, use of colchicine and/or allopurinol, as well as the presence/absence of concomitant osteoarthritis, did not influence colorectal cancer occurrence. On subanalysis, differences in colorectal cancer occurrence between gout and osteoarthritis subjects persisted among those who underwent diagnostic (0.5% in gout vs 4.6% in osteoarthritis subjects, p < 0.001) but not screening (0.9% in gout subjects vs 1% in osteoarthritis subjects, p = 1.0) colonoscopy. There was no significant difference in nonmalignant colorectal polyp occurrence between gout and osteoarthritis subjects. CONCLUSIONS Subjects with gout had decreased colonoscopy-documented occurrence of colorectal cancer compared with osteoarthritis subjects, suggesting a possible protective effect.
Collapse
Affiliation(s)
- Anastasia Slobodnick
- From the Section of Rheumatology, VA New York Harbor Health Care System, New York Campus
- Crystal Diseases Study Group, Division of Rheumatology, New York University School of Medicine, New York, NY
| | - Svetlana Krasnokutsky
- From the Section of Rheumatology, VA New York Harbor Health Care System, New York Campus
- Crystal Diseases Study Group, Division of Rheumatology, New York University School of Medicine, New York, NY
| | - Robert A Lehmann
- From the Section of Rheumatology, VA New York Harbor Health Care System, New York Campus
- Crystal Diseases Study Group, Division of Rheumatology, New York University School of Medicine, New York, NY
| | - Robert T Keenan
- Division of Rheumatology, Duke University School of Medicine, Durham, NC
| | - Jonathan Quach
- Section of Gastroenterology, VA New York Harbor Health Care System, New York Campus
- Division of Gastroenterology, New York University School of Medicine, New York, NY
| | - Fritz Francois
- Section of Gastroenterology, VA New York Harbor Health Care System, New York Campus
- Division of Gastroenterology, New York University School of Medicine, New York, NY
| | - Michael H Pillinger
- From the Section of Rheumatology, VA New York Harbor Health Care System, New York Campus
- Crystal Diseases Study Group, Division of Rheumatology, New York University School of Medicine, New York, NY
| |
Collapse
|
|
8
|
He Z, Chen L, Chen G, Smaldini P, Bongers G, Catalan-Dibene J, Furtado GC, Lira SA. Interleukin 1 beta and Matrix Metallopeptidase 3 Contribute to Development of Epidermal Growth Factor Receptor-Dependent Serrated Polyps in Mouse Cecum. Gastroenterology 2019; 157:1572-1583.e8. [PMID: 31470007 PMCID: PMC7006742 DOI: 10.1053/j.gastro.2019.08.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 08/02/2019] [Accepted: 08/21/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Transgenic mice (HBUS) that express the epidermal growth factor receptor (EGFR) ligand HBEGF (heparin-binding epidermal growth factor-like growth factor) and a constitutively active G protein-coupled receptor (US28) in intestinal epithelial cells develop serrated polyps in the cecum. Development of serrated polyps depends on the composition of the gut microbiota and is associated with bacterial invasion of the lamina propria, accompanied by induction of inflammation and up-regulation of interleukin 1 beta (IL1B) and matrix metalloproteinase (MMP) 3 in the cecum. We investigated the mechanisms by which these changes contribute to development of serrated polyps. METHODS We performed studies with C57BL/6 (control) and HBUS mice. To accelerate polyp development, we increased the exposure of the bacteria to the lamina propria by injecting HBUS mice with diphtheria toxin, which binds transgenic HBEGF expressed by the epithelial cells and causes apoptosis. Mice were given injections of IL1B-neutralizing antibody and the MMP inhibitor N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid. Intestinal tissues were collected from mice and analyzed by histology, reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence, and flow cytometry. We examined fibroblast subsets in polyps using single-cell RNA sequencing. RESULTS Administration of diphtheria toxin to HBUS mice accelerated development of serrated polyps (95% of treated mice developed polyps before 100 days of age, compared with 53% given vehicle). IL1B stimulated subsets of platelet-derived growth factor receptor alpha+ (PDGRFA+) fibroblasts isolated from cecum, resulting in increased expression of MMP3. Neutralizing antibodies against IL1B or administration of the MMP inhibitor reduced the number of serrated polyps that formed in the HBUS mice. Single-cell RNA sequencing analysis showed subsets of fibroblasts in serrated polyps that express genes that regulate matrix fibroblasts and inflammation. CONCLUSIONS In studies of mice, we found that barrier breakdown and expression of inflammatory factors contribute to development of serrated polyps. Subsets of cecal PDGFRA+ fibroblasts are activated by release of IL1B from myeloid cells during the early stages of serrated polyp development. MMP3 produced by PDGFRA+ fibroblasts is important for serrated polyp development. Our findings confirm the functions of previously identified serrated polyp-associated molecules and indicate roles for immune and stromal cells in serrated polyp development.
Collapse
Affiliation(s)
- Zhengxiang He
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Lili Chen
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Grace Chen
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Paola Smaldini
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gerold Bongers
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jovani Catalan-Dibene
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Glaucia C. Furtado
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sergio A. Lira
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
9
|
Yamaguchi M, Okamura S, Yamaji T, Iwasaki M, Tsugane S, Shetty V, Koizumi T. Plasma cytokine levels and the presence of colorectal cancer. PLoS One 2019; 14:e0213602. [PMID: 30883594 PMCID: PMC6422333 DOI: 10.1371/journal.pone.0213602] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 02/25/2019] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Cancer-related activation of cytokine networks are central aspects of tumor development. The goal of the study was to examine the possibility of plasma cytokines for the screening of colorectal cancer (CRC). Methods We carried out a multicenter, hospital-based case-control study in 66 adult Japanese patients with CRC and 87 healthy adult Japanese. A multiplex bead array immunoassay was used to examine 27 different plasma cytokines. Their association with the presence of CRC was evaluated by logistic regression analysis after adjusting for potential confounding factors. Results Thirteen plasma cytokines were notably associated with the presence of CRC (p< 0.05). Receiver operating characteristic analysis revealed that the combinatorial assessment of some of these plasma cytokines showed “good” capability for discriminating between CRC patients and control subjects (area under the curve (AUC): 0.819 for the combination of IL-9, Eotaxin, G-CSF, and TNF-α; 0.832 for the combination of IL-4, IL-8, Eotaxin, IP-10, and TNF-α). Individual cytokine assessments presented lower AUCs (0.657–0.755) than the combinatorial cytokine assessments. Conclusions The levels of several plasma cytokines varied significantly between CRC patients and control subjects, suggesting the possibility of differentially expressed plasma cytokines as potential biomarkers for detecting the presence of CRC. Our results should be validated in other populations.
Collapse
Affiliation(s)
- Masaki Yamaguchi
- Shinshu University, Graduate School of Science & Technology, Department of Mechanical Engineering & Robotics, Ueda, Nagano, Japan
- * E-mail:
| | - Shin Okamura
- Shinshu University, Graduate School of Science & Technology, Department of Mechanical Engineering & Robotics, Ueda, Nagano, Japan
| | - Taiki Yamaji
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Shoichiro Tsugane
- Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Vivek Shetty
- Section of Oral & Maxillofacial Surgery, UCLA Health Sciences Center, Los Angeles, CA, United States of America
| | - Tomonobu Koizumi
- Shinshu University School of Medicine, Department of Comprehensive Cancer Therapy, Matsumoto, Nagano, Japan
| |
Collapse
|
|
10
|
He X, Wu K, Ogino S, Giovannucci EL, Chan AT, Song M. Association Between Risk Factors for Colorectal Cancer and Risk of Serrated Polyps and Conventional Adenomas. Gastroenterology 2018; 155:355-373.e18. [PMID: 29702117 PMCID: PMC6067965 DOI: 10.1053/j.gastro.2018.04.019] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/29/2018] [Accepted: 04/13/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Serrated polyps (SPs) and conventional adenomas are precursor lesions for colorectal cancer (CRC), but they are believed to arise via distinct pathways. We characterized risk factor profiles for SPs and conventional adenomas in a post hoc analysis of data from 3 large prospective studies. METHODS We collected data from the Nurses' Health Study, the Nurses' Health Study 2, and the Health Professionals Follow-up Study on subjects who developed SPs or conventional adenomas. Our analysis comprised 141,143 participants who had undergone lower gastrointestinal endoscopy, provided updated diet and lifestyle data every 2-4 years, and were followed until diagnosis of a first polyp. We assessed 13 risk factors for CRC in patients with SPs or conventional adenomas and examined the associations according to histopathology features. RESULTS We documented 7945 SPs, 9212 conventional adenomas, and 2382 synchronous SPs and conventional adenomas during 18-20 years of follow-up. Smoking, body mass index, alcohol intake, family history of CRC, and height were associated with higher risk of SPs and conventional adenomas, whereas higher intake of vitamin D and marine omega-3 fatty acid were associated with lower risk. The associations tended to be stronger for synchronous SPs and conventional adenomas. Smoking, body mass index, and alcohol intake were more strongly associated with SPs than conventional adenomas (P for heterogeneity <.05), whereas physical activity and intake of total folate and calcium were inversely associated with conventional adenomas but not SPs. For SPs and conventional adenomas, the associations tended to be stronger for polyps in the distal colon and rectum, of 10 mm or larger or with advanced histology. CONCLUSIONS In an analysis of data from 3 large prospective studies, we found that although SPs and conventional adenomas share many risk factors, some factors are more strongly associated with one type of lesion than the other. These findings provide support for the etiologic heterogeneity of colorectal neoplasia.
Collapse
Affiliation(s)
- Xiaosheng He
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts; Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
| |
Collapse
|
|
11
|
Zhou W, Duan Z, Yang B, Xiao C. The Effective Regulation of Pro- and Anti-inflammatory Cytokines Induced by Combination of PA-MSHA and BPIFB1 in Initiation of Innate Immune Responses. Open Med (Wars) 2017; 12:299-307. [PMID: 28975158 PMCID: PMC5620450 DOI: 10.1515/med-2017-0044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 06/25/2017] [Indexed: 12/12/2022] Open
Abstract
PA-MSHA and BPIFB1 play especially important roles in triggering innate immune responses by inducing production of pro- or anti-inflammatory cytokines in the oral cavity and upper airway. We found that PA-MSHA had a strong ability to activate pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. However, BPIFB1 alone did not express a directly inductive effect. With incubation of PA-MSHA and BPIFB1, the combination can activate the CD14/TLR4/MyD88 complex and induce secretion of subsequent downstream cytokines. We used a proteome profiler antibody array to evaluate the phosphokinases status with PA-MSHA and BPIFB1 treatment. The results showed that the activation of MAPK, STAT, and PI-3K pathways is involved in PA-MSHA-BPIFB1 treatment, and that the related pathways control the secretion of targeting cytokines in the downstream. When we assessed the content changes of cytokines, we found that PA-MSHA-BPIFB1 treatment increased the production of pro-inflammatory cytokines in the early phase of treatment and induced the increase of IL-4 in the late phase. Our observations suggest that PA-MSHA-BPIFB1 stimulates the release of pro-inflammatory cytokines, and thereby initiates the innate immune system against inflammation. Meanwhile, the gradual release of anti-inflammatory cytokine IL-4 by PA-MSHA-BPIFB1 can also regulate the degree of inflammatory response; thus the host can effectively resist the environmental risks, but also manipulate inflammatory response in an appropriate and adjustable manner.
Collapse
Affiliation(s)
- Weiqiang Zhou
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No.146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro, P. R. China110034
| | - Zhiwen Duan
- Department of Toxicology, School of Public Health, Shenyang Medical College, No.146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro, P. R. China110034
| | - Biao Yang
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No.146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro, P. R. China110034
| | - Chunling Xiao
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No.146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro, P. R. China110034
| |
Collapse
|
|
12
|
Godos J, Biondi A, Galvano F, Basile F, Sciacca S, Giovannucci EL, Grosso G. Markers of systemic inflammation and colorectal adenoma risk: Meta-analysis of observational studies. World J Gastroenterol 2017; 23:1909-1919. [PMID: 28348498 PMCID: PMC5352933 DOI: 10.3748/wjg.v23.i10.1909] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 01/20/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To perform a meta-analysis of observational studies on inflammatory markers levels and occurrence of colorectal adenoma.
METHODS PubMed and EMBASE databases were searched until March 2016 for the articles reporting on the circulating levels of inflammatory markers, including: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) and risk of colorectal adenoma. Random-effects models were used to calculate summary odds ratios (ORs) with 95%CIs for the highest vs lowest category of exposure. Heterogeneity was assessed by using the Q test and I2 statistic. Subgroup analyses were also performed to test for potential source of heterogeneity.
RESULTS A total of 14 case-control studies were included. Ten studies on CRP including a total of 3350 cases and 4168 controls showed non-significant summary (OR = 1.23, 95%CI: 0.98-1.54; I2 = 54%, Pheterogeneity = 0.01) in the general analysis, but significant increased odds when considering only advanced adenoma (OR = 1.59, 95%CI: 1.09-2.32; I2 = 44%, Pheterogeneity = 0.15). Subgroup and stratified analyses revealed a potential influence of smoking status and aspirin use on the association between CRP levels and colorectal adenoma. Five studies examined the association between circulating levels of TNF-α and colorectal adenoma risk, including a total of 1,568 cases and 2,832 controls. The summary OR for the highest vs the lowest category of exposure was 1.00 (95%CI: 0.77-1.29). The relationship between circulating IL-6 levels and colorectal adenoma risk was investigated in 7 studies including a total of 1936 cases and 3611 controls. The summary OR for the highest vs the lowest category of exposure was 1.19 (95%CI: 0.92-1.55).
CONCLUSION Summary of current evidence suggests a positive association of CRP levels and advanced colorectal adenoma risk. The role of potential confounding factors should be further evaluated.
Collapse
|
|
13
|
Wang Y, Huang D, Chen KY, Cui M, Wang W, Huang X, Awadellah A, Li Q, Friedman A, Xin WW, Di Martino L, Cominelli F, Miron A, Chan R, Fox J, Xu Y, Shen X, Kalady MF, Markowitz S, Maillard I, Lowe JB, Xin W, Zhou L. Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma. Gastroenterology 2017; 152:193-205.e10. [PMID: 27639802 PMCID: PMC5164974 DOI: 10.1053/j.gastro.2016.09.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 08/29/2016] [Accepted: 09/07/2016] [Indexed: 01/29/2023]
Abstract
BACKGROUND & AIMS De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. METHODS FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). RESULTS Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. CONCLUSIONS In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.
Collapse
Affiliation(s)
- Yiwei Wang
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Dan Huang
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Kai-Yuan Chen
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Min Cui
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Weihuan Wang
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Xiaoran Huang
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Amad Awadellah
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Qing Li
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Ann Friedman
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - William W. Xin
- School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104-6304, USA
| | - Luca Di Martino
- Department of Internal Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Fabio Cominelli
- Department of Internal Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Alex Miron
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ricky Chan
- Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - James Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Yan Xu
- Department of Chemistry, Cleveland State University, Cleveland, OH 44106, USA
| | - Xiling Shen
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Mathew F. Kalady
- Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Sanford Markowitz
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ivan Maillard
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - John B. Lowe
- Department of Pathology, Genentech Inc., San Francisco, CA, 94080 USA
| | - Wei Xin
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA,Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Lan Zhou
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
| |
Collapse
|