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1
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Fay ML, Nicol C, Orr C, Wilson B, Hurlbut D, Feilotter H, Davey S. Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients. Curr Oncol 2025; 32:138. [PMID: 40136342 PMCID: PMC11941617 DOI: 10.3390/curroncol32030138] [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] [Received: 01/20/2025] [Revised: 02/18/2025] [Accepted: 02/25/2025] [Indexed: 03/27/2025] Open
Abstract
Type 2 diabetes is a risk factor for colorectal cancer (CRC) development and progression. However, metformin-treated diabetic CRC patients tend to have better clinical outcomes than those managed by other means. To better characterize the molecular underpinnings of metformin's protective effects, we performed a targeted transcriptomic analysis of primary CRC tissue samples (n = 272). A supervised learning algorithm pinpointed molecular features that discriminate between metformin-treated and diet-controlled diabetic CRC samples, as well as those that discriminated between non-diabetic samples based on their five-year overall survival status. Our results show downregulation of TMEM132 in metformin-treated samples (p = 0.05) and non-diabetics with good clinical outcomes (p = 0.05) relative to diet-controlled and non-diabetics with poor survival, respectively. Furthermore, upregulation of SCNN1A is observed in metformin-treated samples (p = 0.04) and non-diabetics with good clinical outcomes (p = 0.01) relative to diet-controlled samples and those with poor clinical outcomes, respectively. We also show that the antiapoptotic protein sFas is downregulated in metformin-treated samples relative to diet-controlled samples (p = 0.005). These findings suggest a role for the unfolded protein response in mediating metformin-related CRC-protective effects by enhancing apoptosis and suggest the investigation of these proteins as targets for novel CRC therapies.
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Affiliation(s)
- Mary L. Fay
- Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen’s University, Kingston, ON K7L 3N6, Canada; (M.L.F.); (C.N.)
| | - Chris Nicol
- Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen’s University, Kingston, ON K7L 3N6, Canada; (M.L.F.); (C.N.)
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada; (C.O.); (D.H.); (H.F.)
| | - Christine Orr
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada; (C.O.); (D.H.); (H.F.)
| | - Brooke Wilson
- Department of Oncology, Queen’s University, Kingston, ON K7L 3N6, Canada;
| | - David Hurlbut
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada; (C.O.); (D.H.); (H.F.)
| | - Harriet Feilotter
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada; (C.O.); (D.H.); (H.F.)
- Laboratory Medicine Program, Division of Genome Diagnostics, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada
| | - Scott Davey
- Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen’s University, Kingston, ON K7L 3N6, Canada; (M.L.F.); (C.N.)
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada; (C.O.); (D.H.); (H.F.)
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2
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Zhao X, Wang Y, Zhou L, Ye A, Zhu Q. Changes of CA19-9 levels and related influencing factors in patients with type 2 diabetes mellitus after antidiabetic therapy. Sci Rep 2025; 15:1264. [PMID: 39779798 PMCID: PMC11711652 DOI: 10.1038/s41598-025-85807-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 01/06/2025] [Indexed: 01/11/2025] Open
Abstract
Abnormalities of carbohydrate antigen 19 - 9 (CA19-9) are common in patients with type 2 diabetes mellitus (T2DM), and in some patients, CA19-9 returns to normal level after glycemic control. The aim of this study was to investigate the factors associated with CA19-9 levels in patients with T2DM and the associated influences on the degree of reduction of CA19-9 levels after antidiabetic therapy (AT). This study was an observational cross-sectional study. A total of 213 patients with T2DM were enrolled in this study, of whom 105 with abnormal CA19-9 and 108 with normal CA19-9. Socio-demographic information, complete blood counts, biochemical indicators, thyroid function indicators, and CA19-9 level were collected separately for each subject. Levels of glycosylated hemoglobin, type A1C (HbA1c), fasting blood glucose (FBG) were significantly higher in T2DM patients with abnormal CA19-9 compared to patients with normal CA19-9 (both FDR < 0.001). CA19-9 level was significantly and positively correlated with neutrophil/lymphocyte ratio (NLR) (r = 0.16, P = 0.02), monocyte/lymphocyte ratio (MLR) (r = 0.16, P = 0.02), and FBG (r = 0.38, P < 0.001), while significantly and negatively correlated with free triiodothyronine (FT3) (r=-0.22, P = 0.002) and albumin count (r=-0.18, P = 0.007). After AT, the degree of decrease in CA19-9 level in T2DM patients with abnormal CA19-9 was significantly positively correlated with degree of decrease in FBG (r = 0.33, P < 0.001), as well as CA19-9 level before AT (r = 0.73, P < 0.001), NLR (r = 0.20, P = 0.04), and MLR (r = 0.25, P = 0.01). In this study, we investigated the influencing factors associated with CA19-9 level and the factors influencing degree of CA19-9 reduction after AT in T2DM patients with abnormal CA19-9.
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Affiliation(s)
- Xiafei Zhao
- Affiliated Xiaoshan Hospital, Hangzhou Normal University/Zhejiang Xiaoshan Hospital, 728 Yucai North Road, Hangzhou, 311200, China
| | - Yan Wang
- Affiliated Xiaoshan Hospital, Hangzhou Normal University/Zhejiang Xiaoshan Hospital, 728 Yucai North Road, Hangzhou, 311200, China
| | - Ling Zhou
- Affiliated Xiaoshan Hospital, Hangzhou Normal University/Zhejiang Xiaoshan Hospital, 728 Yucai North Road, Hangzhou, 311200, China
| | - Aili Ye
- Affiliated Xiaoshan Hospital, Hangzhou Normal University/Zhejiang Xiaoshan Hospital, 728 Yucai North Road, Hangzhou, 311200, China.
| | - Quanfeng Zhu
- Affiliated Xiaoshan Hospital, Hangzhou Normal University/Zhejiang Xiaoshan Hospital, 728 Yucai North Road, Hangzhou, 311200, China.
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3
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Pliszka M, Szablewski L. Associations between Diabetes Mellitus and Selected Cancers. Int J Mol Sci 2024; 25:7476. [PMID: 39000583 PMCID: PMC11242587 DOI: 10.3390/ijms25137476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.
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Affiliation(s)
- Monika Pliszka
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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Abonyi-Tóth Z, Rokszin G, Fábián I, Kiss Z, Jermendy G, Kempler P, Lengyel C, Wittmann I, Molnár GA, Sütő G. Incident Cancer Risk in Patients with Incident Type 2 Diabetes Mellitus in Hungary (Part 1). Cancers (Basel) 2024; 16:1745. [PMID: 38730697 PMCID: PMC11083545 DOI: 10.3390/cancers16091745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
(1) Background: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of cancer but how these two diseases associate is still debated. The goal of this study was the assessment of the overall incidence of cancer among patients with newly diagnosed T2DM in Hungary. (2) Methods: A nationwide, retrospective, longitudinal study was performed using a Hungarian database. After exclusion of cases of age < 18 years, with gestational diabetes, with polycystic ovary syndrome, and with type 1 and prevalent type 2 diabetes mellitus, the incident T2DM (approx. 50,000 cases yearly) and for comparison, the diabetes-free Hungarian adult population (approx. 7,000,000 cases yearly) was included in the study. The primary endpoints were the overall and site-specific incidence and annual percentage change of the incidence of cancer in both populations. (3) Results: The overall incidence of cancer in patients amounted to 29.4/1000 and 6.6/1000 with or without T2DM, respectively, and the OR (95%CI) of cancer of the T2DM group was 4.32 (4.14-4.53), p < 0.0001. The risk of having cancer was age dependent. The incidence of cancer was declining in the non-diabetic but was unchanged in the T2DM population. The average lag time of diagnosing cancer after the detection of T2DM was 3.86 months. (4) Conclusions: Incident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months.
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Affiliation(s)
- Zsolt Abonyi-Tóth
- RxTarget Ltd., 5000 Szolnok, Hungary; (Z.A.-T.); (G.R.); (I.F.)
- Department of Biostatistics, University of Veterinary Medicine, 1078 Budapest, Hungary
| | - György Rokszin
- RxTarget Ltd., 5000 Szolnok, Hungary; (Z.A.-T.); (G.R.); (I.F.)
| | - Ibolya Fábián
- RxTarget Ltd., 5000 Szolnok, Hungary; (Z.A.-T.); (G.R.); (I.F.)
- Department of Biostatistics, University of Veterinary Medicine, 1078 Budapest, Hungary
| | - Zoltán Kiss
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, 7624 Pécs, Hungary; (Z.K.); (G.A.M.); (G.S.)
| | - György Jermendy
- Department of Internal Medicine, Bajcsy-Zsilinszky Hospital, 1106 Budapest, Hungary;
| | - Péter Kempler
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1089 Budapest, Hungary;
| | - Csaba Lengyel
- Department of Internal Medicine, University of Szeged, 6720 Szeged, Hungary;
| | - István Wittmann
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, 7624 Pécs, Hungary; (Z.K.); (G.A.M.); (G.S.)
| | - Gergő A. Molnár
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, 7624 Pécs, Hungary; (Z.K.); (G.A.M.); (G.S.)
| | - Gábor Sütő
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, 7624 Pécs, Hungary; (Z.K.); (G.A.M.); (G.S.)
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5
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Khoa Ta HD, Nguyen NN, Ho DKN, Nguyen HD, Ni YC, Yee KX, Pan SR, Nguyen HS, Thai Hoang Phuoc T, Chen MJ, Lee KH. Association of diabetes mellitus with early-onset colorectal cancer: A systematic review and meta-analysis of 19 studies including 10 million individuals and 30,000 events. Diabetes Metab Syndr 2023; 17:102828. [PMID: 37490785 DOI: 10.1016/j.dsx.2023.102828] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/28/2023] [Accepted: 07/02/2023] [Indexed: 07/27/2023]
Abstract
BACKGROUND AND AIMS Early-onset colorectal cancer (EoCRC) constitutes 2%-10% of all colorectal cancers and is becoming more common globally. Diabetes mellitus (DM) has increased substantially in younger adults; however, its involvement in EoCRC remains unclear. We conducted a systematic review and meta-analysis of observational studies to (1) explore the prevalence of DM in individuals with EoCRC and (2) investigate the association between DM and EoCRC. METHODS A systematic literature search was conducted to identify studies published before May 2022 that evaluated the association between DM and EoCRC risk in four databases, including Medline (PubMed), Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. Results from the studies were summarized in meta-analyses using random effects models. RESULTS Nineteen eligible studies were included. A total of 33,359 EoCRC cases and 14,259,289 controls in 12 studies were included in the meta-analysis. The pooled odds ratio [OR] of 1.43 (95% confidence interval [CI]: 1.08-1.8) indicated significant positive association between DM and increased risk of EoCRC. Subgroup analysis demonstrated that diabetes severity was significantly associated with unmanaged DM (OR = 1.28, 95% CI: 1.02-1.6), but not with managed DM (OR = 1.04, 95% CI: 0.84-1.28). CONCLUSION Our results suggest that DM is a risk factor for EoCRC, and the higher prevalence of DM among younger adults may contribute to the increasing incidence of EoCRC. Interventions to reduce this bidirectional risk should be further investigated for the development of effective prevention and treatment strategies. PROSPERO registration: CRD42022306347.
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Affiliation(s)
- Hoang Dang Khoa Ta
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Nam Nhat Nguyen
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Dang Khanh Ngan Ho
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Hieu Duc Nguyen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yi-Chun Ni
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Ke Xin Yee
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Syu-Ruei Pan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Hung Song Nguyen
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Pediatrics, Division of Infectious Disease, University of Medicine Pham Ngoc Thach, Ho Chi Minh City, Viet Nam; Infectious Disease Department, Children's Hospital 2, Ho Chi Minh City, Viet Nam; Department of Pediatrics, Vinmec Central Park International Hospital, Viet Nam
| | | | - Ming-Jenn Chen
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan; Department of Sports Management, College of Leisure and Recreation Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
| | - Kuen-Haur Lee
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
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6
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Dong W, Kim U, Rose J, Hoehn RS, Kucmanic M, Eom K, Li S, Berger NA, Koroukian SM. Geographic Variation and Risk Factor Association of Early Versus Late Onset Colorectal Cancer. Cancers (Basel) 2023; 15:1006. [PMID: 36831350 PMCID: PMC9954005 DOI: 10.3390/cancers15041006] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023] Open
Abstract
The proportion of patients diagnosed with colorectal cancer (CRC) at age < 50 (early-onset CRC, or EOCRC) has steadily increased over the past three decades relative to the proportion of patients diagnosed at age ≥ 50 (late-onset CRC, or LOCRC), despite the reduction in CRC incidence overall. An important gap in the literature is whether EOCRC shares the same community-level risk factors as LOCRC. Thus, we sought to (1) identify disparities in the incidence rates of EOCRC and LOCRC using geospatial analysis and (2) compare the importance of community-level risk factors (racial/ethnic, health status, behavioral, clinical care, physical environmental, and socioeconomic status risk factors) in the prediction of EOCRC and LOCRC incidence rates using a random forest machine learning approach. The incidence data came from the Surveillance, Epidemiology, and End Results program (years 2000-2019). The geospatial analysis revealed large geographic variations in EOCRC and LOCRC incidence rates. For example, some regions had relatively low LOCRC and high EOCRC rates (e.g., Georgia and eastern Texas) while others had relatively high LOCRC and low EOCRC rates (e.g., Iowa and New Jersey). The random forest analysis revealed that the importance of community-level risk factors most predictive of EOCRC versus LOCRC incidence rates differed meaningfully. For example, diabetes prevalence was the most important risk factor in predicting EOCRC incidence rate, but it was a less important risk factor of LOCRC incidence rate; physical inactivity was the most important risk factor in predicting LOCRC incidence rate, but it was the fourth most important predictor for EOCRC incidence rate. Thus, our community-level analysis demonstrates the geographic variation in EOCRC burden and the distinctive set of risk factors most predictive of EOCRC.
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Affiliation(s)
- Weichuan Dong
- Population Cancer Analytics Shared Resource and Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Uriel Kim
- Population Cancer Analytics Shared Resource and Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Kellogg School of Management, Northwestern University, Evanston, IL 60208, USA
- Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Johnie Rose
- Population Cancer Analytics Shared Resource and Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Richard S. Hoehn
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Matthew Kucmanic
- Department of Geographical and Sustainability Sciences, University of Iowa, Iowa City, IA 52242, USA
| | - Kirsten Eom
- MetroHealth Cancer Center, Cleveland, OH 44109, USA
| | - Shu Li
- School of Digital Sciences, Kent State University, Kent, OH 44240, USA
| | - Nathan A. Berger
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Center for Science, Health and Society, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Siran M. Koroukian
- Population Cancer Analytics Shared Resource and Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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7
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Ngalim SH, Yusoff N, Johnson RR, Abdul Razak SR, Chen X, Hobbs JK, Lee YY. A review on mechanobiology of cell adhesion networks in different stages of sporadic colorectal cancer to explain its tumorigenesis. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2022; 175:63-72. [PMID: 36116549 DOI: 10.1016/j.pbiomolbio.2022.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/07/2022] [Accepted: 09/12/2022] [Indexed: 06/15/2023]
Abstract
Sporadic colorectal cancer (CRC) is strongly linked to extraneous factors, like poor diet and lifestyle, but not to inherent factors like familial genetics. The changes at the epigenomics and signalling pathways are known across the sporadic CRC stages. The catch is that temporal information of the onset, the feedback loop, and the crosstalk of signalling and noise are still unclear. This makes it challenging to diagnose and treat colon cancer effectively with no relapse. Various microbial cells and native cells of the colon, contribute to sporadic CRC development. These cells secrete autocrine and paracrine for their bioenergetics and communications with other cell types. Imbalances of the biochemicals affect the epithelial lining of colon. One side of this epithelial lining is interfacing the dense colon tissue, while the other side is exposed to microbiota and excrement from the lumen. Hence, the epithelial lining is prone to tumorigenesis due to the influence of both biochemical and mechanical cues from its complex surrounding. The role of physical transformations in tumorigenesis have been limitedly discussed. In this context, cellular and tissue structures, and force transductions are heavily regulated by cell adhesion networks. These networks include cell anchoring mechanism to the surrounding, cell structural integrity mechanism, and cell effector molecules. This review will focus on the progression of the sporadic CRC stages that are governed by the underlaying cell adhesion networks within the epithelial cells. Additionally, current and potential technologies and therapeutics that target cell adhesion networks for treatments of sporadic CRC will be incorporated.
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Affiliation(s)
- Siti Hawa Ngalim
- Advanced Medical and Dental Institute, Universiti Sains Malaysia (USM) Bertam, 13200 Kepala Batas, Penang, Malaysia.
| | - Norwahida Yusoff
- School of Mechanical Engineering, Universiti Sains Malaysia (USM) Engineering Campus, 14300 Nibong Tebal, Penang, Malaysia
| | - Rayzel Renitha Johnson
- Advanced Medical and Dental Institute, Universiti Sains Malaysia (USM) Bertam, 13200 Kepala Batas, Penang, Malaysia
| | - Siti Razila Abdul Razak
- Advanced Medical and Dental Institute, Universiti Sains Malaysia (USM) Bertam, 13200 Kepala Batas, Penang, Malaysia
| | - Xinyue Chen
- Department of Physics and Astronomy, University of Sheffield, Hounsfield Road, Sheffield, S3 7RH, United Kingdom
| | - Jamie K Hobbs
- Department of Physics and Astronomy, University of Sheffield, Hounsfield Road, Sheffield, S3 7RH, United Kingdom
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia (USM) Kubang Kerian, 16150 Kota Bharu, Kelantan, Malaysia
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8
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El-Sayed NNE, Almaneai NM, Ben Bacha A, El-Ashrey MK, Al-Zaben MI, Almarhoon ZM. Biological Evaluation, Molecular Docking Analyses, and ADME Profiling of Certain New Quinazolinones as Anti-colorectal Agents. ACS OMEGA 2022; 7:18443-18458. [PMID: 35694504 PMCID: PMC9178606 DOI: 10.1021/acsomega.2c00812] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/29/2022] [Indexed: 06/15/2023]
Abstract
Colorectal carcinogenesis is a complex process, which is linked to dysregulation of human secretory phospholipases A2 (hsPLA2-G-IIA, hsPLA2-G-V, and hsPLA2-G-X), proteases (cathepsin-B, collagenase, thrombin, elastase, and trypsin), carbohydrate hydrolyzing enzymes (α-amylase and α-glucosidase), and free radical generating enzyme (xanthine oxidoreductase (XOR)). Therefore, some new quinazolinones were synthesized and evaluated as inhibitors against this array of enzymes as well as cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer. Compounds 3g, 10, 8, 3c, and 1c exhibited promising cytotoxic effects with IC50 values ranging from 206.07 to 459.79 μM. Nine compounds showed promising enzymatic inhibitory effects, 3b, 3d, 3f, 5, 1a, and 12 (α-amylase), 8 (thrombin, elastase and trypsin), 10 (hsPLA2-G-IIA and hsPLA2-G-V), and 3f (α-glucosidase and XOR). Therefore, the most active inhibitors, were subjected to validated molecular docking studies to identify their affinities and binding modes. The expected physicochemical and pharmacokinetic features of the active candidates, 1a, 1c, 3b, 3c, 3d, 3f, 3g, 5, 8, 10, and 12 were predicted using bioavailability radar charts and boiled-egg graphical representations along with the Lipinski rule of five filter. Collectively, these studies showed the significance of derivatives 1c, 3b, 3c, 3d, 8, 10, and 12 as lead scaffolds for further optimization to develop enzymes inhibitors and anti-colorectal agents.
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Affiliation(s)
- Nahed N. E. El-Sayed
- National
Organization for Drug Control and Research, Egyptian Drug Authority, 51 Wezaret El-Zerra Street, Giza 35521, Egypt
| | - Norah M. Almaneai
- Department
of Chemistry, College of Science, King Saud
University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Abir Ben Bacha
- Biochemistry
Department, College of Science, King Saud
University, P. O. Box 22452, Riyadh 11495, Saudi Arabia
- Laboratory
of Plant Biotechnology Applied to Crop Improvement, Faculty of Science
of Sfax, University of Sfax, Sfax 3038, Tunisia
| | - Mohamed K. El-Ashrey
- Pharmaceutical
Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini Street, Cairo 11562, Egypt
- Medicinal
Chemistry Department, Faculty of Pharmacy, King Salman International University, Ras-Sedr, South Sinai, Egypt
| | - Maha I. Al-Zaben
- Department
of Chemistry, College of Science, King Saud
University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Zainab M. Almarhoon
- Department
of Chemistry, College of Science, King Saud
University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
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9
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Xiao W, Huang J, Zhao C, Ding L, Wang X, Wu B. Diabetes and Risks of Right-Sided and Left-Sided Colon Cancer: A Meta-Analysis of Prospective Cohorts. Front Oncol 2022; 12:737330. [PMID: 35463382 PMCID: PMC9021717 DOI: 10.3389/fonc.2022.737330] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 03/17/2022] [Indexed: 11/22/2022] Open
Abstract
Background and Aims Diabetes is associated with an increased risk of colon cancer (CC). Epidemiologic studies previously reported a higher risk for right-sided colon cancer (RCC) compare to left-sided colon cancer (LCC), although data are conflicting. We performed a meta-analysis to investigate this issue. Methods We systematically searched the PubMed, EMBASE, Web of Science and Cochrane Library database for prospective cohort studies published up to June 2021. Studies were included if they reported site-specific estimates of the relative risk (RR) between diabetes and the risks of RCC and LCC. Random effects meta-analyses with inverse variance weighting were used to estimate the pooled site-specific RRs and the RCC-to-LCC ratio of RRs (RRRs). Results Data from 10 prospective cohort studies, representing 1,642,823 individuals (mainly white) and 17,624 CC patients, were included in the analysis. Diabetes was associated with an increased risk of both RCC (RR =1.35, 95% CI = 1.24-1.47) and LCC (RR = 1.18, 95% CI = 1.08-1.28). After adjusting for major risk factors, individuals with diabetes had a greater risk for RCC than for LCC (RRR = 1.13, 95% CI = 1.02-1.26), with no significant heterogeneity between studies (I2 = 0%). Conclusions This meta-analysis indicates that diabetes is associated with a higher risk for RCC than for LCC. Our findings suggest that colonoscopic surveillance in diabetic patients with careful examination of the right colon is warranted.
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Affiliation(s)
- Wenxuan Xiao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinglong Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chuanyi Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Ding
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuan Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bian Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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10
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Affiliation(s)
- Frank A Sinicrope
- From the Departments of Oncology and Medicine, Mayo Clinic Alix School of Medicine, Mayo Comprehensive Cancer Center, Rochester, MN
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11
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Loponte HF, Oliveira IA, Rodrigues BC, Nunes-da-Fonseca R, Mohana-Borges R, Alisson-Silva F, Dias WB, Todeschini AR. Hyperglycemia alters N-glycans on colon cancer cells through increased production of activated monosaccharides. Glycoconj J 2022; 39:663-675. [PMID: 35380345 DOI: 10.1007/s10719-022-10057-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/26/2022] [Accepted: 03/09/2022] [Indexed: 12/01/2022]
Abstract
Diabetes Mellitus (DM) is both, correlated and a known risk factor for colorectal cancer (CRC). Besides favoring the incidence of CRC, DM also accelerates its progression, worsening its prognosis. Previously, hyperglycemia, the DM hallmark, has been shown to lead to aberrant glycosylation of CRC cells, heightening their malignancy both in vivo and in vitro. Here we use mass spectrometry to elucidate the composition and putative structures of N-glycans expressed by MC38 cultured in normoglycemic (LG) and hyperglycemic-like conditions (HG). N-glycans, 67, were identified in MC38 cells cultured in LG and HG. The cells grown in HG showed a greater abundance of N-glycans when compared to LNG cells, without changes in the proportion of sialylated, fucosylated and mannosylated N-glycans. Among the identified N-glycans, 16 were differentially expressed, mostly mannosylated and fucosylated, with a minority of them being sialylated. Metabolomics analysis indicates that the alterations observed in the N-glycosylation may be mostly due to increase of the activated monosaccharides pool, through an increased glucose entrance into the cells. The alterations found here corroborate data from the literature regarding the progression of CRC, advocating for development or repositioning of effective treatments against CRC in diabetic patients.
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Affiliation(s)
- H F Loponte
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil.,Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil
| | - I A Oliveira
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil
| | - B C Rodrigues
- Instituto de Biodiversidade e Sustentabilidade, Universidade Federal do Rio de Janeiro, 27965‑550, Macaé, Brazil
| | - R Nunes-da-Fonseca
- Instituto de Biodiversidade e Sustentabilidade, Universidade Federal do Rio de Janeiro, 27965‑550, Macaé, Brazil
| | - R Mohana-Borges
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil
| | - F Alisson-Silva
- Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil
| | - W B Dias
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil
| | - A R Todeschini
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil.
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12
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Zhou H, Beltrán JF, Brito IL. Host-microbiome protein-protein interactions capture disease-relevant pathways. Genome Biol 2022; 23:72. [PMID: 35246229 PMCID: PMC8895870 DOI: 10.1186/s13059-022-02643-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 02/22/2022] [Indexed: 01/02/2023] Open
Abstract
Background Host-microbe interactions are crucial for normal physiological and immune system development and are implicated in a variety of diseases, including inflammatory bowel disease (IBD), colorectal cancer (CRC), obesity, and type 2 diabetes (T2D). Despite large-scale case-control studies aimed at identifying microbial taxa or genes involved in pathogeneses, the mechanisms linking them to disease have thus far remained elusive. Results To identify potential pathways through which human-associated bacteria impact host health, we leverage publicly-available interspecies protein-protein interaction (PPI) data to find clusters of microbiome-derived proteins with high sequence identity to known human-protein interactors. We observe differential targeting of putative human-interacting bacterial genes in nine independent metagenomic studies, finding evidence that the microbiome broadly targets human proteins involved in immune, oncogenic, apoptotic, and endocrine signaling pathways in relation to IBD, CRC, obesity, and T2D diagnoses. Conclusions This host-centric analysis provides a mechanistic hypothesis-generating platform and extensively adds human functional annotation to commensal bacterial proteins. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-022-02643-9.
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Affiliation(s)
- Hao Zhou
- Department of Microbiology, Cornell University, Ithaca, NY, USA
| | - Juan Felipe Beltrán
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Ilana Lauren Brito
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
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13
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Venugopal A, Carethers JM. Epidemiology and biology of early onset colorectal cancer. EXCLI JOURNAL 2022; 21:162-182. [PMID: 35221839 PMCID: PMC8859644 DOI: 10.17179/excli2021-4456] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in men or women in the United States. Average-risk screening that begins at age 50 years has reduced incidence and mortality of CRC in those over 50 years of age, whereas CRC incidence in those under age 50 years (early onset colorectal cancer (eoCRC)) has recently and dramatically increased. In this review, we summarize the recent literature including risk factors for eoCRC, differences in clinicopathologic presentation and outcomes in eoCRC, and emerging evidence regarding the molecular pathways that are altered in eoCRC compared to later onset CRC (loCRC). Epidemiologic studies of eoCRC show predominance in distal colon and rectum, and association with several modifiable risk factors, including diabetes, obesity, diet, sedentary time, alcohol consumption and smoking. Data regarding potential risk factors of prior antibiotic exposure and microbiome alterations or direct carcinogen exposure are still emerging. Aggressive clinicopathologic features of eoCRC at presentation may be due to delay in diagnosis or more aggressive tumor biology. EoCRC outcomes are similar to loCRC when matched for stage, but overall mortality is greater due to higher frequency of advanced disease at a younger presentation, with more life-years lost. There are only few molecular evaluations of eoCRC to date, with findings of potential increase in TP53 and CTNNB1 somatic mutation and decrease in APC, KRAS and BRAF somatic mutation, compared to loCRC. Other findings include LINE-1 hypomethylation, absence of microsatellite instability (MSI-H), presence of chromosomal instability (CIN) or microsatellite and chromosomal stability (MACS). These studies are only now emerging and have not yet identified a specific molecular signature defining eoCRC. Further research evaluating genetic and molecular differences as well as environmental triggers for eoCRCs should provide a clearer understanding to inform targeted screening for pre-symptomatic at-risk younger individuals.
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Affiliation(s)
- Anand Venugopal
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - John M Carethers
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Department of Human Genetics and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
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14
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Ranasinghe R, Mathai M, Zulli A. A synopsis of modern - day colorectal cancer: Where we stand. Biochim Biophys Acta Rev Cancer 2022; 1877:188699. [DOI: 10.1016/j.bbcan.2022.188699] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023]
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15
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Popescu-Vâlceanu HC, Stoicea MC, Enache V, Bratu RM, Mustăţea P, Drăguţ RM, Rusu E, Ionescu-Tîrgovişte C, Radulian G. Bcl-2 and p53 immunophenotypes in colorectal adenocarcinoma in type 2 diabetes mellitus versus non-diabetic patients. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2022; 63:521-528. [PMID: 36588490 PMCID: PMC9926153 DOI: 10.47162/rjme.63.3.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
We aimed to investigate immunohistochemical expression of the p53 tumor suppressor protein, and the B-cell lymphoma-2 (Bcl-2) apoptotic protein in colorectal adenocarcinoma patients with or without type 2 diabetes mellitus (T2DM). Tissue sections from 95 paraffin-embedded colorectal adenocarcinomas, originating from 52 T2DM and 43 non-diabetic patients, were immunostained for p53 [Ventana mouse monoclonal primary antibody (mAb) in vitro diagnostic (IVD) anti-p53, clone Bp53-11] and Bcl-2 (Ventana mAb IVD anti-Bcl-2, clone Bcl-2/124). Immunohistochemistry analysis did not find statistically significant differences between the two groups, but analysis on subgroups of patients in terms of presence or absence of obesity identified overexpression of p53 (>70% of cells) in the T2DM obese patients compared to non-diabetics. Overexpression of p53 was present in 80% of tumor cells coming from T2DM obese patients compared to 37.2% of tumor cells coming from non-diabetics obese and non-obese, and in 36.6% of tumor cells coming from non-diabetic non-obese patients (p=0.024). There was a single non-diabetic obese patient with p53 overexpression. Most cancer cells of T2DM obese patients presented more frequently p53 overexpression by comparison with cancer cells of the T2DM non-obese patients (80% vs 40.5%, p=0.028). Bcl-2/p53 co-expression was an infrequent event in T2DM patients' group. The results of this study suggest that patients with colorectal adenocarcinoma that associate T2DM and obesity exhibit higher p53 protein expression in malignant cells. In conclusion, our research highlights that obesity is a potential key factor in the relationship between T2DM and colorectal cancer.
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Affiliation(s)
| | - Mihai Ciprian Stoicea
- Department of Pathology, Regina Maria Central Reference Laboratory, Bucharest, Romania
| | - Valentin Enache
- Department of Pathology, Emergency Clinical Hospital, Bucharest, Romania
| | - Răzvan Matei Bratu
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Petronel Mustăţea
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Ramona Maria Drăguţ
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Emilia Rusu
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Constantin Ionescu-Tîrgovişte
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania , Department of Diabetes, Nutrition and Metabolic Diseases, Prof. Dr. N. C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
| | - Gabriela Radulian
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania , Department of Diabetes, Nutrition and Metabolic Diseases, Prof. Dr. N. C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
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16
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Diabetes mellitus Typ 2 und Krebserkrankungen. DIABETOLOGE 2021. [DOI: 10.1007/s11428-021-00819-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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17
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Elangovan A, Skeans J, Landsman M, Ali SMJ, Elangovan AG, Kaelber DC, Sandhu DS, Cooper GS. Colorectal Cancer, Age, and Obesity-Related Comorbidities: A Large Database Study. Dig Dis Sci 2021; 66:3156-3163. [PMID: 32954457 DOI: 10.1007/s10620-020-06602-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The association between obesity and colorectal cancer (CRC) is well established in older individuals, but evidence is limited in the younger population. The study aims to analyze the relationship of obesity and its related comorbidities in early-onset CRC (E-CRC) and compare it to late-onset CRC (L-CRC). METHODS A retrospective, cross-sectional study was performed on average-risk individuals ≥ 20 years who were active patients in the commercial database, IBM Watson Health Explorys in the last 5 years. Individuals with CRC were compared to those without CRC across different age groups (20-39, 40-49, and 50-74 years). Individuals with CRC diagnosed < 50 years (E-CRC) were compared to those with CRC between 50 and 74 years (L-CRC). Variables included sex, smoking, obese BMI, diabetes mellitus type 2 (DM2), hypertension (HTN), and hyperlipidemia (HLD). Since Explorys aggregates population-level, de-identified data, approval from institutional review board was not required. RESULTS Among 37,483,140 individuals, 162,150 cases of sporadic CRC were identified. Compared to the general population, obesity and HLD were independent risk factors for CRC across all age groups; DM2, HTN, and smoking were independent risk factors for CRC in men of all age groups and women with L-CRC. Compared to L-CRC, individuals with E-CRC had lower percentages of obesity-related comorbidities. CONCLUSION In E-CRC, obesity, DM2, HTN, HLD, and smoking are independent risk factors for CRC among men; obesity and HLD are independent risk factors for CRC in women. These subgroups may benefit from a personalized screening approach to detect early-onset CRC.
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Affiliation(s)
- Abbinaya Elangovan
- Department of Internal Medicine-Pediatrics, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Jacob Skeans
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Marc Landsman
- Department of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Sajjadh M J Ali
- Department of Internal Medicine, Saint Vincent Hospital, Worchester, MA, USA
| | | | - David C Kaelber
- Department of Internal Medicine-Pediatrics, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Dalbir S Sandhu
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gregory S Cooper
- Division of Gastroenterology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Wearn 244, Cleveland, OH, 44106-5066, USA.
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18
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Wu J, He H, Zhang Q, Zhang Y. Fasting blood glucose was linearly associated with colorectal cancer risk in the population without self-reported diabetes mellitus history. Medicine (Baltimore) 2021; 100:e26974. [PMID: 34449465 PMCID: PMC8389900 DOI: 10.1097/md.0000000000026974] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/30/2021] [Indexed: 01/04/2023] Open
Abstract
Fasting plasma glucose level was linearly associated with colorectal cancer (CRC) risk. However, the dose-response relationship between fasting blood glucose (FBG) and CRC risk was still uncertain.A total of 11,632 patients without self-reported diabetes mellitus and colorectal polyps' history were identified in the Korean Multicenter Cancer Cohort (1993-2005). The nonlinear relationship was estimated through a restricted cubic spline regression, and a two-piece-wise Cox proportional hazards model was further performed to calculate the threshold effect. Multiple imputation was used to control the bias from missing data.Overall, 1.1% (n = 132) of participants were diagnosed with CRC in the follow-up duration. With a median follow-up duration of 12.0 years, participants with FBG ≥126 mg/dL were associated with higher CRC risk (adjusted hazard ratio [HR], 1.67; 95% confidence interval [CI]: 1.01, 2.76). Landmark analyses limited to long-term survivors demonstrated increased CRC risk with FBG ≥ 126 mg/dL in all subsets (≥3years: HR,1.93 (95% CI: 1.13-3.29); ≥5years: HR, 2.04 (95% CI: 1.-3.63); ≥10years: HR, 2.50 (95% CI: 1.19-5.25)). With FBG smoothly increasing before, the latter increased dramatically after the turning point (P for nonlinearity = 0.283). When FBG was increasing per mmol/L, HR was 1.07(95% CI: 0.90, 1.29) for FBG < 126 mg/dL and 1.27 (95% CI: 1.06, 1.53) for FBG ≥ 126 mg/dL. Besides, HR was 1.09 (95% CI: 1.02, 1.16) for the CRC risk.In the population without self-reported diabetes mellitus and colorectal polyps' history. FBG was linearly associated with CRC risk, especially for FBG over 126 mg/dL.
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Affiliation(s)
- Jingjing Wu
- Department of Oncology, the 900th Hospital of Joint Logistic Support Force, PLA, Fuzong Clinical College of Fujian Medical University, Fuzhou, Fujian, PR China
| | - Huimin He
- Department of Oncology, the 900th Hospital of Joint Logistic Support Force, PLA, Fuzong Clinical College of Fujian Medical University, Fuzhou, Fujian, PR China
| | - Qi Zhang
- Department of Natural Medicine, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, PR China
| | - Yan Zhang
- Department of Oncology, the 900th Hospital of Joint Logistic Support Force, PLA, Fuzong Clinical College of Fujian Medical University, Fuzhou, Fujian, PR China
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19
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Done JZ, Fang SH. Young-onset colorectal cancer: A review. World J Gastrointest Oncol 2021; 13:856-866. [PMID: 34457191 PMCID: PMC8371519 DOI: 10.4251/wjgo.v13.i8.856] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/30/2021] [Accepted: 07/19/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the general decrease in overall incidence of colorectal cancer since the early 1990s, the incidence of colorectal cancer in patients less than 50 years old has nearly doubled. A systematic review was performed using the PubMed database (2011-2020) and Cochrane Database of Systematic Reviews (2011-2021) to identify studies (published in English) evaluating epidemiologic, clinical, hereditary, and molecular features; as well as evaluation, management, and prognosis of young-onset colorectal cancer patients. Our search yielded a total of 3401 articles, after applying our inclusion criteria. We fully reviewed 94 full-length studies. This systematic review demonstrates the increasing incidence of young-onset colorectal cancer and highlights the importance of being hypervigilant for the differential diagnosis colorectal cancer when evaluating a young adult who presents with gastrointestinal symptoms.
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Affiliation(s)
- Joy Zhou Done
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Sandy H Fang
- Department of Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287, United States
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20
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Yang F, Liang H, Rosenthal RJ, Wexner SD. The significant interaction between age and diabetes mellitus for colorectal cancer: Evidence from NHANES data 1999-2016. Prim Care Diabetes 2021; 15:518-521. [PMID: 33664013 DOI: 10.1016/j.pcd.2021.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/12/2021] [Accepted: 02/13/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Diabetes mellitus has been associated with elevated risk of colorectal cancer (CRC), although interaction between age and DM is unclear. We examined the relationship among DM, CRC and age. METHODS 22,580 subjects aged ≥18 years were identified from the National Health and Nutrition Examination Survey (NHANES) database collected between 1999-2016. To account for the complex, stratified, multistage probability sampling design in NHANES, SASv9.4 Procedure Survey Methodology was applied. Univariate analysis compared individual baseline characteristics between subjects with and without DM. Multivariate logistic regression model assessed association between DM and CRC, in which the model included factors with p<0.05 in univariate analysis as covariates. RESULTS Univariate analysis showed significant differences in age (p<0.0001), race (p<0.0001), smoking (p=0.0023) and body mass index (p<0.0001) between No-DM and DM. Multivariate analysis revealed significant interaction between age and DM (p=0.0004). Subjects with DM aged 18-65 were more likely to experience CRC (OR=4.47, 95%CI=(1.33-15.07); p=0.0157) compared to those without DM. Subjects with DM aged >65 were not at increased risk for CRC (OR=0.83, 95%CI=(0.43-1.59); p=0.5665) compared to those without DM. CONCLUSIONS Age, DM, and interaction between age and DM are risk factors for CRC. Individuals with DM aged 18-65 years have a higher CRC risk.
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Affiliation(s)
- Feng Yang
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL, USA
| | - Hong Liang
- Department of Clinical Research, Cleveland Clinic Florida, Weston, FL, USA
| | | | - Steven D Wexner
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL, USA.
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21
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Behavioral Risk Factors and Risk of Early-Onset Colorectal Cancer: Review of the Mechanistic and Observational Evidence. CURRENT COLORECTAL CANCER REPORTS 2021. [DOI: 10.1007/s11888-021-00465-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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22
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Wallace K, Nahhas GJ, Bookhout C, Lewin DN, Paulos CM, Nikolaishvili-Feinberg N, Cohen SM, Guglietta S, Bakhtiari A, Camp ER, Hill EG, Baron JA, Wu JD, Alekseyenko AV. Preinvasive Colorectal Lesions of African Americans Display an Immunosuppressive Signature Compared to Caucasian Americans. Front Oncol 2021; 11:659036. [PMID: 33987094 PMCID: PMC8112239 DOI: 10.3389/fonc.2021.659036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/29/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND African Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease. METHODS We selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch. RESULTS We observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001). CONCLUSIONS Overall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.
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Affiliation(s)
- Kristin Wallace
- Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC, United States
- Department of Public Health Sciences, MUSC, Charleston, SC, United States
| | - Georges J. Nahhas
- Department of Public Health Sciences, MUSC, Charleston, SC, United States
- Department of Psychiatry and Behavioral Sciences, MUSC, Charleston, SC, United States
| | - Christine Bookhout
- Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
| | - David N. Lewin
- Department of Pathology and Laboratory Medicine, MUSC, Charleston, SC, United States
| | - Chrystal M. Paulos
- Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC, United States
- Department of Microbiology/Immunology, Emory University School of Medicine, Atlanta, GA, United States
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | | | - Stephanie M. Cohen
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States
| | - Silvia Guglietta
- Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC, United States
| | - Ali Bakhtiari
- Department of Public Health Sciences, MUSC, Charleston, SC, United States
| | - E. Ramsay Camp
- Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC, United States
| | - Elizabeth G. Hill
- Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC, United States
- Department of Public Health Sciences, MUSC, Charleston, SC, United States
| | - John A. Baron
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States
| | - Jennifer D. Wu
- Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Alexander V. Alekseyenko
- Department of Public Health Sciences, MUSC, Charleston, SC, United States
- Bioinformatics Center, MUSC, Charleston, SC, United States
- Department of Oral Health Sciences, MUSC, Charleston, SC, United States
- Department of Healthcare Leadership and Management, MUSC, Charleston, SC, United States
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Holowatyj AN, Viskochil R, Ose D, Tingey B, Haaland B, Wilson D, Larson M, Feltz S, Lewis MA, Colman H, Ulrich CM. Diabetes, Body Fatness, and Insulin Prescription Among Adolescents and Young Adults with Cancer. J Adolesc Young Adult Oncol 2021; 10:217-225. [PMID: 32749900 PMCID: PMC8064923 DOI: 10.1089/jayao.2020.0071] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Purpose: Rates of obesity and obesity-related health consequences, including type 2 diabetes (T2D) and cancer, continue to rise. While cancer patients are at an increased risk of developing T2D, the prevalence of T2D and insulin prescription among young patients with cancer remains unknown. Methods: Using the Total Cancer Care Study cohort at Huntsman Cancer Institute (Salt Lake City, UT), we identified individuals age 18-39 years at cancer diagnosis between 2009 and 2019. Multivariable logistic regression was used to investigate associations between body mass index (BMI) with insulin prescription within 1 year of cancer diagnosis. Results: In total, 344 adolescents and young adults (AYAs) were diagnosed with primary invasive cancer. Within this cohort, 19 patients (5.5%) were ever diagnosed with T2D, 48 AYAs ever received an insulin prescription (14.0%), and 197 were overweight or obese (BMI: 25+ kg/m2) at cancer diagnosis. Each kg/m2 unit increase in BMI was associated with 6% increased odds of first insulin prescription within 1 year of cancer diagnosis among AYAs, even after adjustment for age, sex, smoking history, marital status, glucocorticoid prescription, and cancer treatments (odds ratio = 1.06, 95% confidence interval 1.02-1.11; p = 0.005). Conclusion: One in every 18 AYAs with cancer ever had T2D, 1 in 7 AYA patients with cancer ever received an insulin prescription, and higher BMI was associated with increased risk of insulin prescription within a year of cancer diagnosis among AYAs. Understanding the incidence of T2D and insulin prescription/use is critical for short-term and long-term clinical management of AYAs with cancer.
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Affiliation(s)
- Andreana N. Holowatyj
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
- Huntsman Cancer Institute, Salt Lake City, Utah, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Richard Viskochil
- Huntsman Cancer Institute, Salt Lake City, Utah, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Dominik Ose
- Huntsman Cancer Institute, Salt Lake City, Utah, USA
- Department of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Benjamin Tingey
- Department of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Benjamin Haaland
- Huntsman Cancer Institute, Salt Lake City, Utah, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Dalton Wilson
- Huntsman Cancer Institute, Salt Lake City, Utah, USA
| | | | - Sara Feltz
- Data Science Services, University of Utah, Salt Lake City, Utah, USA
| | - Mark A. Lewis
- Department of Internal Medicine, Intermountain Healthcare, Murray, Utah, USA
| | - Howard Colman
- Huntsman Cancer Institute, Salt Lake City, Utah, USA
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
- Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA
| | - Cornelia M. Ulrich
- Huntsman Cancer Institute, Salt Lake City, Utah, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
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24
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Storey S, Zhang Z, Luo X, Von Ah D, Metzger M, Zhang J, Jakka A, Huang K. Association of Comorbid Diabetes With Clinical Outcomes and Healthcare Utilization in Colorectal Cancer Survivors. Oncol Nurs Forum 2021; 48:195-206. [PMID: 33600395 DOI: 10.1188/21.onf.195-206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVES To compare clinical outcomes and healthcare utilization in colorectal cancer (CRC) survivors with and without diabetes. SAMPLE & SETTING CRC survivors (N = 3,287) were identified from a statewide electronic health record database using International Classification of Diseases (ICD) codes. Data were extracted on adults aged 21 years or older with an initial diagnosis of stage II or III CRC with diabetes present before CRC diagnosis or no diagnosis of diabetes (control). METHODS & VARIABLES ICD codes were used to extract diabetes diagnosis and clinical outcome variables. Healthcare utilization was determined by encounter type. Data were analyzed using descriptive statistics, multivariable logistic, and Cox regression. RESULTS CRC survivors with diabetes were more likely to develop anemia and infection than CRC survivors without diabetes. In addition, CRC survivors with diabetes were more likely to utilize emergency resources sooner than CRC survivors without diabetes. IMPLICATIONS FOR NURSING Oncology nurses can facilitate the early identification of high-risk survivor groups, reducing negative clinical outcomes and unnecessarily high healthcare resource utilization in CRC survivors with diabetes.
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Affiliation(s)
| | | | - Xiao Luo
- Indiana University-Purdue University Indianapolis
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25
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Mikaeel RR, Symonds EL, Kimber J, Smith E, Horsnell M, Uylaki W, Tapia Rico G, Hewett PJ, Yong J, Tonkin D, Jesudason D, Poplawski NK, Ruszkiewicz AR, Drew PA, Hardingham JE, Wong S, Frank O, Tomita Y, Patel D, Vatandoust S, Townsend AR, Roder D, Young GP, Parry S, Tomlinson IP, Wittert G, Wattchow D, Worthley DL, Brooks WJ, Price TJ, Young JP. Young-onset colorectal cancer is associated with a personal history of type 2 diabetes. Asia Pac J Clin Oncol 2021; 17:131-138. [PMID: 32885561 DOI: 10.1111/ajco.13428] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 06/20/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC). METHODS The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions. RESULTS The median age of YOCRC cases was 44 years (18-54) and of controls was 45 years (18-54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0-9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen. CONCLUSIONS Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients. IMPACT A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate.
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Affiliation(s)
- Reger R Mikaeel
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- SAHMRI Colorectal Node, Basil Hetzel Institute, Woodville South, South Australia, Australia
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
- Biology Department, College of Science, University of Duhok, Duhok, Kurdistan, Iraq
| | - Erin L Symonds
- Bowel Health Service, Flinders Medical Centre, Bedford Park, South Australia, Australia
- Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, South Australia, Australia
| | - James Kimber
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Eric Smith
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- University of Adelaide Department of Surgery, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Mehgan Horsnell
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Wendy Uylaki
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- Department of Gastroenterology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Gonzalo Tapia Rico
- Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, Australia
| | - Peter J Hewett
- University of Adelaide Department of Surgery, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Jonathan Yong
- University of Adelaide Department of Surgery, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Darren Tonkin
- University of Adelaide Department of Surgery, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - David Jesudason
- Department of Endocrinology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Nicola K Poplawski
- Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- Discipline of Paediatrics, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Andrew R Ruszkiewicz
- Division of Anatomical Pathology, SA Pathology, Adelaide, South Australia, Australia
- Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia
| | - Paul A Drew
- University of Adelaide Department of Surgery, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Jenny E Hardingham
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- SAHMRI Colorectal Node, Basil Hetzel Institute, Woodville South, South Australia, Australia
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Stephanie Wong
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Oliver Frank
- Discipline of General Practice, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Yoko Tomita
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Dainik Patel
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
- Department of Medical Oncology, Lyell McEwin Hospital, Elizabeth Vale, South Australia, Australia
| | - Sina Vatandoust
- Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Amanda R Townsend
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - David Roder
- Cancer Epidemiology and Population Health, University of South Australia, Adelaide, South Australia, Australia
| | - Graeme P Young
- Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, South Australia, Australia
| | - Susan Parry
- New Zealand Familial GI Cancer Service, Auckland City Hospital, Auckland, New Zealand
- National Bowel Screening Programme, Ministry of Health, New Zealand
| | - Ian P Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Gary Wittert
- Discipline of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - David Wattchow
- Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Daniel L Worthley
- South Australian Health & Medical Research Institute & School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - William J Brooks
- Adelaide Medical Solutions, Adelaide Health Solutions, Woodville, South Australia, Australia
| | - Timothy J Price
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Joanne P Young
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- SAHMRI Colorectal Node, Basil Hetzel Institute, Woodville South, South Australia, Australia
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
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26
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Kim DB, Lee KM, Lee JM, Ko SH, Han KD, Park YG. Waist circumference, body mass index, and colorectal cancer risk according to diabetes status: A Korean nationwide population-based cohort study. J Gastroenterol Hepatol 2021; 36:397-405. [PMID: 32542773 DOI: 10.1111/jgh.15152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 05/24/2020] [Accepted: 06/05/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM We investigated the relationship of BMI and waist circumference with the risk of colorectal cancer (CRC) using a population-based cohort database and to explore the relationship of CRC with diabetes status. METHODS Retrospective data (age >20 years) on anthropometric variables, blood parameters of fasting sugar, lipid levels, and blood pressure were collected from the National Health Insurance Corporation database between 2009 and 2012. Cox regression models were used to estimate hazard ratio (HR) and corresponding 95% confidence intervals (95% CI). RESULTS Of the 23 121 360 people studied, 120 579 were diagnosed with CRC after a median follow-up period of 5.4 years. Both waist circumference and body mass index were positively associated with increased risk of CRC, regardless of age or sex. After mutual adjustment, only waist circumference was significantly associated with increased risk of CRC (HR = 1.275, 95% CI: 1.205-1.349). When the risk of CRC was compared according to diabetes status among people with the same waist circumference range, risk of CRC was higher for those with worse diabetes status. CONCLUSION When waist circumference and body mass index were mutually adjusted, only waist circumference was associated with CRC risk. In addition, the risk of CRC is gradually higher in those with worsening diabetes, even if their waist circumferences are within the same range.
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Affiliation(s)
- Dae Bum Kim
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Kang-Moon Lee
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ji Min Lee
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung-Hyun Ko
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Kyung-Do Han
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yong Gyu Park
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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Assessing the relationship between institutional cancer and diabetes mortality rates using National Death Index data. Future Sci OA 2020; 6:FSO633. [PMID: 33312702 PMCID: PMC7720374 DOI: 10.2144/fsoa-2020-0055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Aim: To evaluate overall survival (OS), glycemic control in cancer patients with and without diabetes mellitus (DM). Patients & methods: Patients (2010–2015) with newly diagnosed prostate, breast, lung, colorectal and pancreatic cancers were identified in institutional cancer registry. Data linked to National Death Index for vital status. 5-year OS estimated; glucose and hemoglobin A1c assessed during year postdiagnosis. Results: We identified 1404 patients (non-DM, n = 936; DM, n = 468). DM cohort had 168 deaths (36%); non-DM, 267 (29%). 5-year OS estimated at 58% (95% CI: 53–64%) for DM and 67% (95% CI: 64–71%) for controls; for matched pairs, hazard ratio: 1.35 (95% CI: 1.02–1.79). Cancer did not harm glycemic control. Conclusion: OS among cancer patients with DM was lower than without DM. The aim of this study was to assess how diabetes mellitus (DM) and cancer interact to influence overall survival and glycemic control, through use of a national mortality database, the National Death Index. Institutional records of patients with prostate, lung, breast, colorectal and pancreatic cancers were linked to the National Death Index. Analyses showed that DM was associated with lower overall survival, but a diagnosis of cancer did not worsen glycemic control in patients with or without DM.
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28
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A clinical prediction nomogram to assess risk of colorectal cancer among patients with type 2 diabetes. Sci Rep 2020; 10:14359. [PMID: 32873885 PMCID: PMC7463255 DOI: 10.1038/s41598-020-71456-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 08/12/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer remains a major health burden worldwide and is closely related to type 2 diabetes. This study aimed to develop and validate a colorectal cancer risk prediction model to identify high-risk individuals with type 2 diabetes. Records of 930 patients with type 2 diabetes were reviewed and data were collected from 1 November 2013 to 31 December 2019. Clinical and demographic parameters were analyzed using univariable and multivariable logistic regression analysis. The nomogram to assess the risk of colorectal cancer was constructed and validated by bootstrap resampling. Predictors in the prediction nomogram included age, sex, other blood-glucose-lowering drugs and thiazolidinediones. The nomogram demonstrated moderate discrimination in estimating the risk of colorectal cancer, with Hosmer-Lemeshow test P = 0.837, an unadjusted C-index of 0.713 (95% CI 0.670-0.757) and a bootstrap-corrected C index of 0.708. In addition, the decision curve analysis demonstrated that the nomogram would be clinically useful. We have developed a nomogram that can predict the risk of colorectal cancer in patients with type 2 diabetes. The nomogram showed favorable calibration and discrimination values, which may help clinicians in making recommendations about colorectal cancer screening for patients with type 2 diabetes.
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Scheurlen KM, Billeter AT, O'Brien SJ, Galandiuk S. Metabolic dysfunction and early-onset colorectal cancer - how macrophages build the bridge. Cancer Med 2020; 9:6679-6693. [PMID: 33624450 PMCID: PMC7520341 DOI: 10.1002/cam4.3315] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
Background The incidence of colorectal cancer (CRC) among patients <50 years of age has increased dramatically over the last decades. At the same time, the growing proportion of obese children and adolescents and the increasing proportion of young and obese patients with CRC suggests an association between metabolic dysfunction and carcinogenesis. Tumor‐associated macrophages (TAMs) are able to orchestrate tumor promoting and suppressing mechanisms in CRC. The aim of this review was to discuss the different roles of TAMs in CRC and their phenotype‐specific metabolic pathways to identify potential new targets for CRC treatment. Methods A literature search was performed using PubMed, Cochrane and Embase to identify studies on TAMs and their metabolism in CRC. The following search terms were used in various combinations: (obesity OR adiposity OR obese) AND (macrophage OR polarization OR macrophage metabolism) AND ((colon cancer*) OR (colon carcinoma) OR (colonic tumor*) OR (colonic neoplasm[MeSH]) OR (rectal cancer*) OR (rectal carcinoma) OR (rectal tumor*) OR (rectal neoplasm[MeSH]) OR (colorectal cancer*) OR (colorectal carcinoma) OR (colorectal tumor*) OR (colorectal neoplasm[MeSH])). Studies including data on the phenotype and metabolism of TAMs in CRC were analyzed. Results Evidence for the prognostic utility of macrophage markers in CRC is currently evolving, with a particular role of stage‐dependent cellular metabolism profiles of TAMs. Itaconate is one of the metabolites produced by proinflammatory subtypes of TAMs and it is known to have tumor promoting effects. Metabolic pathways that are involved in macrophage activation and reprogramming play a role in a chronic inflammatory setting, consequently affecting the onset and development of CRC. Conclusions Tumor‐promoting metabolites, such as itaconate, are directly regulating these mechanisms, thereby triggering carcinogenesis. Metabolic reprogramming in TAMs can build a bridge between metabolic dysfunction and the onset and progression of CRC through inflammatory pathways, particularly in younger patients with early‐onset CRC.
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Affiliation(s)
- Katharina M Scheurlen
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Adrian T Billeter
- Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany
| | - Stephen J O'Brien
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA
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30
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Abstract
Debate is ongoing regarding the relationship between type 2 diabetes and cancer, and the pathways linking the two are incompletely understood. Some posit that the relationship hinges on a common predisposing factor such as obesity, insulin resistance, or chronic inflammation that increases the risk of cancer independently. Others speculate that diabetes acts as an independent risk factor for cancer because of other molecular pathways and interactions. Additionally, antidiabetic medications have been associated with changes in cancer risk. This review presents a summary of the latest studies and data concerning the relationships among type 2 diabetes, antidiabetic medications, cancer risk, and cancer prognosis.
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31
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Rennert G, Rennert HS, Gronich N, Pinchev M, Gruber SB. Use of metformin and risk of breast and colorectal cancer. Diabetes Res Clin Pract 2020; 165:108232. [PMID: 32446797 DOI: 10.1016/j.diabres.2020.108232] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 04/15/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diabetes has been associated with increased risk of cancer, including breast cancer and colorectal cancer. Metformin, an oral hypoglycemic drug, but not other anti-diabetic drugs, has been associated with reduced risk of breast and of colon cancers in some, but not in other, studies. METHODS Data from two large-scale, population-based, case-control studies of breast and colorectal cancers etiology, conducted in Northern Israel since 1998 were analyzed to evaluate the association between regular use (>3 times) of metformin prior to diagnosis and risk of developing cancer. The multivariate analyses for both cancer sites included age, family history of breast/colorectal cancer, history of diabetes, sports participation, fruits/vegetables consumption, aspirin and statins use, and for breast cancer, also included use of oral contraceptives and postmenopausal hormones and number of pregnancies. Use of metformin and diabetes status were determined based on valid electronic medical records of the participants. RESULTS Metformin use prior to diagnosis of cancer was associated with a decrease in risk of both breast cancer (OR = 0.821, 0.726-0.928, p = 0.002) and colorectal cancer (OR = 0.754, 0.623-0.912, p = 0.004). An inverse association was not identified with use of other anti-diabetic medications. Diabetes was found to be associated with risk of colorectal cancer (OR = 1.204, 1.014-1.431, p = 0.034) but not of breast cancer. No dose response by years of use of metformin was found. CONCLUSION These analyses of large population-based studies provide evidence of a strong inverse association of metformin with breast and, even more so, with colorectal cancer risk.
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Affiliation(s)
- Gad Rennert
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Clalit Health Services National Cancer Control Center (NICCC), Haifa, Israel.
| | - Hedy S Rennert
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Naomi Gronich
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Mila Pinchev
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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Guo J, Wang B, Hou W, Ma K. Risk factors for elevated serum colorectal cancer markers in patients with type 2 diabetes mellitus. Open Life Sci 2020; 15:267-273. [PMID: 33817215 PMCID: PMC7874651 DOI: 10.1515/biol-2020-0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 02/16/2020] [Accepted: 03/11/2020] [Indexed: 11/23/2022] Open
Abstract
The study aims to examine the risk factors for increased colorectal cancer (CRC) markers in patients with type 2 diabetes mellitus (T2DM). The 229 patients retrospectively reviewed were categorized into two groups: CRC tumor marker-positive and -negative groups. Patients who tested positive for all three of the following CRC markers were included in the CRC tumor marker-positive group: serum carcinoembryonic antigen, carbohydrate antigen 19-9 and septin9 methylation. Univariate analysis revealed that most CRC marker-positive patients had higher age, a family history of CRC, history of smoking and alcohol intake, high body mass index (BMI; overweight), longer history of T2DM, worse diabetes control (with high glycated hemoglobin A1c [HbA1c]), lower level of serum vitamin D (VD), high-density lipoprotein cholesterol and higher level of total cholesterol and triglyceride (TG). Logistic regression analysis showed that BMI, VD, HbA1c and TG were independent predictors of CRC marker-positive status (OR, 95% confidence intervals and P values were 1.912 [1.346–2.716], <0.001; 0.773 [0.633–0.943], 0.011; 9.082 [3.52–23.433], <0.001; and 11.597 [3.267–41.164], <0.001, respectively). In this retrospective study, high BMI, HbA1c and TG as well as low level of VD were correlated with CRC tumor marker-positive status in T2DM patients. Patients with these risk factors may benefit from more frequent screening for CRC tumor markers.
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Affiliation(s)
- Jingjing Guo
- Department of Health, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
| | - Bin Wang
- Department of Health, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
| | - Weikai Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 105, Jiefang Road, Jinan 250012, China
| | - Kun Ma
- Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, No. 16766, Jing Shi Road, Jinan 250014, China
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Martisova A, Sommerova L, Kuricova K, Podhorec J, Vojtesek B, Kankova K, Hrstka R. AGR2 silencing contributes to metformin-dependent sensitization of colorectal cancer cells to chemotherapy. Oncol Lett 2019; 18:4964-4973. [PMID: 31612008 DOI: 10.3892/ol.2019.10800] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 06/19/2019] [Indexed: 02/06/2023] Open
Abstract
There is growing epidemiological evidence indicating an association between diabetes mellitus and the increased incidence of colorectal cancer (CRC). The preferred initial and most widely used pharmacological agent for the treatment of type 2 diabetes is metformin, which in parallel reduces the risk of CRC and improves patient prognosis. AMP-activated protein kinase (AMPK) appears to be tightly associated with the beneficial metabolic effects of metformin, serving as a cellular energy sensor activated in response to a variety of conditions that deplete cellular energy levels. Such conditions include nutrient starvation (particularly glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. The aim of the present study was to determine the effect of metformin on CRC cell lines, with different levels of anterior gradient 2 (AGR2) expression, exposed to 5-fluorouracil (5-FU) and oxaliplatin, alone or in combination with metformin. AGR2 has recently emerged as a factor involved in colon carcinogenesis. In AGR2-knockout cells, markedly higher levels of phosphorylated-AMPK were observed in comparison with control cells transfected with GFP-scrambled guide RNA, which indicated that the presence of AGR2 may interfere with the metformin-dependent activation of AMPK. In addition, metformin in combination with 5-FU and oxaliplatin induced ROS production and attenuated autophagy. This effect was enhanced in AGR2-knockout cells.
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Affiliation(s)
- Andrea Martisova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Lucia Sommerova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Katarina Kuricova
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - Jan Podhorec
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Borivoj Vojtesek
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Katerina Kankova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.,Department of Pathophysiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - Roman Hrstka
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
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Hendriks AM, Schrijnders D, Kleefstra N, de Vries EGE, Bilo HJG, Jalving M, Landman GWD. Sulfonylurea derivatives and cancer, friend or foe? Eur J Pharmacol 2019; 861:172598. [PMID: 31408647 DOI: 10.1016/j.ejphar.2019.172598] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/07/2019] [Accepted: 08/08/2019] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.
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Affiliation(s)
- Anne M Hendriks
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Dennis Schrijnders
- Langerhans Medical Research Group, Zwolle, the Netherlands; Diabetes Center, Isala Hospital, Zwolle, the Netherlands
| | | | - Elisabeth G E de Vries
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Henk J G Bilo
- Diabetes Center, Isala Hospital, Zwolle, the Netherlands; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Gijs W D Landman
- Langerhans Medical Research Group, Zwolle, the Netherlands; Department of Internal Medicine, Gelre Hospital, Apeldoorn, the Netherlands
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de Kort S, Simons CCJM, van den Brandt PA, Janssen-Heijnen MLG, Sanduleanu S, Masclee AAM, Weijenberg MP. Diabetes mellitus, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk. Int J Cancer 2019; 145:1774-1781. [PMID: 31018241 PMCID: PMC6767781 DOI: 10.1002/ijc.32365] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 03/24/2019] [Accepted: 04/02/2019] [Indexed: 12/31/2022]
Abstract
Genetic variation in the insulin‐like growth factor (IGF) pathway may further increase the risk of colorectal cancer (CRC) associated with type 2 diabetes mellitus (T2DM). Joint effects of T2DM and genetic variation in the IGF pathway on CRC risk can increase mechanistic insights. Participants from the Netherlands Cohort Study (n = 120, 852) completed a baseline questionnaire in 1986 when 55–69 years old (case–cohort, nsubcohort = 5,000, ncases = 3,441 after 16.3 years follow‐up). Self‐reported DM at baseline with onset at ≥30 years was classified as T2DM. Eighteen single nucleotide polymorphisms (SNPs) from the IGF pathway were aggregated in a genetic risk score (GRS). Cox proportional hazard ratios (HRs) for CRC were estimated according to combinations of T2DM status with GRS tertiles and categories of an IGF1 19‐CA repeat polymorphism. Baseline T2DM prevalence was 3.1% in subcohort members and 3.8% in CRC cases. Comparison of combined categories with non‐T2DM individuals in the lowest GRS tertile as reference showed that those in the highest GRS tertiles with and without T2DM had significantly increased CRC risks, particularly those with T2DM (HR = 2.28, 95% CI: 1.11, 4.66). As compared to IGF1 19‐CA wild‐type carriers without T2DM, carrying two IGF1 19‐CA variant repeat alleles were associated with a significantly decreased CRC risk in those without T2DM (HR = 0.76, 95% CI: 0.63–0.91). This association was absent when T2DM was present. Our study of joint effects indicated that the presence of unfavorable alleles in the IGF pathway may further increase the risk of CRC associated with T2DM. What's new? Colorectal cancer (CRC) and type‐2 diabetes mellitus (T2DM) have several risk factors in common (high BMI, physical inactivity, etc.). In this study, the authors identified several SNPs in the insulin‐like growth factor (IGF) pathway that further increase CRC risk, particularly in people with T2DM. These results support the hypothesis that T2DM increases CRC risk by influencing the IGF pathway. Screening for these unfavorable genetic variations in the IGF pathway may also help to improve the assessment of personalized CRC risk.
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Affiliation(s)
- Sander de Kort
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.,GROW-School for Oncology and Developmental Biology, NUTRIM, School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Colinda C J M Simons
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Piet A van den Brandt
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Maryska L G Janssen-Heijnen
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.,Department of Clinical Epidemiology, VieCuri Medical Centre, Venlo, The Netherlands
| | - Silvia Sanduleanu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.,GROW-School for Oncology and Developmental Biology, NUTRIM, School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Ad A M Masclee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.,GROW-School for Oncology and Developmental Biology, NUTRIM, School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Matty P Weijenberg
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
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Choi YJ, Lee DH, Han KD, Kim HS, Yoon H, Shin CM, Park YS, Kim N. Optimal Starting Age for Colorectal Cancer Screening in an Era of Increased Metabolic Unhealthiness: A Nationwide Korean Cross-Sectional Study. Gut Liver 2019; 12:655-663. [PMID: 29938455 PMCID: PMC6254626 DOI: 10.5009/gnl17514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 02/16/2018] [Accepted: 03/29/2018] [Indexed: 12/11/2022] Open
Abstract
Background/Aims The association between metabolic syndrome and colorectal cancer (CRC) has been suggested as one of causes for the increasing incidence of CRC, particularly in younger age groups. The present study examined whether the current age threshold (50 years) for CRC screening in Korea requires modification when considering increased metabolic syndrome. Methods We analyzed data from the National Health Insurance Corporation database, which covers ~97% of the population in Korea. CRC risk was evaluated with stratification based on age and the presence/absence of relevant metabolic syndrome components (diabetes, dyslipidemia, and hypertension). Results A total of 51,612,316 subjects enrolled during 2014 to 2015 were analyzed. Among them, 19.3% had diabetes, hypertension, dyslipidemia, or some combination thereof. This population had a higher incidence of CRC than did those without these conditions, and this was more prominent in subjects <40 years of age. The optimal cutoff age for detecting CRC, based on the highest Youden index, was 45 years among individuals without diabetes, dyslipidemia, and hypertension. Individuals with at least one of these components of metabolic syndrome had the highest Youden index at 62 years old, but the value was only 0.2. Resetting the cutoff age from 50 years to 45 years achieved a 6% increase in sensitivity for CRC detection among the total population. Conclusions Starting CRC screening earlier, namely, at 45 rather than at 50 years of age, may improve secondary prevention of CRC in Korea.
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Affiliation(s)
- Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Do Han
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyun Soo Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Guo X, Dai X, Ni J, Cao N, Yang G, Xue J, Wang X. High concentration of sugars is genotoxic to folate-deficient cells. Mutat Res 2019; 814:15-22. [DOI: 10.1016/j.mrfmmm.2019.01.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/29/2018] [Accepted: 01/08/2019] [Indexed: 04/08/2023]
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Geagea AG, Rizzo M, Jurjus A, Cappello F, Leone A, Tomasello G, Gracia C, Al Kattar S, Massaad-Massade L, Eid A. A novel therapeutic approach to colorectal cancer in diabetes: role of metformin and rapamycin. Oncotarget 2019; 10:1284-1305. [PMID: 30863490 PMCID: PMC6407684 DOI: 10.18632/oncotarget.26641] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/14/2019] [Indexed: 12/28/2022] Open
Abstract
The link between colorectal cancer (CRC), diabetes mellitus (DM) and inflammation is well established, and polytherapy, including rapamycin, has been adopted. This study is a novel approach that aimed at assessing the effect of a combination therapy of metformin and rapamycin on the control or prevention of CRC in diabetic animals, in presence or absence of probiotics. Fifty NOD/SCIDs male mice developed xenograft by inoculating HCT116 cells. They were equally divided into diabetics (induced by Streptozotocin) and non-diabetics. Metformin was given in drinking water, whereas rapamycin was administered via intra-peritoneal injections. Probiotics were added to the double therapy two weeks before the sacrifice. Assessment was performed by clinical observation, histological analysis, Reactive oxygen species (ROS) activities and molecular analysis of Interleukin 3 and 6, Tumor Necrosis Factor alpha, AMP-activated protein Kinase and the mammalian target of rapamycin. Decreases in the level of tumorigenesis resulted, to various extents, with the different treatment regimens. The combination of rapamycin and metformin had no significant result, however, after adding probiotics to the combination, there was a marked delay in tumor formation and reduction of its size, suppression of ROS and a decrease in inflammatory cytokines as well as an inhibition of phosphorylated mTOR. Existing evidence clearly supports the use of rapamycin and metformin especially in the presence of probiotics. It also highlighted the possible mechanism of action of the 2 drugs through AMPK and mTOR signaling pathways and offered preliminary data on the significant role of probiotics in the combination. Further investigation to clarify the exact role of probiotics and decipher in more details the involved pathways is needed.
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Affiliation(s)
- Alice Gerges Geagea
- Department of Internal Medicine, University of Palermo, Palermo, Italy
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Manfredi Rizzo
- Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Francesco Cappello
- Department of Biomedicine, Neurosciences and Advanced Diagnosis, School Of Medicine of Palermo, Palermo, Italy
| | - Angelo Leone
- Department of Biomedicine, Neurosciences and Advanced Diagnosis, School Of Medicine of Palermo, Palermo, Italy
| | - Giovanni Tomasello
- Department of Biomedicine, Neurosciences and Advanced Diagnosis, School Of Medicine of Palermo, Palermo, Italy
| | - Céline Gracia
- Equipe Nouvelles Thérapies Anticancéreuses, UMR8203 CNRS, Gustave Roussy, Villejuif, France
| | - Sahar Al Kattar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Assaad Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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40
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Sex- and site-specific differences in colorectal cancer risk among people with type 2 diabetes. Int J Colorectal Dis 2019; 34:269-276. [PMID: 30421309 PMCID: PMC6331739 DOI: 10.1007/s00384-018-3191-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/05/2018] [Indexed: 02/04/2023]
Abstract
PURPOSE The prevalence of colorectal cancer is higher among patients with type 2 diabetes mellitus (T2D) than among patients without diabetes. Furthermore, men are at higher risk for developing colorectal cancer than women in the general population and also subsite-specific risks differ per sex. The aim was to evaluate the impact of T2D on these associations. METHODS A population-based matched cohort study was performed using data from the PHARMO Database Network. Patients with T2D were selected and matched (1:4) to diabetes free controls. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CRC and its subsites. HRs were determined per sex and adjusted for age and socioeconomic status. The ratio of distal versus proximal colon cancer was calculated for people with T2D and controls per sex and stratified by age. RESULTS Over 55,000 people with T2D were matched to > 215,000 diabetes free controls. Men and women with T2D were 1.3 times more likely to develop colorectal cancer compared to controls. Men with T2D were at higher risk to develop distal colon cancer (hazard ratio (95% confidence interval), 1.42 (1.08-1.88)), and women with T2D were at higher risk for developing proximal colon cancer (hazard ratio (95% confidence interval), 1.58 (1.13-2.19)). For rectal cancer, no statistically significant risk was observed for both men and women. CONCLUSIONS Sex-specific screening strategies and prevention protocols should be considered for people with T2D. More tailored screening strategies may optimize the effectiveness of colorectal cancer screening in terms of reducing incidence and mortality.
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Zhang Q, Berger FG, Love B, Banister CE, Murphy EA, Hofseth LJ. Maternal stress and early-onset colorectal cancer. Med Hypotheses 2018; 121:152-159. [PMID: 30396471 DOI: 10.1016/j.mehy.2018.09.035] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 09/10/2018] [Accepted: 09/20/2018] [Indexed: 02/07/2023]
Abstract
Early-onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) diagnosed before the age of 50. Alarmingly, there has been a significant increase in EOCRC diagnoses' worldwide over the past several decades. Emerging data suggest EOCRCs have distinguishing clinical, pathological, biological and molecular features; and thus, are a fundamentally different subtype of CRCs. Unfortunately, there is no simple explanation for the causes of EOCRC. Scientifically rigorous studies are needed to determine what may be driving the challenging epidemiology of EOCRC. We contend here that a reasonable hypothesis is that prenatal risk factors such as maternal stress and associated sleeping disorders influence offspring epigenetic make-up, and shape immune system and gut health contributing to an increased risk for EOCRC.
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Affiliation(s)
- Qi Zhang
- Department of Drug Discovery and Biomedical Science, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Franklin G Berger
- Department of Biology, College of Arts and Sciences, University of South Carolina, Columbia, SC, USA
| | - Bryan Love
- Department of Clinical Pharmacy & Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Carolyn E Banister
- Department of Drug Discovery and Biomedical Science, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Elizabeth A Murphy
- Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC, USA
| | - Lorne J Hofseth
- Department of Drug Discovery and Biomedical Science, College of Pharmacy, University of South Carolina, Columbia, SC, USA.
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Sacerdote C, Ricceri F. Epidemiological dimensions of the association between type 2 diabetes and cancer: A review of observational studies. Diabetes Res Clin Pract 2018; 143:369-377. [PMID: 29596949 DOI: 10.1016/j.diabres.2018.03.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 02/27/2018] [Accepted: 03/01/2018] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes (T2D) is a major cause of complications and death in many countries. The possible causal relation between T2D and cancer has been the aim of many research investigations. In view of the importance of the topic we carried out a narrative review of observational studies to summarize the available evidence of the association between T2D and cancer. To deal with the problem of abundance of published studies, we reviewed up to December 2017, the literature of meta-analyses of observational studies first, then we reviewed cohort studies not reported in meta-analyses because of more recent publication. We found that the association of T2D with risk of colorectal cancer was robust, whereas the evidence of the associations with other cancer sites was lower. Some of the observed associations could be overestimated, due to publication bias, unmeasured confounders (such as obesity) and surveillance bias. In conclusion a probable causal association of T2D with risk of colorectal cancer was confirmed. A possible causal association with pancreatic, endometrial, hepatocellular and gallbladder carcinoma was also found. Substantial uncertainty exists for other cancer sites.
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Affiliation(s)
- Carlotta Sacerdote
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
| | - Fulvio Ricceri
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy; Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Turin, Italy
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Sonbol MB, Bekaii-Saab TS, Puccini A, Salem ME. Young Patients with Colorectal Cancer: Risk, Screening, and Treatment. CURRENT COLORECTAL CANCER REPORTS 2018. [DOI: 10.1007/s11888-018-0412-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Survival and glycemic control in patients with colorectal cancer and diabetes mellitus. Future Sci OA 2018; 4:FSO335. [PMID: 30416744 PMCID: PMC6222275 DOI: 10.4155/fsoa-2018-0044] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/16/2018] [Indexed: 12/19/2022] Open
Abstract
Aim: The impact of diabetes mellitus (DM) on survival in patients with colorectal cancer and the impact of colorectal cancer on glycemic control were examined. Materials & methods: Patients with colorectal cancer with and without DM were matched 1:1 (2007–2015). Characteristics were compared between the two groups and survival assessed with the Kaplan–Meier method. Mixed models compared hemoglobin A1c and glucose levels over time. Results: In both groups, glucose values decreased during the year following cancer diagnosis (p < 0.001). 5-year overall survival was 56% (95% CI: 42–68%) for DM patients versus 57% (95% CI: 43–69%) for non-DM patients (p = 0.62). Conclusion: DM did not adversely impact survival of patients with colorectal cancer. Colorectal cancer did not affect glycemic control. The aim of this study was to evaluate the effect of diabetes mellitus (DM) on survival of patients with colorectal cancer and to determine whether colorectal cancer affected glycemic control. From an institutional cancer registry, 170 patients with colorectal cancer were identified and grouped by the presence (n = 85) or absence of DM (n = 85). The groups were matched by age and year of colorectal cancer diagnosis. DM did not decrease the survival and colorectal cancer did not significantly affect glucose levels of patients with DM.
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Kachekouche Y, Dali-Sahi M, Benmansour D, Dennouni-Medjati N. Hematological profile associated with type 2 diabetes mellitus. Diabetes Metab Syndr 2018; 12:309-312. [PMID: 29287841 DOI: 10.1016/j.dsx.2017.12.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 12/19/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Hematological changes affecting blood cells and the coagulation factors are shown to be associated with diabetes mellitus. We investigated some of the hematological risk factors implicated in the development of type 2 diabetes mellitus. METHODS The study conducted in western Algeria on a sample of 1852 subjects, 1059 with type 2 diabetes and 793 witnesses, were evaluated for peripheral blood parameters using hematology analyzer. All the informations related to the disease were collected from the patients and recorded using predesigned questionnaire. RESULTS The logistic model retained, the mean corpuscular hemoglobin concentration reveals that subjects with concentration over the normal ratio (>36 g/dl) have an exposure risk six and half times higher than subjects with normal concentration (OR = 6.59; 95% CI = 2.51-17.31, P = 0.000). As regards to the platelets blood ratio, subjects with a ratio lower are five times more exposed to type 2 diabetes compared to subjects with a normal ratio (OR = 5.01; 95% CI = 1.78-14.13, P < 0.002). Our logistic model also retained basophils ratio (OR = 2.18; 95% CI = 1.35-3.53, P < 0.001) and sedimentation rate at one hour (OR = 7.83; 95% CI = 3.39-18.06, P = 0.000). CONCLUSIONS Hematological profile associated with type 2 diabetes mellitus retained the mean corpuscular hemoglobin concentration over the normal ratio, lower platelets blood ratio, basophils ratio and sedimentation rate at one hour.
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Affiliation(s)
- Youssouf Kachekouche
- Departement of Biology, Valorisation of Human Actions for the Protection of the Environment and Application in Public Health Laboratory, University of Tlemcen, 13000, Algeria.
| | - Madjda Dali-Sahi
- Departement of Biology, Valorisation of Human Actions for the Protection of the Environment and Application in Public Health Laboratory, University of Tlemcen, 13000, Algeria
| | - Djamel Benmansour
- Departement of Ecology and Environment, Statistics and Random Models Laboratory, University of Tlemcen, 13000, Algeria
| | - Nouria Dennouni-Medjati
- Departement of Biology, Analytical Chemistry and Electrochemistry Laoboratory, University of Tlemcen, 13000, Algeria
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Kaur K, Saxena A, Debnath I, O'Brien JL, Ajami NJ, Auchtung TA, Petrosino JF, Sougiannis AJ, Depaep S, Chumanevich A, Gummadidala PM, Omebeyinje MH, Banerjee S, Chatzistamou I, Chakraborty P, Fayad R, Berger FG, Carson JA, Chanda A. Antibiotic-mediated bacteriome depletion in Apc Min/+ mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression. Cancer Med 2018; 7:2003-2012. [PMID: 29624892 PMCID: PMC5943478 DOI: 10.1002/cam4.1460] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 02/15/2018] [Accepted: 02/28/2018] [Indexed: 12/19/2022] Open
Abstract
Recent epidemiological evidence suggests that exposure to antibiotics in early‐to‐middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long‐term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the ApcMin/+ mouse, an established genetic model for familial adenomatous polyposis. Clinical pathologies related to tumor development as well as intestinal and colon tissue histopathology were studied at ages 8, 12, and 16 weeks of age, which correspond to the approximate ages of development of neoplasia, gut inflammation with polyposis, and cancer progression, respectively, in this animal model. We show that the antibiotics significantly increase the severity of clinical symptoms, including effects on intestinal histology and goblet cell numbers. In addition, they promote small intestinal polyposis. Finally, metagenomic analysis of fecal samples demonstrated that antibiotic exposure is associated with a significant but nonuniform depletion of the animal's natural gut flora. Overall, these findings support the premise that long‐term antibiotic exposure mediates the selected depletion of gut microbial communities and the concomitant thinning of the protective mucus layer, resulting in an increase in tumor development.
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Affiliation(s)
- Kamaljeet Kaur
- Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Arpit Saxena
- Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Irina Debnath
- Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Jacqueline L O'Brien
- The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Nadim J Ajami
- The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Thomas A Auchtung
- The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Joseph F Petrosino
- The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | | | - Sarah Depaep
- Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Alexander Chumanevich
- Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Phani M Gummadidala
- Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Mayomi H Omebeyinje
- Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
| | - Sourav Banerjee
- Mechanical Engineering, University of South Carolina, Columbia, South Carolina
| | - Ioulia Chatzistamou
- Pathology, Microbiology& Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina
| | - Paramita Chakraborty
- Department of Statistics, University of South Carolina, Columbia, South Carolina
| | - Raja Fayad
- Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.,Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina
| | - Franklin G Berger
- Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina
| | - James A Carson
- Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.,Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina
| | - Anindya Chanda
- Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.,Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina
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47
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Chen Z, Yin X, Li K, Chen S, Li H, Li Y, Zhang Q, Wang H, Qiu Y. Serum Levels of TRIM72 Are Lower among Patients with Colon Cancer: Identification of a Potential Diagnostic Marker. TOHOKU J EXP MED 2018; 245:61-68. [DOI: 10.1620/tjem.245.61] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Zhuoyu Chen
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Xiaofeng Yin
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Kaifei Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Shuyu Chen
- Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, The State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University
| | - Haixia Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Yao Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Qiong Zhang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Haifang Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Yurong Qiu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
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48
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Piper MS, Saad RJ. Diabetes Mellitus and the Colon. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2017; 15:460-474. [PMID: 29063998 PMCID: PMC6049816 DOI: 10.1007/s11938-017-0151-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OPINION STATEMENT Diabetes mellitus (DM) can affect the structure and function of the colon promoting commonly encountered lower gastrointestinal symptoms such as constipation, diarrhea, abdominal distention, bloating, and abdominal pain. Specific colonic disorders for which adults with DM are at greater risk include chronic constipation, enteropathic diarrhea, colorectal cancer (CRC), inflammatory bowel disease, microscopic colitis, and Clostridium difficile colitis. Smooth muscle structure and function, density of the interstitial cells of Cajal, and the health and function of the autonomic and enteric nerves of the colon are all potential affected by DM. These effects can in turn lead to alterations in colon motility, visceral sensation, immune function, endothelial function, and the colonic microbiome. The evaluation and treatment for slow transit constipation as well as pelvic floor dysfunction should be considered when constipation symptoms are refractory to initial treatment measures. DM-related medications and small bowel conditions such as celiac disease and small intestinal bowel overgrowth should be considered and excluded before a diagnosis of enteropathic diarrhea is made. Given the higher risk of CRC, adults with DM should be appropriately screened and may require a longer bowel preparation to ensure an adequate evaluation.
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Affiliation(s)
- Marc S Piper
- Providence-Park Hospital, Michigan State University College of Human Medicine, Lansing, MI, USA
| | - Richard J Saad
- Michigan Medicine at the University of Michigan, 3912 Taubman Center, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.
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