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Fatfat Z, Hussein M, Fatfat M, Gali-Muhtasib H. Omics technologies as powerful approaches to unravel colorectal cancer complexity and improve its management. Mol Cells 2025; 48:100200. [PMID: 40024318 PMCID: PMC11976254 DOI: 10.1016/j.mocell.2025.100200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/31/2025] [Accepted: 02/22/2025] [Indexed: 03/04/2025] Open
Abstract
Colorectal cancer (CRC) continues to rank among the deadliest and most prevalent cancers worldwide, necessitating an innovative and comprehensive approach that addresses this serious health challenge at various stages, from screening and diagnosis to treatment and prognosis. As CRC research progresses, the adoption of an omics-centered approach holds transformative potential to revolutionize the management of this disease. Advances in omics technologies encompassing genomics, transcriptomics, proteomics, metabolomics, and epigenomics allow to unravel the oncogenic alterations at these levels, elucidating the intricacies and the heterogeneous nature of CRC. By providing a comprehensive molecular landscape of CRC, omics technologies enable the discovery of potential biomarkers for early non-invasive detection of CRC, definition of CRC subtypes, prediction of its staging, prognosis, and overall survival of CRC patients. They also allow the identification of potential therapeutic targets, prediction of drug response, tracking treatment efficacy, detection of residual disease and cancer relapse, and deciphering the mechanisms of drug resistance. Moreover, they allow the distinction of non-metastatic CRC patients from metastatic ones as well as the stratification of metastatic risk. Importantly, omics technologies open up new opportunities to establish molecular-based criteria to guide the selection of effective treatment paving the way for the personalization of therapy for CRC patients. This review consolidates current knowledge on the omics-based preclinical discoveries in CRC research emphasizing the significant potential of these technologies to improve CRC screening, diagnosis, and prognosis and promote the implementation of personalized medicine to ultimately reduce CRC prevalence and mortality.
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Affiliation(s)
- Zaynab Fatfat
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Marwa Hussein
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Maamoun Fatfat
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon
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2
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Bhattacharyya D, LeVatte MA, Singh U, Issac F, Karim M, Ali S, Sieben A, Huang S, Wishart DS. A novel colorimetric assay for the detection of urinary N 1, N 12-diacetylspermine, a known biomarker for colorectal cancer. Anal Biochem 2025; 697:115717. [PMID: 39536927 DOI: 10.1016/j.ab.2024.115717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/08/2024] [Accepted: 11/09/2024] [Indexed: 11/16/2024]
Abstract
Urinary N1, N12-diacetylspermine (DAS) is a known biomarker for colorectal cancer (CRC). However, DAS levels in both healthy and CRC patients' urine samples are extremely low and often challenging to quantify. Complex and expensive methods do exist to detect DAS in urine, but simpler, less expensive methods to detect DAS are needed, especially in low resource settings. Here we describe a highly efficient, fast, precise, and inexpensive colorimetric assay to detect low levels of DAS in human urine samples. We used recombinant diacetylspermine oxidase (rDAS Ox), expressed and extracted from E. coli, to oxidize DAS, producing three products including hydrogen peroxide (H2O2). The level of DAS present, which correlates with H2O2 levels, was measured using horseradish peroxidase (HRP), which together with H2O2, oxidized Amplex™ Red to produce the pink-colored resorufin. The concentration of resorufin is directly proportional to H2O2 (and DAS) levels. As urine contains metabolites which interfere with these oxidation reactions, we developed a simple two column-based protocol using ion exchange resins to remove these compounds and concentrate the DAS. With this novel cleaning and concentrating method, DAS was concentrated 15 times (confirmed by nuclear magnetic resonance (NMR) spectroscopy) and <1 μM DAS could be detected. Correlation graphs of urine samples spiked with known DAS concentrations versus assay-determined DAS concentrations had high coefficients of determination (R2) for 0-10 μM DAS (0.94) and for 0-1 μM DAS (0.91), clearly demonstrating the excellent performance of the two-column protocol with the rDAS Ox reaction mixture. To the best of our knowledge, this is first reported colorimetric enzymatic assay that quantitates DAS in urine.
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Affiliation(s)
| | - Marcia A LeVatte
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Upasana Singh
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Fleur Issac
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Mahmoud Karim
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada; Fisher Scientific, 10720 178 St Edmonton, AB, T5S 1J3, Canada
| | - Saira Ali
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - August Sieben
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Suyenna Huang
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - David S Wishart
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada; Department of Computer Sciences, University of Alberta, Edmonton, AB, T6G 2E8, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, T6G 1C9, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
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Jo K, Linh VTN, Yang JY, Heo B, Kim JY, Mun NE, Im JH, Kim KS, Park SG, Lee MY, Yoo SW, Jung HS. Machine learning-assisted label-free colorectal cancer diagnosis using plasmonic needle-endoscopy system. Biosens Bioelectron 2024; 264:116633. [PMID: 39126906 DOI: 10.1016/j.bios.2024.116633] [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: 06/07/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Early and accurate detection of colorectal cancer (CRC) is critical for improving patient outcomes. Existing diagnostic techniques are often invasive and carry risks of complications. Herein, we introduce a plasmonic gold nanopolyhedron (AuNH)-coated needle-based surface-enhanced Raman scattering (SERS) sensor, integrated with endoscopy, for direct mucus sampling and label-free detection of CRC. The thin and flexible stainless-steel needle is coated with polymerized dopamine, which serves as an adhesive layer and simultaneously initiates the nucleation of gold nanoparticle (AuNP) seeds on the needle surface. The AuNP seeds are further grown through a surface-directed reduction using Au ions-hydroxylamine hydrochloride solution, resulting in the formation of dense AuNHs. The formation mechanism of AuNHs and the layered structure of the plasmonic needle-based SERS (PNS) sensor are thoroughly analyzed. Furthermore, a strong field enhancement of the PNS sensor is observed, amplified around the edges of the polyhedral shapes and at nanogap sites between AuNHs. The feasibility of the PNS sensor combined with endoscopy system is further investigated using mouse models for direct colonic mucus sampling and verifying noninvasive label-free classification of CRC from normal controls. A logistic regression-based machine learning method is employed and successfully differentiates CRC and normal mice, achieving 100% sensitivity, 93.33% specificity, and 96.67% accuracy. Moreover, Raman profiling of metabolites and their correlations with Raman signals of mucus samples are analyzed using the Pearson correlation coefficient, offering insights for identifying potential cancer biomarkers. The developed PNS-assisted endoscopy technology is expected to advance the early screening and diagnosis approach of CRC in the future.
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Affiliation(s)
- Kangseok Jo
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea; School of Chemical Engineering, Pusan National University, Busan, 46241, South Korea
| | - Vo Thi Nhat Linh
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea
| | - Jun-Yeong Yang
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea
| | - Boyou Heo
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea
| | - Jun Young Kim
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea
| | - Na Eun Mun
- Biomedical Science Graduate Program, Chonnam National University, Hwasun, 58128, South Korea; Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Hwasun, 58128, South Korea; Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Hwasun, 58128, South Korea
| | - Jin Hee Im
- Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Hwasun, 58128, South Korea; Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Hwasun, 58128, South Korea
| | - Ki Su Kim
- School of Chemical Engineering, Pusan National University, Busan, 46241, South Korea
| | - Sung-Gyu Park
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea
| | - Min-Young Lee
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea
| | - Su Woong Yoo
- Biomedical Science Graduate Program, Chonnam National University, Hwasun, 58128, South Korea; Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Hwasun, 58128, South Korea; Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Hwasun, 58128, South Korea.
| | - Ho Sang Jung
- Advanced Bio and Healthcare Materials Research Division, Korea Institute of Materials Science (KIMS), Changwon, 51508, South Korea; Advanced Materials Engineering Division, University of Science and Technology (UST), Daejeon, 34113, South Korea; School of Convergence Science and Technology, Medical Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang, 37673, South Korea.
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4
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Nakane K, Yagi K, Yajima S, Nomura S, Sugimoto M, Seto Y. Salivary metabolomic biomarkers for esophageal and gastric cancers by liquid chromatography-mass spectrometry. Cancer Sci 2024; 115:3089-3098. [PMID: 39004809 PMCID: PMC11463073 DOI: 10.1111/cas.16256] [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: 12/19/2023] [Revised: 05/24/2024] [Accepted: 06/12/2024] [Indexed: 07/16/2024] Open
Abstract
Early detection of esophageal and gastric cancers is essential for patients' prognosis; however, optimal noninvasive screening tests are currently not available. Saliva is a biofluid that is readily available, allowing for frequent screening tests. Thus, we explored salivary diagnostic biomarkers for esophageal and gastric cancers using metabolomic analyses. Saliva samples were collected from patients with esophageal (n = 50) and gastric cancer (n = 63), and patients without cancer as controls (n = 20). Salivary metabolites were analyzed by liquid chromatography-mass spectrometry to identify salivary biomarkers. We also examined the metabolic profiles of gastric cancer tissues and compared them with the salivary biomarkers. The sensitivity of the diagnostic models based on salivary biomarkers was assessed by comparing it with that of serum tumor markers. Additionally, using postoperative saliva samples collected from patients with gastric cancer, we analyzed the changes in the biomarkers' concentrations before and after surgery. Cytosine was detected as a salivary biomarker for gastric cancer, and cytosine, 2-oxoglutarate, and arginine were detected as salivary biomarkers for esophageal cancer. Cytidine, a cytosine nucleotide, showed decreased concentrations in gastric cancer tissues. The sensitivity of the diagnostic models for esophageal and gastric cancers was 66.0% and 47.6%, respectively, while that of serum tumor markers was 40%. Salivary cytosine concentration increased significantly postoperatively relative to the preoperative value. In summary, we identified salivary biomarkers for esophageal and gastric cancers, which showed diagnostic sensitivity at least comparable to that of serum tumor markers. Salivary metabolomic tests could be promising screening tests for these types of cancer.
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Affiliation(s)
- Kosuke Nakane
- Department of Gastrointestinal Surgery, Graduate School of MedicineUniversity of TokyoTokyoJapan
| | - Koichi Yagi
- Department of Gastrointestinal Surgery, Graduate School of MedicineUniversity of TokyoTokyoJapan
| | - Sho Yajima
- Department of Gastrointestinal Surgery, Graduate School of MedicineUniversity of TokyoTokyoJapan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of MedicineUniversity of TokyoTokyoJapan
| | - Masahiro Sugimoto
- Institute of Medical ScienceTokyo Medical UniversityTokyoJapan
- Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of MedicineUniversity of TokyoTokyoJapan
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Raj AK, Lokhande KB, Khunteta K, Sarode SC, Sharma NK. Elevated N1-Acetylspermidine Levels in Doxorubicin-treated MCF-7 Cancer Cells: Histone Deacetylase 10 Inhibition with an N1-Acetylspermidine Mimetic. J Cancer Prev 2024; 29:32-44. [PMID: 38957589 PMCID: PMC11215339 DOI: 10.15430/jcp.24.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/04/2024] [Accepted: 05/18/2024] [Indexed: 07/04/2024] Open
Abstract
Cancer drug resistance is associated with metabolic adaptation. Cancer cells have been shown to implicate acetylated polyamines in adaptations during cell death. However, exploring the mimetic of acetylated polyamines as a potential anticancer drug is lacking. We performed intracellular metabolite profiling of human breast cancer MCF-7 cells treated with doxorubicin (DOX), a well known anticancer drug. A novel and in-house vertical tube gel electrophoresis assisted procedure followed by LC-HRMS analysis was employed to detect acetylated polyamines such as N1-acetylspermidine. We designed a mimetic N1-acetylspermidine (MINAS) which is a known substrate of histone deacetylase 10 (HDAC10). Molecular docking and molecular dynamics (MDs) simulations were used to evaluate the inhibitory potential of MINAS against HDAC10. The inhibitory potential and the ADMET profile of MINAS were compared to a known HDAC10 inhibitor Tubastatin A. N1-acetylspermidine, an acetylated form of polyamine, was detected intracellularly in MCF-7 cells treated with DOX over DMSO-treated MCF-7 cells. We designed and curated MINAS (PubChem CID 162679241). Molecular docking and MD simulations suggested the strong and comparable inhibitory potential of MINAS (-8.2 kcal/mol) to Tubastatin A (-8.4 kcal/mol). MINAS and Tubastatin A share similar binding sites on HDAC10, including Ser138, Ser140, Tyr183, and Cys184. Additionally, MINAS has a better ADMET profile compared to Tubastatin A, with a high MRTD value and lower toxicity. In conclusion, the data show that N1-acetylspermidine levels rise during DOX-induced breast cancer cell death. Additionally, MINAS, an N1-acetylspermidine mimetic compound, could be investigated as a potential anticancer drug when combined with chemotherapy like DOX.
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Affiliation(s)
- Ajay Kumar Raj
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, India
| | - Kiran Bharat Lokhande
- Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, India
| | - Kratika Khunteta
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, India
| | - Sachin Chakradhar Sarode
- Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pune, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, India
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Bailleux C, Chardin D, Gal J, Guigonis JM, Lindenthal S, Graslin F, Arnould L, Cagnard A, Ferrero JM, Humbert O, Pourcher T. Metabolomic Signatures of Scarff-Bloom-Richardson (SBR) Grade in Non-Metastatic Breast Cancer. Cancers (Basel) 2023; 15:cancers15071941. [PMID: 37046602 PMCID: PMC10093598 DOI: 10.3390/cancers15071941] [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: 02/06/2023] [Revised: 03/19/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
PURPOSE Identification of metabolomic biomarkers of high SBR grade in non-metastatic breast cancer. METHODS This retrospective bicentric metabolomic analysis included a training set (n = 51) and a validation set (n = 49) of breast cancer tumors, all classified as high-grade (grade III) or low-grade (grade I-II). Metabolomes of tissue samples were studied by liquid chromatography coupled with mass spectrometry. RESULTS A molecular signature of the top 12 metabolites was identified from a database of 602 frequently predicted metabolites. Partial least squares discriminant analyses showed that accuracies were 0.81 and 0.82, the R2 scores were 0.57 and 0.55, and the Q2 scores were 0.44431 and 0.40147 for the training set and validation set, respectively; areas under the curve for the Receiver Operating Characteristic Curve were 0.882 and 0.886. The most relevant metabolite was diacetylspermine. Metabolite set enrichment analyses and metabolic pathway analyses highlighted the tryptophan metabolism pathway, but the concentration of individual metabolites varied between tumor samples. CONCLUSIONS This study indicates that high-grade invasive tumors are related to diacetylspermine and tryptophan metabolism, both involved in the inhibition of the immune response. Targeting these pathways could restore anti-tumor immunity and have a synergistic effect with immunotherapy. Recent studies could not demonstrate the effectiveness of this strategy, but the use of theragnostic metabolomic signatures should allow better selection of patients.
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Affiliation(s)
- Caroline Bailleux
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
- Medical Oncology Department, Centre Antoine Lacassagne, University Côte d'Azur, 06189 Nice, France
| | - David Chardin
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
- Department of Nuclear Medicine, Antoine Lacassagne Centre, 06189 Nice, France
| | - Jocelyn Gal
- Department of Epidemiology and Biostatistics, Antoine Lacassagne Centre, University of Côte d'Azur, 06189 Nice, France
| | - Jean-Marie Guigonis
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
| | - Sabine Lindenthal
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
| | - Fanny Graslin
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
- Department of Nuclear Medicine, Antoine Lacassagne Centre, 06189 Nice, France
| | - Laurent Arnould
- Department of Tumour Biology and Pathology, Georges-François Leclerc Centre, 21079 Dijon, France
- Cenre de Ressources Biologiques (CRB) Ferdinand Cabanne, 21000 Dijon, France
| | - Alexandre Cagnard
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
| | - Jean-Marc Ferrero
- Medical Oncology Department, Centre Antoine Lacassagne, University Côte d'Azur, 06189 Nice, France
| | - Olivier Humbert
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
- Department of Nuclear Medicine, Antoine Lacassagne Centre, 06189 Nice, France
| | - Thierry Pourcher
- Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Université Côte d'Azur (UCA), 06100 Nice, France
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Zhang L, Zheng J, Ismond KP, MacKay S, LeVatte M, Constable J, Alatise OI, Kingham TP, Wishart DS. Identification of urinary biomarkers of colorectal cancer: Towards the development of a colorectal screening test in limited resource settings. Cancer Biomark 2023; 36:17-30. [PMID: 35871322 PMCID: PMC10627333 DOI: 10.3233/cbm-220034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND African colorectal cancer (CRC) rates are rising rapidly. A low-cost CRC screening approach is needed to identify CRC from non-CRC patients who should be sent for colonoscopy (a scarcity in Africa). OBJECTIVE To identify urinary metabolite biomarkers that, combined with easy-to-measure clinical variables, would identify patients that should be further screened for CRC by colonoscopy. Ideal metabolites would be water-soluble and easily translated into a sensitive, low-cost point-of-care (POC) test. METHODS Liquid-chromatography mass spectrometry (LC-MS/MS) was used to quantify 142 metabolites in spot urine samples from 514 Nigerian CRC patients and healthy controls. Metabolite concentration data and clinical characteristics were used to determine optimal sets of biomarkers for identifying CRC from non-CRC subjects. RESULTS Our statistical analysis identified N1, N12-diacetylspermine, hippurate, p-hydroxyhippurate, and glutamate as the best metabolites to discriminate CRC patients via POC screening. Logistic regression modeling using these metabolites plus clinical data achieved an area under the receiver-operator characteristic (AUCs) curves of 89.2% for the discovery set, and 89.7% for a separate validation set. CONCLUSIONS Effective urinary biomarkers for CRC screening do exist. These results could be transferred into a simple, POC urinary test for screening CRC patients in Africa.
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Affiliation(s)
- Lun Zhang
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
| | - Jiamin Zheng
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
| | | | - Scott MacKay
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
| | - Marcia LeVatte
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
| | - Jeremy Constable
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Olusegun Isaac Alatise
- Department of Surgery, Obafemi Awolowo University and Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria
| | - T. Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David S. Wishart
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
- Department of Computing Science, University of Alberta, Edmonton, AB, Canada
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8
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Velenosi TJ, Krausz KW, Hamada K, Dorsey TH, Ambs S, Takahashi S, Gonzalez FJ. Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer. NPJ Precis Oncol 2022; 6:70. [PMID: 36207498 PMCID: PMC9547066 DOI: 10.1038/s41698-022-00313-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/15/2022] [Indexed: 12/05/2022] Open
Abstract
Triple-negative breast cancer (TNBC) patients receive chemotherapy treatment, including doxorubicin, due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore, there is a need to identify biomarkers that determine effective drug response. A pharmacometabolomics study was performed using doxorubicin sensitive and resistant TNBC patient-derived xenograft (PDX) models to detect urinary metabolic biomarkers of treatment effectiveness. Evaluation of metabolite production was assessed by directly studying tumor levels in TNBC-PDX mice and human subjects. Metabolic flux leading to biomarker production was determined using stable isotope-labeled tracers in TNBC-PDX ex vivo tissue slices. Findings were validated in 12-h urine samples from control (n = 200), ER+/PR+ (n = 200), ER+/PR+/HER2+ (n = 36), HER2+ (n = 81) and TNBC (n = 200) subjects. Diacetylspermine was identified as a urine metabolite that robustly changed in response to effective doxorubicin treatment, which persisted after the final dose. Urine diacetylspermine was produced by the tumor and correlated with tumor volume. Ex vivo tumor slices revealed that doxorubicin directly increases diacetylspermine production by increasing tumor spermidine/spermine N1-acetyltransferase 1 expression and activity, which was corroborated by elevated polyamine flux. In breast cancer patients, tumor diacetylspermine was elevated compared to matched non-cancerous tissue and increased in HER2+ and TNBC compared to ER+ subtypes. Urine diacetylspermine was associated with breast cancer tumor volume and poor tumor grade. This study describes a pharmacometabolomics strategy for identifying cancer metabolic biomarkers that indicate drug response. Our findings characterize urine diacetylspermine as a non-invasive biomarker of doxorubicin effectiveness in TNBC.
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Affiliation(s)
- Thomas J Velenosi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA. .,Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Keisuke Hamada
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Tiffany H Dorsey
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Stefan Ambs
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Shogo Takahashi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA.
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9
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Kuwabara H, Katsumata K, Iwabuchi A, Udo R, Tago T, Kasahara K, Mazaki J, Enomoto M, Ishizaki T, Soya R, Kaneko M, Ota S, Enomoto A, Soga T, Tomita M, Sunamura M, Tsuchida A, Sugimoto M, Nagakawa Y. Salivary metabolomics with machine learning for colorectal cancer detection. Cancer Sci 2022; 113:3234-3243. [PMID: 35754317 PMCID: PMC9459332 DOI: 10.1111/cas.15472] [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: 05/09/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 11/29/2022] Open
Abstract
As the worldwide prevalence of colorectal cancer (CRC) increases, it is vital to reduce its morbidity and mortality through early detection. Saliva‐based tests are an ideal noninvasive tool for CRC detection. Here, we explored and validated salivary biomarkers to distinguish patients with CRC from those with adenoma (AD) and healthy controls (HC). Saliva samples were collected from patients with CRC, AD, and HC. Untargeted salivary hydrophilic metabolite profiling was conducted using capillary electrophoresis–mass spectrometry and liquid chromatography–mass spectrometry. An alternative decision tree (ADTree)‐based machine learning (ML) method was used to assess the discrimination abilities of the quantified metabolites. A total of 2602 unstimulated saliva samples were collected from subjects with CRC (n = 235), AD (n = 50), and HC (n = 2317). Data were randomly divided into training (n = 1301) and validation datasets (n = 1301). The clustering analysis showed a clear consistency of aberrant metabolites between the two groups. The ADTree model was optimized through cross‐validation (CV) using the training dataset, and the developed model was validated using the validation dataset. The model discriminating CRC + AD from HC showed area under the receiver‐operating characteristic curves (AUC) of 0.860 (95% confidence interval [CI]: 0.828‐0.891) for CV and 0.870 (95% CI: 0.837‐0.903) for the validation dataset. The other model discriminating CRC from AD + HC showed an AUC of 0.879 (95% CI: 0.851‐0.907) and 0.870 (95% CI: 0.838‐0.902), respectively. Salivary metabolomics combined with ML demonstrated high accuracy and versatility in detecting CRC.
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Affiliation(s)
- Hiroshi Kuwabara
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kenji Katsumata
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Atsuhiro Iwabuchi
- Center for Health Surveillance and Preventive Medicine, Tokyo Medical University Hospital, Tokyo, Japan
| | - Ryutaro Udo
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Tomoya Tago
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kenta Kasahara
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Junichi Mazaki
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Masanobu Enomoto
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Tetsuo Ishizaki
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Ryoko Soya
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Miku Kaneko
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Sana Ota
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Ayame Enomoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Masaru Tomita
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Makoto Sunamura
- Digestive Surgery and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan
| | - Akihiko Tsuchida
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.,Research and Development Center for Minimally Invasive Therapies Health Promotion and Preemptive Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
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10
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Ahmed N, Kidane B, Wang L, Nugent Z, Moldovan N, McElrea A, Shariati-Ievari S, Qing G, Tan L, Buduhan G, Srinathan SK, Meyers R, Aliani M. Metabolic Alterations in Sputum and Exhaled Breath Condensate of Early Stage Non-Small Cell Lung Cancer Patients After Surgical Resection: A Pilot Study. Front Oncol 2022; 12:874964. [PMID: 35719971 PMCID: PMC9204221 DOI: 10.3389/fonc.2022.874964] [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: 02/13/2022] [Accepted: 04/27/2022] [Indexed: 12/19/2022] Open
Abstract
Every year, close to two million people world-wide are diagnosed with and die of lung cancer. Most patients present with advanced-stage cancer with limited curative options and poor prognosis. Diagnosis of lung cancer at an early stage provides the best chance for a cure. Low- dose CT screening of the chest in the high-risk population is the current standard of care for early detection of lung cancer. However, CT screening is invasive due to radiation exposure and carries the risk of unnecessary biopsies in non-cancerous tumors. In this pilot study, we present metabolic alterations observed in sputum and breath condensate of the same population of early- stage non-small cell lung cancer (NSCLC) patients cancer before and after surgical resection (SR), which could serve as noninvasive diagnostic tool. Exhaled breath condensate (EBC) (n=35) and sputum (n=15) were collected from early-stage non-small cell lung cancer (NSCLC) patients before and after SR. Median number of days for EBC and sputum collection before and after SR were 7 and 42; and 7 and 36 respectively Nuclear magnetic resonance (NMR) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) were used to analyze the metabolic profile of the collected samples. A total of 26 metabolites with significant alteration post SR were identified, of which 14 (54%) were lipids and 12 constituted nine different chemical metabolite classes. Eighteen metabolites (69%) were significantly upregulated and 8 (31%) were downregulated. Median fold change for all the up- and downregulated metabolites (LC-QTOF-MS) were 10 and 8, respectively. Median fold change (MFC) in concentration of all the up- and downregulated metabolites (NMR) were 0.04 and 0.27, respectively. Furthermore, glucose (median fold change, 0.01, p=0.037), adenosine monophosphate (13 log fold, p=0.0037) and N1, N12- diacetylspermine (8 log fold p=0.011) sputum levels were significantly increased post-SR. These identified sputa and EBC indices of altered metabolism could serve as basis for further exploration of biomarkers for early detection of lung cancer, treatment response, and targets for drug discovery. Validation of these promising results by larger clinical studies is warranted.
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Affiliation(s)
- Naseer Ahmed
- CancerCare Manitoba Research Institute, Winnipeg, MB, Canada
- Department of Radiology, Section of Radiation Oncology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Biniam Kidane
- CancerCare Manitoba Research Institute, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Le Wang
- Department of Epidemiology and Cancer Registry, CancerCare Manitoba, Winnipeg, MB, Canada
- St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Zoann Nugent
- Department of Epidemiology and Cancer Registry, CancerCare Manitoba, Winnipeg, MB, Canada
| | - Nataliya Moldovan
- Department of Radiology, Section of Radiation Oncology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - April McElrea
- St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | | | - Gefei Qing
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Lawrence Tan
- Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Gordon Buduhan
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Sadeesh K. Srinathan
- Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Renelle Meyers
- BC Cancer Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Michel Aliani
- St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada
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11
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Nissinen SI, Venäläinen M, Kumpulainen P, Roine A, Häkkinen MR, Vepsäläinen J, Oksala N, Rantanen T. Discrimination between Pancreatic Cancer, Pancreatitis and Healthy Controls Using Urinary Polyamine Panel. Cancer Control 2022; 28:10732748211039762. [PMID: 35135363 PMCID: PMC8832577 DOI: 10.1177/10732748211039762] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKROUND Polyamines play an important role in cellular proliferation, and the change in polyamine metabolism is reported in various cancers. We searched for urinary polyamine signature for distinguishing between pancreatic cancer, premalignant lesions of the pancreas (PLP), acute and chronic pancreatitis, and controls. METHODS Patients and controls were prospectively recruited in three Finnish hospitals between October 2013 and June 2016. The patients provided a urine sample at the time of the diagnosis. The panel of 14 polyamines was obtained in a single run with mass spectrometry. The polyamine concentrations were analysed with quadratic discriminant analysis and cross-validated with leave-one-out cross-validation. RESULTS Sixty-eight patients with pancreatic cancer, 36 with acute pancreatitis, 18 with chronic pancreatitis and 7 with PLP were recruited, as were 53 controls. The combination of 4 polyamines - acetylputrescine, diacetylspermidine, N8-acetylspermidine and diacetylputrescine - distinguished pancreatic cancer and PLP from controls (sensitivity = 94%, specificity = 68% and AUC = 0.88). The combination of diacetylspermidine, N8-acetylspermidine and diacetylspermine distinguished acute pancreatitis from controls (sensitivity = 94%, specificity = 92%, AUC = 0.98). The combination of acetylputrescine, diacetylspermidine and diacetylputrescine distinguished chronic pancreatitis from controls (sensitivity = 98%, specificity = 71%, AUC = 0.93). CONCLUSIONS Optimally selected urinary polyamine panels discriminate between pancreatic cancer and controls, as well as between acute and chronic pancreatitis and controls.
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Affiliation(s)
- Samuli I Nissinen
- Department of Internal Medicine, School of Medicine, 205537University of Eastern Finland, Kuopio, Finland.,Department of Internal Medicine, 3701Kanta-Häme Central Hospital, Hämeenlinna, Finland
| | - Markus Venäläinen
- Department of Internal Medicine, School of Medicine, 205537University of Eastern Finland, Kuopio, Finland
| | | | - Antti Roine
- Faculty of Medicine and Health Technology, 7840Tampere University, Tampere, Finland
| | - Merja R Häkkinen
- School of Pharmacy, Biocenter Kuopio, 205537University of Eastern Finland, Kuopio, Finland
| | - Jouko Vepsäläinen
- School of Pharmacy, Biocenter Kuopio, 205537University of Eastern Finland, Kuopio, Finland
| | - Niku Oksala
- Faculty of Medicine and Health Technology, 7840Tampere University, Tampere, Finland.,Centre for Vascular Surgery and Interventional Radiology, 60670Tampere University Hospital, Tampere, Finland
| | - Tuomo Rantanen
- Department of Surgery, School of Medicine, 205537University of Eastern Finland, Kuopio, Finland
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12
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Mirzaei R, Sabokroo N, Ahmadyousefi Y, Motamedi H, Karampoor S. Immunometabolism in biofilm infection: lessons from cancer. Mol Med 2022; 28:10. [PMID: 35093033 PMCID: PMC8800364 DOI: 10.1186/s10020-022-00435-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Biofilm is a community of bacteria embedded in an extracellular matrix, which can colonize different human cells and tissues and subvert the host immune reactions by preventing immune detection and polarizing the immune reactions towards an anti-inflammatory state, promoting the persistence of biofilm-embedded bacteria in the host. MAIN BODY OF THE MANUSCRIPT It is now well established that the function of immune cells is ultimately mediated by cellular metabolism. The immune cells are stimulated to regulate their immune functions upon sensing danger signals. Recent studies have determined that immune cells often display distinct metabolic alterations that impair their immune responses when triggered. Such metabolic reprogramming and its physiological implications are well established in cancer situations. In bacterial infections, immuno-metabolic evaluations have primarily focused on macrophages and neutrophils in the planktonic growth mode. CONCLUSION Based on differences in inflammatory reactions of macrophages and neutrophils in planktonic- versus biofilm-associated bacterial infections, studies must also consider the metabolic functions of immune cells against biofilm infections. The profound characterization of the metabolic and immune cell reactions could offer exciting novel targets for antibiofilm therapy.
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Affiliation(s)
- Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Niloofar Sabokroo
- Department of Microbiology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Yaghoub Ahmadyousefi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Motamedi
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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13
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N1, N12-Diacetylspermine Is Elevated in Colorectal Cancer and Promotes Proliferation through the miR-559/CBS Axis in Cancer Cell Lines. JOURNAL OF ONCOLOGY 2021; 2021:6665704. [PMID: 34603448 PMCID: PMC8486517 DOI: 10.1155/2021/6665704] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 08/06/2021] [Accepted: 08/15/2021] [Indexed: 01/05/2023]
Abstract
N1, N12-Diacetylspermine (DiAcSpm) has been reported to be upregulated in the urine of cancer patients. Mass spectrometry has shown elevated DiAcSpm expressions in colorectal cancer (CRC) tissues. However, the diagnostic application of DiAcSpm is not available due to a lack of diagnostic grade antibodies. Also, its biological roles in CRC cells remain unexplored. In the present study, we developed an antibody that directly detected DiAcSpm expression in paraffin-embedded tissues. We also characterized its biological characteristics and underlying mechanisms. Polyclonal antibodies were generated by immunizing animals with a synthetic product of DiAcSpm. Antibody DAS AB016 showed strong sensitivity against DiAcSpm in CRC tissues. Immunohistochemistry results showed that DiAcSpm expression was significantly elevated in CRC tissues. High levels of DiAcSpm correlated with the clinical stage and Ki67 index. DiAcSpm treatment increased levels of proliferation, cell cycle progression, and cyclin D1 and cyclin E proteins in CRC cell lines, SW480 and Caco-2. DiAcSpm also upregulated ATP production in these two cell lines. RNA-sequencing showed that DiAcSpm downregulated miR-559, which was confirmed using RT-qPCR. The luciferase reporter assay, western blotting, and RT-qPCR showed that cystathionine β-synthase (CBS) was the target of miR-559. miR-559 inhibited, while CBS accelerated, CRC proliferation. In addition, CBS siRNA knockdown blocked the biological effects of DiAcSpm on CRC cells. In conclusion, DiAcSpm was found to be increased in CRC tissues using a newly developed antibody. DiAcSpm accelerated CRC proliferation by regulating the miR-559/CBS axis.
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14
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Mallafré-Muro C, Llambrich M, Cumeras R, Pardo A, Brezmes J, Marco S, Gumà J. Comprehensive Volatilome and Metabolome Signatures of Colorectal Cancer in Urine: A Systematic Review and Meta-Analysis. Cancers (Basel) 2021; 13:2534. [PMID: 34064065 PMCID: PMC8196698 DOI: 10.3390/cancers13112534] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/13/2021] [Accepted: 05/17/2021] [Indexed: 01/22/2023] Open
Abstract
To increase compliance with colorectal cancer screening programs and to reduce the recommended screening age, cheaper and easy non-invasiveness alternatives to the fecal immunochemical test should be provided. Following the PRISMA procedure of studies that evaluated the metabolome and volatilome signatures of colorectal cancer in human urine samples, an exhaustive search in PubMed, Web of Science, and Scopus found 28 studies that met the required criteria. There were no restrictions on the query for the type of study, leading to not only colorectal cancer samples versus control comparison but also polyps versus control and prospective studies of surgical effects, CRC staging and comparisons of CRC with other cancers. With this systematic review, we identified up to 244 compounds in urine samples (3 shared compounds between the volatilome and metabolome), and 10 of them were relevant in more than three articles. In the meta-analysis, nine studies met the criteria for inclusion, and the results combining the case-control and the pre-/post-surgery groups, eleven compounds were found to be relevant. Four upregulated metabolites were identified, 3-hydroxybutyric acid, L-dopa, L-histidinol, and N1, N12-diacetylspermine and seven downregulated compounds were identified, pyruvic acid, hydroquinone, tartaric acid, and hippuric acid as metabolites and butyraldehyde, ether, and 1,1,6-trimethyl-1,2-dihydronaphthalene as volatiles.
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Affiliation(s)
- Celia Mallafré-Muro
- Department of Electronics and Biomedical Engineering, University of Barcelona, 08028 Barcelona, Spain; (C.M.-M.); (A.P.); (S.M.)
- Signal and Information Processing for Sensing Systems Group, Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Maria Llambrich
- Metabolomics Interdisciplinary Group (MiL@b), Department of Electrical Electronic Engineering and Automation, Universitat Rovira i Virgili (URV), IISPV, CERCA, 43007 Tarragona, Spain; (M.L.); (J.B.)
| | - Raquel Cumeras
- Metabolomics Interdisciplinary Group (MiL@b), Department of Electrical Electronic Engineering and Automation, Universitat Rovira i Virgili (URV), IISPV, CERCA, 43007 Tarragona, Spain; (M.L.); (J.B.)
- Biomedical Research Centre, Diabetes and Associated Metabolic Disorders (CIBERDEM), ISCIII, 28029 Madrid, Spain
- Fiehn Lab, NIH West Coast Metabolomics Center, University of California Davis, Davis, CA 95616, USA
| | - Antonio Pardo
- Department of Electronics and Biomedical Engineering, University of Barcelona, 08028 Barcelona, Spain; (C.M.-M.); (A.P.); (S.M.)
| | - Jesús Brezmes
- Metabolomics Interdisciplinary Group (MiL@b), Department of Electrical Electronic Engineering and Automation, Universitat Rovira i Virgili (URV), IISPV, CERCA, 43007 Tarragona, Spain; (M.L.); (J.B.)
- Biomedical Research Centre, Diabetes and Associated Metabolic Disorders (CIBERDEM), ISCIII, 28029 Madrid, Spain
| | - Santiago Marco
- Department of Electronics and Biomedical Engineering, University of Barcelona, 08028 Barcelona, Spain; (C.M.-M.); (A.P.); (S.M.)
- Signal and Information Processing for Sensing Systems Group, Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Josep Gumà
- Oncology Department, Hospital Universitari Sant Joan de Reus, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43204 Reus, Spain;
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15
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DeDecker L, Coppedge B, Avelar-Barragan J, Karnes W, Whiteson K. Microbiome distinctions between the CRC carcinogenic pathways. Gut Microbes 2021; 13:1854641. [PMID: 33446008 PMCID: PMC8288036 DOI: 10.1080/19490976.2020.1854641] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 10/01/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer, the third leading cause of cancer-related deaths, and has been on the rise among young adults in the United States. Research has established that the colonic microbiome is different in patients with CRC compared to healthy controls, but few studies have investigated if and how the microbiome may relate to CRC progression through the serrated pathway versus the adenoma-carcinoma sequence.Our view is that progress in CRC microbiome research requires consideration of how the microbiome may contribute to CRC carcinogenesis through the distinct pathways that lead to CRC, which could enable the creation of novel and tailored prevention, screening, and therapeutic interventions. We first highlight the limitations in existing CRC microbiome research and offer corresponding solutions for investigating the microbiome's role in the adenoma-carcinoma sequence and serrated pathway. We then summarize the findings in the select human studies that included data points related to the two major carcinogenic pathways. These studies investigate the microbiome in CRC carcinogenesis and 1) utilize mucosal samples and 2) compare polyps or tumors by histopathologic type, molecular/genetic type, or location in the colon.Key findings from these studies include: 1) Fusobacterium is associated with right-sided, more advanced, and serrated lesions; 2) the colons of people with CRC have bacteria typically associated with normal oral flora; and 3) colons from people with CRC have more biofilms, and these biofilms are predominantly located in the proximal colon (single study).
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Affiliation(s)
- Lauren DeDecker
- School of Medicine, University of California, Irvine, California, USA
| | - Bretton Coppedge
- School of Biological Sciences, University of California, Irvine, California, USA
| | | | - William Karnes
- School of Medicine, University of California, Irvine, California, USA
| | - Katrine Whiteson
- School of Biological Sciences, University of California, Irvine, California, USA
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16
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Urinary charged metabolite profiling of colorectal cancer using capillary electrophoresis-mass spectrometry. Sci Rep 2020; 10:21057. [PMID: 33273632 PMCID: PMC7713069 DOI: 10.1038/s41598-020-78038-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) has increasing global prevalence and poor prognostic outcomes, and the development of low- or less invasive screening tests is urgently required. Urine is an ideal biofluid that can be collected non-invasively and contains various metabolite biomarkers. To understand the metabolomic profiles of different stages of CRC, we conducted metabolomic profiling of urinary samples. Capillary electrophoresis-time-of-flight mass spectrometry was used to quantify hydrophilic metabolites in 247 subjects with stage 0 to IV CRC or polyps, and healthy controls. The 154 identified and quantified metabolites included metabolites of glycolysis, TCA cycle, amino acids, urea cycle, and polyamine pathways. The concentrations of these metabolites gradually increased with the stage, and samples of CRC stage IV especially showed a large difference compared to other stages. Polyps and CRC also showed different concentration patterns. We also assessed the differentiation ability of these metabolites. A multiple logistic regression model using three metabolites was developed with a randomly designated training dataset and validated using the remaining data to differentiate CRC and polys from healthy controls based on a panel of urinary metabolites. These data highlight the changes in metabolites from early to late stage of CRC and also the differences between CRC and polyps.
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17
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Moriya SS, Samejima K, Taira H, Hiramatsu K, Kawakita M. ESI-Q-TOF-MS determination of polyamines and related enzyme activity for elucidating cellular polyamine metabolism. Anal Biochem 2020; 607:113831. [PMID: 32739346 DOI: 10.1016/j.ab.2020.113831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 02/17/2020] [Accepted: 06/12/2020] [Indexed: 11/28/2022]
Abstract
We developed a new procedure for the comprehensive analysis of metabolites and enzymes involved in polyamine metabolism pathways. The procedure utilizes stable isotope-labeled polyamines and directly and precisely determines labeled products from enzymatic reactions by ESI-Q-TOF-MS. The activity of different enzymes could be determined in essentially the same manner by suitably adjusting the reaction conditions for each individual enzyme. We applied the procedure to extracts of regenerating rat liver and analyzed the changes in polyamine-metabolizing enzymes and polyamine contents during recovery from partial hepatectomy. A general outline of polyamine metabolism and information of polyamine dynamics were obtained. This kind of comprehensive information would be valuable in unifying detailed but fragmentary information obtained through conventional analyses focusing on one or a few enzymes and on a limited aspect of polyamine metabolic pathway.
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Affiliation(s)
- Shun-Suke Moriya
- Stem Cell Project, Department of Advanced Research for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
| | - Keijiro Samejima
- Stem Cell Project, Department of Advanced Research for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Hideharu Taira
- Stem Cell Project, Department of Advanced Research for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Kyoko Hiramatsu
- Stem Cell Project, Department of Advanced Research for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Masao Kawakita
- Stem Cell Project, Department of Advanced Research for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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18
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Lo C, Hsu YL, Cheng CN, Lin CH, Kuo HC, Huang CS, Kuo CH. Investigating the Association of the Biogenic Amine Profile in Urine with Therapeutic Response to Neoadjuvant Chemotherapy in Breast Cancer Patients. J Proteome Res 2020; 19:4061-4070. [PMID: 32819094 DOI: 10.1021/acs.jproteome.0c00362] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Neoadjuvant treatment (NAT) can downstage breast cancer and can be utilized for different clinical applications. However, the response to NAT varies among individuals. Having effective biomarkers is important to optimize the treatment of breast cancer. Concentrations of biogenic amines have been found to show an association with cancer cell proliferation, but their clinical utility remains unclear. This study developed a postcolumn-infused internal standard (PCI-IS)-assisted liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) method for profiling biogenic amines in human urine. Putrescine-d8 was selected as the PCI-IS to calibrate the errors caused by matrix effects in the urine sample. The optimized method was applied to investigate the association between changes in 14 amines and the therapeutic response to NAT in breast cancer patients. Urine samples were collected before initiation of chemotherapy (n = 60). Our results indicated that the levels of N1-acetylspermine, spermidine, norepinephrine, and dopamine were significantly higher in the responder group than the nonresponder group. These metabolites were incorporated with clinical factors to identify NAT responders, and the prediction model showed an area under the curve value of 0.949. These observations provide remarkable insights for future studies in elucidating the roles of biogenic amines in breast cancer. Additionally, the PCI-IS-assisted amine profiling method can facilitate these studies.
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Affiliation(s)
- Chiao Lo
- Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| | - Ya-Lin Hsu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan
| | - Chih-Ning Cheng
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan
| | - Ching-Hung Lin
- Department of Medical Oncology, National Taiwan University Cancer Center Hospital, Taipei 106, Taiwan
| | - Han-Chun Kuo
- The Metabolomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei 10055, Taiwan
| | - Chiun-Sheng Huang
- Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Ching-Hua Kuo
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan.,The Metabolomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei 10055, Taiwan.,Department of Pharmacy, National Taiwan University Hospital, Taipei 100, Taiwan
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Mirzaei R, Abdi M, Gholami H. The host metabolism following bacterial biofilm: what is the mechanism of action? REVIEWS IN MEDICAL MICROBIOLOGY 2020; 31:175-182. [DOI: 10.1097/mrm.0000000000000216] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The interplay of biofilm with host leads to a range of physiological reactions of the interacting members aimed at an adaptation to the novel position. These reactions include metabolic shifts in the influenced host cell, which is most apparent when the biofilm-forming bacteria replicates surround host cells. Whilst the bacteria try to deprive micronutrients of the host, the host cell, in turn, takes many metabolic countermeasures toward the micronutrient steal. During these conflicting interplays, the bacteria stimulate metabolic host cell reactions by means of common cell envelope ingredients and particular factors mediated to virulence. Hence, there is a crucial need for cellular models that more closely reflect the in-vivo infection conditions. The profound comprehension of the metabolic host cell reactions can provide novel interesting concepts for antibacterial treatments. In this review, a summarize of the metabolic changes of the host cells after bacterial biofilm formation is presented.
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Affiliation(s)
- Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan
| | - Milad Abdi
- Student research committee, Faculty of Medicine
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran
| | - Hamid Gholami
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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20
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Loktionov A. Biomarkers for detecting colorectal cancer non-invasively: DNA, RNA or proteins? World J Gastrointest Oncol 2020; 12:124-148. [PMID: 32104546 PMCID: PMC7031146 DOI: 10.4251/wjgo.v12.i2.124] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/30/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a global problem affecting millions of people worldwide. This disease is unique because of its slow progress that makes it preventable and often curable. CRC symptoms usually emerge only at advanced stages of the disease, consequently its early detection can be achieved only through active population screening, which markedly reduces mortality due to this cancer. CRC screening tests that employ non-invasively detectable biomarkers are currently being actively developed and, in most cases, samples of either stool or blood are used. However, alternative biological substances that can be collected non-invasively (colorectal mucus, urine, saliva, exhaled air) have now emerged as new sources of diagnostic biomarkers. The main categories of currently explored CRC biomarkers are: (1) Proteins (comprising widely used haemoglobin); (2) DNA (including mutations and methylation markers); (3) RNA (in particular microRNAs); (4) Low molecular weight metabolites (comprising volatile organic compounds) detectable by metabolomic techniques; and (5) Shifts in gut microbiome composition. Numerous tests for early CRC detection employing such non-invasive biomarkers have been proposed and clinically studied. While some of these studies generated promising early results, very few of the proposed tests have been transformed into clinically validated diagnostic/screening techniques. Such DNA-based tests as Food and Drug Administration-approved multitarget stool test (marketed as Cologuard®) or blood test for methylated septin 9 (marketed as Epi proColon® 2.0 CE) show good diagnostic performance but remain too expensive and technically complex to become effective CRC screening tools. It can be concluded that, despite its deficiencies, the protein (haemoglobin) detection-based faecal immunochemical test (FIT) today presents the most cost-effective option for non-invasive CRC screening. The combination of non-invasive FIT and confirmatory invasive colonoscopy is the current strategy of choice for CRC screening. However, continuing intense research in the area promises the emergence of new superior non-invasive CRC screening tests that will allow the development of improved disease prevention strategies.
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21
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Huang YC, Chung HH, Dutkiewicz EP, Chen CL, Hsieh HY, Chen BR, Wang MY, Hsu CC. Predicting Breast Cancer by Paper Spray Ion Mobility Spectrometry Mass Spectrometry and Machine Learning. Anal Chem 2019; 92:1653-1657. [DOI: 10.1021/acs.analchem.9b03966] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Ying-Chen Huang
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
| | - Hsin-Hsiang Chung
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
| | | | - Chih-Lin Chen
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
| | - Hua-Yi Hsieh
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
| | - Bo-Rong Chen
- Department of Surgery, National Taiwan University Hospital, Taipei 10002, Taiwan
| | - Ming-Yang Wang
- Department of Surgery, National Taiwan University Hospital, Taipei 10002, Taiwan
| | - Cheng-Chih Hsu
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
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22
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Suntornsuk W, Suntornsuk L. Recent applications of paper‐based point‐of‐care devices for biomarker detection. Electrophoresis 2019; 41:287-305. [DOI: 10.1002/elps.201900258] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 09/30/2019] [Accepted: 10/05/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Worapot Suntornsuk
- Department of Microbiology, Faculty of ScienceKing Mongkut's University of Technology Thonburi Bangkok Thailand
| | - Leena Suntornsuk
- Department of Pharmaceutical ChemistryFaculty of PharmacyMahidol University Bangkok Thailand
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23
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Iwasaki H, Shimura T, Kataoka H. Current status of urinary diagnostic biomarkers for colorectal cancer. Clin Chim Acta 2019; 498:76-83. [PMID: 31421118 DOI: 10.1016/j.cca.2019.08.011] [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: 07/11/2019] [Revised: 08/13/2019] [Accepted: 08/13/2019] [Indexed: 02/07/2023]
Abstract
Fecal occult blood test (FOBT) and flexible sigmoidoscopy are the currently using screening methods for colorectal cancer (CRC). However, these methods still have problems of high false positive rates in FOBT and increased invasiveness and cost associated with endoscopy. The development of non-invasive biomarkers is thus important for the diagnosis of CRC. Urine is one of the most commonly used samples for mass screening owing to its non-invasive and simple process of collection; however, the discovery of urinary diagnostic biomarkers for malignancies is still challenging and developing. Since urine contains abundant substances reflecting systemic body condition, urinary biomarker might contribute to detect CRC in a completely non-invasive manner. In this review, we describe the current utility of urinary diagnostic biomarkers for CRC.
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Affiliation(s)
- Hiroyasu Iwasaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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24
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Deng L, Ismond K, Liu Z, Constable J, Wang H, Alatise OI, Weiser MR, Kingham TP, Chang D. Urinary Metabolomics to Identify a Unique Biomarker Panel for Detecting Colorectal Cancer: A Multicenter Study. Cancer Epidemiol Biomarkers Prev 2019; 28:1283-1291. [PMID: 31151939 PMCID: PMC6677589 DOI: 10.1158/1055-9965.epi-18-1291] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/29/2019] [Accepted: 05/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Population-based screening programs are credited with earlier colorectal cancer diagnoses and treatment initiation, which reduce mortality rates and improve patient health outcomes. However, recommended screening methods are unsatisfactory as they are invasive, are resource intensive, suffer from low uptake, or have poor diagnostic performance. Our goal was to identify a urine metabolomic-based biomarker panel for the detection of colorectal cancer that has the potential for global population-based screening. METHODS Prospective urine samples were collected from study participants. Based upon colonoscopy and histopathology results, 342 participants (colorectal cancer, 171; healthy controls, 171) from two study sites (Canada, United States) were included in the analyses. Targeted liquid chromatography-mass spectrometry (LC-MS) was performed to quantify 140 highly valuable metabolites in each urine sample. Potential biomarkers for colorectal cancer were identified by comparing the metabolomic profiles from colorectal cancer versus controls. Multiple models were constructed leading to a good separation of colorectal cancer from controls. RESULTS A panel of 17 metabolites was identified as possible biomarkers for colorectal cancer. Using only two of the selected metabolites, namely diacetylspermine and kynurenine, a predictor for detecting colorectal cancer was developed with an AUC of 0.864, a specificity of 80.0%, and a sensitivity of 80.0%. CONCLUSIONS We present a potentially "universal" metabolomic biomarker panel for colorectal cancer independent of cohort clinical features based on a North American population. Further research is needed to confirm the utility of the profile in a prospective, population-based colorectal cancer screening trial. IMPACT A urinary metabolomic biomarker panel was identified for colorectal cancer with the potential of clinical application.
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Affiliation(s)
- Lu Deng
- Metabolomic Technologies Inc., Edmonton, Alberta, Canada.
| | - Kathleen Ismond
- Metabolomic Technologies Inc., Edmonton, Alberta, Canada
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Zhengjun Liu
- Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Jeremy Constable
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Haili Wang
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Olusegun I Alatise
- Department of Surgery, Obafemi Awolowo University and Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria
| | - Martin R Weiser
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - T P Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David Chang
- Metabolomic Technologies Inc., Edmonton, Alberta, Canada
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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25
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Salivary metabolomics with alternative decision tree-based machine learning methods for breast cancer discrimination. Breast Cancer Res Treat 2019; 177:591-601. [PMID: 31286302 DOI: 10.1007/s10549-019-05330-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 06/18/2019] [Indexed: 12/15/2022]
Abstract
PURPOSE The aim of this study is to explore new salivary biomarkers to discriminate breast cancer patients from healthy controls. METHODS Saliva samples were collected after 9 h fasting and were immediately stored at - 80 °C. Capillary electrophoresis and liquid chromatography with mass spectrometry were used to quantify hundreds of hydrophilic metabolites. Conventional statistical analyses and artificial intelligence-based methods were used to assess the discrimination abilities of the quantified metabolites. A multiple logistic regression (MLR) model and an alternative decision tree (ADTree)-based machine learning method were used. The generalization abilities of these mathematical models were validated in various computational tests, such as cross-validation and resampling methods. RESULTS One hundred sixty-six unstimulated saliva samples were collected from 101 patients with invasive carcinoma of the breast (IC), 23 patients with ductal carcinoma in situ (DCIS), and 42 healthy controls (C). Of the 260 quantified metabolites, polyamines were significantly elevated in the saliva of patients with breast cancer. Spermine showed the highest area under the receiver operating characteristic curves [0.766; 95% confidence interval (CI) 0.671-0.840, P < 0.0001] to discriminate IC from C. In addition to spermine, polyamines and their acetylated forms were elevated in IC only. Two hundred each of two-fold, five-fold, and ten-fold cross-validation using different random values were conducted and the MLR model had slightly better accuracy. The ADTree with an ensemble approach showed higher accuracy (0.912; 95% CI 0.838-0.961, P < 0.0001). These prediction models also included spermine as a predictive factor. CONCLUSIONS These data indicated that combinations of salivary metabolomics with the ADTree-based machine learning methods show potential for non-invasive screening of breast cancer.
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26
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Hong JT, Kim ER. Current state and future direction of screening tool for colorectal cancer. World J Meta-Anal 2019; 7:184-208. [DOI: 10.13105/wjma.v7.i5.184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 05/25/2019] [Accepted: 05/28/2019] [Indexed: 02/06/2023] Open
Abstract
As the second-most-common cause of cancer death, colorectal cancer (CRC) has been recognized as one of the biggest health concerns in advanced countries. The 5-year survival rate for patients with early-stage CRC is significantly better than that for patients with CRC detected at a late stage. The primary target for CRC screening and prevention is advanced neoplasia, which includes both CRC itself, as well as benign but histologically advanced adenomas that are at increased risk for progression to malignancy. Prevention of CRC through detection of advanced adenomas is important. It is, therefore, necessary to develop more efficient detection methods to enable earlier detection and therefore better prognosis. Although a number of CRC diagnostic methods are currently used for early detection, including stool-based tests, traditional colonoscopy, etc., they have not shown optimal results due to several limitations. Hence, development of more reliable screening methods is required in order to detect the disease at an early stage. New screening tools also need to be able to accurately diagnose CRC and advanced adenoma, help guide treatment, and predict the prognosis along with being relatively simple and non-invasive. As part of such efforts, many proposals for the early detection of colorectal neoplasms have been introduced. For example, metabolomics, referring to the scientific study of the metabolism of living organisms, has been shown to be a possible approach for discovering CRC-related biomarkers. In addition, a growing number of high-performance screening methodologies could facilitate biomarker identification. In the present, evidence-based review, the authors summarize the current state as recognized by the recent guideline recommendation from the American Cancer Society, US Preventive Services Task Force and the United States Multi-Society Task Force and discuss future direction of screening tools for colorectal cancer. Further, we highlight the most interesting publications on new screening tools, like molecular biomarkers and metabolomics, and discuss these in detail.
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Affiliation(s)
- Ji Taek Hong
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24253, South Korea
| | - Eun Ran Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
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27
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DeFelice BC, Fiehn O. Rapid LC-MS/MS quantification of cancer related acetylated polyamines in human biofluids. Talanta 2018; 196:415-419. [PMID: 30683386 DOI: 10.1016/j.talanta.2018.12.074] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 12/21/2018] [Accepted: 12/24/2018] [Indexed: 11/17/2022]
Abstract
Increased urinary acetylated polyamines (APs) are reported as cancer biomarkers in many studies. N1,N12-diacetylspermine has been proposed as a biomarker indicative of different cancers in urine and plasma. N1-Acetylspermine has previously been found to be increased in the saliva of patients with breast cancer; however, in plasma this metabolite was too low abundant to be detected by previous analytical methods. In addition, no method has been reported to perform AP analysis on the level of speed, robustness and sensitivity required for daily clinical routines. Here we describe a high-throughput sample preparation and LC-MS/MS method for the fast, accurate and precise quantification of three APs: N8-acetylspermidine, N1-acetylspermine, and N1,N12-diacetylspermine in plasma, urine and saliva. Stable isotope labeled N1,N12-diacetylspermine was used as internal standard. Robustness was validated by intra- and inter-day reproducibility. Precision and accuracy of the method were tested at six concentration levels from 0.0375 to 750 ng/mL resulting in less than 15% relative standard deviation and less than 15% percent error in quantification. Using 96-well plates, the assay described herein allows for preparing, analyzing, and quantifying 240 samples per day for a single researcher to quantify three APs commonly related to cancer status.
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Affiliation(s)
- Brian C DeFelice
- University of California, One Shields Avenue, Davis, CA 95616, USA
| | - Oliver Fiehn
- University of California, One Shields Avenue, Davis, CA 95616, USA.
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28
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Gerner EW, Bruckheimer E, Cohen A. Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer. J Biol Chem 2018; 293:18770-18778. [PMID: 30355737 DOI: 10.1074/jbc.tm118.003343] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cancer is a set of diseases characterized by uncontrolled cell growth. In certain cancers of the gastrointestinal tract, the adenomatous polyposis coli (APC) tumor suppressor gene is altered in either germline or somatic cells and causes formation of risk factors, such as benign colonic or intestinal neoplasia, which can progress to invasive cancer. APC is a key component of the WNT pathway, contributing to normal GI tract development, and APC alteration results in dysregulation of the pathway for production of polyamines, which are ubiquitous cations essential for cell growth. Studies with mice have identified nonsteroidal anti-inflammatory drugs (NSAIDs) and difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, as potent inhibitors of colon carcinogenesis. Moreover, gene expression profiling has uncovered that NSAIDs activate polyamine catabolism and export. Several DFMO-NSAID combination strategies are effective and safe methods for reducing risk factors in clinical trials with patients having genetic or sporadic risk of colon cancer. These strategies affect cancer stem cells, inflammation, immune surveillance, and the microbiome. Pharmacotherapies consisting of drug combinations targeting the polyamine pathway provide a complementary approach to surgery and cytotoxic cancer treatments for treating patients with cancer risk factors. In this Minireview, we discuss the role of polyamines in colon cancer and highlight the mechanisms of select pharmacoprevention agents to delay or prevent carcinogenesis in humans.
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Affiliation(s)
- Eugene W Gerner
- From Cancer Prevention Pharmaceuticals, Tucson, Arizona 85718 and .,the Department of Cell and Molecular Medicine, University of Arizona, Tucson, Arizona 85711
| | | | - Alfred Cohen
- From Cancer Prevention Pharmaceuticals, Tucson, Arizona 85718 and
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29
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Schunkert EM, Zhao W, Zänker K. Breast Cancer Recurrence Risk Assessment: Is Non-Invasive Monitoring an Option? Biomed Hub 2018; 3:1-17. [PMID: 31988964 PMCID: PMC6945973 DOI: 10.1159/000492929] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 08/13/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Metastatic breast cancer (MBC) represents a life-threatening disease with a median survival time of 18-24 months that often can only be treated palliatively. The majority of women suffering from MBC are those who had been previously diagnosed with locally advanced disease and subsequently experienced cancer recurrence in the form of metastasis. However, according to guidelines, no systemic follow-up for monitoring purposes is recommended for these women. The purpose of this article is to review current methods of recurrent risk assessment as well as non-invasive monitoring options for women at risk for distant disease relapse and metastasis formation. METHODS We used PubMed and national guidelines, such as the National Comprehensive Cancer Network (NCCN), to find recently published studies on breast cancer recurrence risk assessment and systemic monitoring of breast cancer patients through non-invasive means. RESULTS The options for recurrence risk assessment of locally invasive breast cancer has improved due to diverse genetic tests, such as Oncotype DX, MammaPrint, the PAM50 (now known as the "Prosigna Test") assay, EndoPredict (EP), and the Breast Cancer Index (BCI), which evaluate a women's risk of relapse according to certain cancer-gene expression patterns. Different promising non-invasive urinary protein-based biomarkers with metastasis surveillance potential that have been identified are MMP-2, MMP-9, NGAL, and ADAM12. In particular, ααCTX, ββCTX, and NTX could help to monitor bone metastasis. CONCLUSION In times of improved recurrence risk assessment of women with breast cancer, non-invasive biomarkers are urgently needed as potential monitoring options for women who have an increased risk of recurrence. Urine as a bioliquid of choice provides several advantages - it is non-invasive, can be obtained easily and frequently, and is economical. Promising biomarkers that could help to follow up women with increased recurrence risk have been identified. In order for them to be implemented in clinical usage and national guideline recommendations, further validation in larger independent cohorts will be needed.
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Affiliation(s)
- Elisa M. Schunkert
- Institute of Immunology, Faculty of Health Science, Department of Medicine and School of Life Sciences (ZBAF), University of Witten-Herdecke, Witten, Germany
| | - Wanzhou Zhao
- Nanjing Han and Zaenker Cancer Institute, Nanjing, China
| | - Kurt Zänker
- Institute of Immunology, Faculty of Health Science, Department of Medicine and School of Life Sciences (ZBAF), University of Witten-Herdecke, Witten, Germany
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30
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Erben V, Bhardwaj M, Schrotz-King P, Brenner H. Metabolomics Biomarkers for Detection of Colorectal Neoplasms: A Systematic Review. Cancers (Basel) 2018; 10:E246. [PMID: 30060469 PMCID: PMC6116151 DOI: 10.3390/cancers10080246] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 07/23/2018] [Accepted: 07/25/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Several approaches have been suggested to be useful in the early detection of colorectal neoplasms. Since metabolites are closely related to the phenotype and are available from different human bio-fluids, metabolomics are candidates for non-invasive early detection of colorectal neoplasms. OBJECTIVES We aimed to summarize current knowledge on performance characteristics of metabolomics biomarkers that are potentially applicable in a screening setting for the early detection of colorectal neoplasms. DESIGN We conducted a systematic literature search in PubMed and Web of Science and searched for biomarkers for the early detection of colorectal neoplasms in easy-to-collect human bio-fluids. Information on study design and performance characteristics for diagnostic accuracy was extracted. RESULTS Finally, we included 41 studies in our analysis investigating biomarkers in different bio-fluids (blood, urine, and feces). Although single metabolites mostly had limited ability to distinguish people with and without colorectal neoplasms, promising results were reported for metabolite panels, especially amino acid panels in blood samples, as well as nucleosides in urine samples in several studies. However, validation of the results is limited. CONCLUSIONS Panels of metabolites consisting of amino acids in blood and nucleosides in urinary samples might be useful biomarkers for early detection of advanced colorectal neoplasms. However, to make metabolomic biomarkers clinically applicable, future research in larger studies and external validation of the results is required.
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Affiliation(s)
- Vanessa Erben
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
- Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany.
| | - Megha Bhardwaj
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
- Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany.
| | - Petra Schrotz-King
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
- German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
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31
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Urinary Polyamine Biomarker Panels with Machine-Learning Differentiated Colorectal Cancers, Benign Disease, and Healthy Controls. Int J Mol Sci 2018. [PMID: 29518931 PMCID: PMC5877617 DOI: 10.3390/ijms19030756] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most daunting diseases due to its increasing worldwide prevalence, which requires imperative development of minimally or non-invasive screening tests. Urinary polyamines have been reported as potential markers to detect CRC, and an accurate pattern recognition to differentiate CRC with early stage cases from healthy controls are needed. Here, we utilized liquid chromatography triple quadrupole mass spectrometry to profile seven kinds of polyamines, such as spermine and spermidine with their acetylated forms. Urinary samples from 201 CRCs and 31 non-CRCs revealed the N1,N12-diacetylspermine showing the highest area under the receiver operating characteristic curve (AUC), 0.794 (the 95% confidence interval (CI): 0.704–0.885, p < 0.0001), to differentiate CRC from the benign and healthy controls. Overall, 59 samples were analyzed to evaluate the reproducibility of quantified concentrations, acquired by collecting three times on three days each from each healthy control. We confirmed the stability of the observed quantified values. A machine learning method using combinations of polyamines showed a higher AUC value of 0.961 (95% CI: 0.937–0.984, p < 0.0001). Computational validations confirmed the generalization ability of the models. Taken together, polyamines and a machine-learning method showed potential as a screening tool of CRC.
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32
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Xie Y, Chen L, Lv X, Hou G, Wang Y, Jiang C, Zhu H, Xu N, Wu L, Lou X, Liu S. The levels of serine proteases in colon tissue interstitial fluid and serum serve as an indicator of colorectal cancer progression. Oncotarget 2018; 7:32592-606. [PMID: 27081040 PMCID: PMC5078036 DOI: 10.18632/oncotarget.8693] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 03/28/2016] [Indexed: 02/06/2023] Open
Abstract
The proteins in tissue interstitial fluids (TIFs) can spread into the blood and have been proposed as an ideal material to find blood biomarkers. The colon TIFs were collected from 8-, 13-, 18-, and 22-week ApcMin/+, a typical mouse model of colorectal cancer (CRC), and wild-type mice. iTRAQ-based quantification proteomics was conducted to survey the TIF proteins whose abundance appeared to depend on tumor progression. A total of 46 proteins that exhibited consecutive changes in abundance were identified, including six serine proteases, chymotrypsin-like elastase 1 (CELA1), chymotrypsin-like elastase 2A (CEL2A), chymopasin, chymotrypsinogen B (CTRB1), trypsin 2 (TRY2), and trypsin 4 (TRY4). The observed increases in the abundance of serine proteases were supported in another quantitative evaluation of the individual colon TIFs using a multiple reaction monitor (MRM) assay. Importantly, the increases in the abundance of serine proteases were also verified in the corresponding sera. The quantitative verification of the serine proteases was further extended to the clinical sera, revealing significantly higher levels of CELA1, CEL2A, CTRL/chymopasin, and TRY2 in CRC patients. The receiver operating characteristic analysis illustrated that the combination of CELA1 and CTRL reached the best diagnostic performance, with 90.0% sensitivity and 80.0% specificity. Thus, the quantitative target analysis demonstrated that some serine proteases are indicative of CRC progression.
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Affiliation(s)
- Yingying Xie
- CAS Key Laboratory of Genome Sciences and Information, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lechuang Chen
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaolei Lv
- Beijing Protein Innovation, Beijing, 101318, China
| | - Guixue Hou
- CAS Key Laboratory of Genome Sciences and Information, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yang Wang
- CAS Key Laboratory of Genome Sciences and Information, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cuicui Jiang
- Beijing Protein Innovation, Beijing, 101318, China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ningzhi Xu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Wu
- CAS Key Laboratory of Genome Sciences and Information, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaomin Lou
- CAS Key Laboratory of Genome Sciences and Information, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Siqi Liu
- CAS Key Laboratory of Genome Sciences and Information, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China.,Beijing Protein Innovation, Beijing, 101318, China.,Proteomics Division, BGI-Shenzhen, Shenzhen, Guangdong, 518083, China
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Niemi RJ, Roine AN, Häkkinen MR, Kumpulainen PS, Keinänen TA, Vepsäläinen JJ, Lehtimäki T, Oksala NK, Mäenpää JU. Urinary Polyamines as Biomarkers for Ovarian Cancer. Int J Gynecol Cancer 2017; 27:1360-1366. [PMID: 28604456 DOI: 10.1097/igc.0000000000001031] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVES Elevated concentrations of polyamines have been found in urine of patients with malignant tumors, including ovarian cancer. Previous research has suffered from poorly standardized detection methods. Our liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is capable of simultaneous standardized analysis of most known polyamines. Liquid chromatography-tandem mass spectrometry has not previously been used in the differential diagnostics of ovarian tumors in postmenopausal women. MATERIALS AND METHODS In this prospective study, postmenopausal women (n = 71) presenting with an adnexal mass and, as controls, women with genital prolapse or urinary incontinence scheduled for surgery (n = 22) were recruited in the study. For analysis of the polyamines, a morning urine sample was obtained before surgery. Preoperative serum CA125 concentrations were determined in the study group. RESULTS Twenty-three women with benign and 37 with malignant ovarian tumors were eligible. Of all analyzed polyamines, only urinary N,N-diacetylspermine showed statistically significant differences between all groups except controls versus benign tumors. N,N-diacetylspermine was elevated in malignant versus benign tumors (P < 0.001), in high-grade versus low malignant potential tumors (P < 0.001), in stage III to IV versus stage I to II cancers (P < 0.001), and even in early-stage cancer (stage I-II) versus benign tumors (P = 0.017). N,N-diacetylspermine had better sensitivity (86.5%) but lower specificity (65.2%) for distinguishing benign and malignant ovarian tumors than CA125 with a cut-off value of 35 kU/L (sensitivity, 75.7%; specificity, 69.6%). CONCLUSIONS Urinary N,N-diacetylspermine seems to be able to distinguish benign and malignant ovarian tumors as well as early and advanced stage, and low malignant potential and high-grade ovarian cancers from each other, respectively.
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Affiliation(s)
- Riikka Johanna Niemi
- *Department of Obstetrics and Gynecology, Tampere University Hospital; †Faculty of Medicine and Life Sciences, University of Tampere, Tampere; ‡School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Kuopio; §Digital Health Solutions; ∥Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences; ¶Department of Surgery, Faculty of Medicine and Life Sciences, University of Tampere; #Department of Vascular Surgery, Tampere University Hospital; and **Department of Obstetrics and Gynecology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
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Rattray NJW, Charkoftaki G, Rattray Z, Hansen JE, Vasiliou V, Johnson CH. Environmental influences in the etiology of colorectal cancer: the premise of metabolomics. CURRENT PHARMACOLOGY REPORTS 2017; 3:114-125. [PMID: 28642837 PMCID: PMC5475285 DOI: 10.1007/s40495-017-0088-z] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW In this review we discuss how environmental exposures predominate the etiology of colorectal cancer (CRC). With CRC being a personalized disease influenced by genes and environment, our goal was to explore the role metabolomics can play in identifying exposures, assessing the interplay between co-exposures, and the development of personalized therapeutic interventions. RECENT FINDINGS Approximately 10 % of CRC cases can be explained by germ-line mutations, whereas the prevailing majority are caused by an initiating exposure event occurring decades prior to diagnosis. Recent research has shown that dietary metabolites are linked to a procarcinogenic or protective environment in the colon which is modulated by the microbiome. In addition, excessive alcohol has been shown to increase the risk of CRC and is dependent on diet (folate), the response of microbiome, and genetic polymorphisms within the folate and alcohol metabolic pathways. Metabolomics can not only be used to identify this modulation of host metabolism, which could affect the progression of the tumors but also response to targeted therapeutics. SUMMARY This review highlights the current understanding of the multifaceted etiology and mechanisms of CRC development but also highlights where the field of metabolomics can contribute to a greater understanding of environmental exposure in CRC.
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Affiliation(s)
- Nicholas J. W. Rattray
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
| | - Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
| | - Zahra Rattray
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Yale University, CT, USA 06520
| | - James E. Hansen
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Yale University, CT, USA 06520
- Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA 06520
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
| | - Caroline H. Johnson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520
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Altobelli E, Angeletti PM, Latella G. Role of Urinary Biomarkers in the Diagnosis of Adenoma and Colorectal Cancer: A Systematic Review and Meta-Analysis. J Cancer 2016; 7:1984-2004. [PMID: 27877214 PMCID: PMC5118662 DOI: 10.7150/jca.16244] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 07/16/2016] [Indexed: 12/23/2022] Open
Abstract
The growing interest in enhancing and spreading colorectal cancer (CRC) screening has been stimulating the exploration of novel biomarkers with greater sensitivity and specificity than immunochemical faecal occult blood test (iFOBT). The present study provides i) a systematic review of the urinary biomarkers that have been tested to achieve early CRC diagnosis and assess the risk of colorectal adenoma and adenocarcinoma, and ii) a meta-analysis of the data regarding the urinary prostaglandin (PG) metabolite PGE-M. As regard to gene markers, we found significantly different percent methylation of the vimentin gene in CRC patients and healthy controls (HC) (p<0.0001). Respect to metabolism of nitrogenous bases, cytidine, 1-methyladenosine, and adenosine, have higher concentrations in CRC patients than in HC (respectively, p<0.01, p=0.01, and p<0.01). As regard to spermine we found that N1,N12 diacetyl spermine (DiAcSpm) and N1, N8 diacetylspermidine (DiAcSpd) were significantly higher in CRC than in HC (respectively p=0.01 and p<0.01). Respect to PGE-M, levels were higher in CRC than in those with multiple polyposis (p<0.006) and HC subjects (p<0.0004). PGE-M seems to be the most interesting and promising urinary marker for CRC and adenoma risk assessment and for CRC screening. In conclusion, evidence suggests that urinary biomarker could have a potential role as urinary biomarkers in the diagnosis of colorectal cancer. Particularly, PGE-M seems to be the most promising urinary marker for CRC early detection.
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Affiliation(s)
- Emma Altobelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
- Epidemiology and Biostatistics Unit, AUSL Teramo, University of L'Aquila, L'Aquila, Italy
| | - Paolo Matteo Angeletti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Giovanni Latella
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
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Urinary Polyamines: A Pilot Study on Their Roles as Prostate Cancer Detection Biomarkers. PLoS One 2016; 11:e0162217. [PMID: 27598335 PMCID: PMC5012650 DOI: 10.1371/journal.pone.0162217] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 08/18/2016] [Indexed: 12/17/2022] Open
Abstract
Current screening methods towards prostate cancer (PCa) are not without limitations. Research work has been on-going to assess if there are other better tests suitable for primary or secondary screening of PCa to supplement the serum prostate specific antigen (PSA) test, which fails to work accurately in a grey zone of 4-10ng/ml. In this pilot study, the potential roles of urinary polyamines as prostate cancer biomarkers were evaluated. PCa, benign prostatic hyperplasia (BPH) patients and healthy controls (HC) showing PSA>4.0ng/ml were enrolled in the study. Their urine samples were obtained, and the urinary levels of putrescine (Put), spermidine (Spd) and spermine (Spm) were determined by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometer (UPLC-MS/MS). Receiver operating characteristics (ROC) curve and Student’s t-test were used to evaluate their diagnostic accuracies. Among the three biogenic polyamines, Spm had demonstrated a good diagnostic performance when comparing their levels in PCa patients with BPH patients (1.47 in PCa vs 5.87 in BPH; p<0.0001). Results are in accordance with transrectal ultrasound prostatic biopsy (TRUSPB) results, with an area under curve (AUC) value of 0.83±0.03. Therefore urinary Spm shows potential to serve as a novel PCa diagnostic biomarker, which in turn can help to address the limited sensitivity and specificity problem of serum PSA test.
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Abstract
It is now widely recognized that a range of human diseases, including obesity, cancer and inflammatory bowel disease, is strongly linked to the microbiota. For decades, the microbiota has been proposed to contribute to the pathogenesis of colon cancer. Our recent work reveals that the organization of the mucosal microbiota into biofilms marks a subset of human colon cancer. Further, biofilm-positive colon mucosa in the colon cancer host yields an infrequently detected polyamine metabolite, N(1), N(12)-diacetylspermine, that deserves further study to determine its utility as a marker for colon neoplasia.
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Affiliation(s)
- Christine M. Dejea
- Department of Oncology, Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Cynthia L. Sears
- Department of Oncology, Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA,Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
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Takahashi Y, Sakaguchi K, Horio H, Hiramatsu K, Moriya S, Takahashi K, Kawakita M. Urinary N1, N12-diacetylspermine is a non-invasive marker for the diagnosis and prognosis of non-small-cell lung cancer. Br J Cancer 2015; 113:1493-501. [PMID: 26505680 PMCID: PMC4815893 DOI: 10.1038/bjc.2015.349] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 09/05/2015] [Accepted: 09/09/2015] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Early detection of non-small-cell lung cancer (NSCLC) and accurate prognostic risk assessment could improve patient outcome. We examined the significance of urinary N(1), N(12)-diacetylspermine (DiAcSpm) in the detection and prognostic stratification of NSCLC patients. METHODS A DiAcSpm/cutoff ratio (DASr) was established for 260 NSCLC patients, 99 benign lung disease patients, and 140 healthy volunteers, using colloidal gold aggregation methods. The DASr was compared between patients and healthy controls, and the prognostic significance of DASr was examined. RESULTS The median urinary DASr of NSCLC patients was significantly higher than that of healthy controls (0.810 vs 0.534, P<0.001). The DASr was higher in squamous cell carcinoma (SqCC) patients than in adenocarcinoma patients (1.18 vs 0.756, respectively, P=0.039). An increased urinary DASr value was significantly associated with pathological stage, other histological invasive factors and unfavourable outcomes in patients with completely resected NSCLC. Multivariate Cox regression analysis showed that increased urinary DASr was an independent prognostic factor (hazard ratio=4.652, 95% confidence interval (CI), 2.092-10.35; P<0.001). CONCLUSIONS Urinary DASr was significantly increased in NSCLC, especially in SqCC. Urinary DASr was an independent poor prognostic indicator in patients with completely resected NSCLC. The DASr could be a useful biomarker for detecting malignancies and predicting prognosis.
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Affiliation(s)
- Yusuke Takahashi
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
- Department of General Thoracic Surgery, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Koji Sakaguchi
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
- Department of Thoracic Surgery, Nagano Prefectural Suzaka Hospital, Suzaka, Nagano, Japan
| | - Hirotoshi Horio
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Kyoko Hiramatsu
- Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan
| | - Shunsuke Moriya
- Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan
| | - Keiichi Takahashi
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Masao Kawakita
- Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan
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Wikoff WR, Hanash S, DeFelice B, Miyamoto S, Barnett M, Zhao Y, Goodman G, Feng Z, Gandara D, Fiehn O, Taguchi A. Diacetylspermine Is a Novel Prediagnostic Serum Biomarker for Non-Small-Cell Lung Cancer and Has Additive Performance With Pro-Surfactant Protein B. J Clin Oncol 2015; 33:3880-6. [PMID: 26282655 DOI: 10.1200/jco.2015.61.7779] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE We have investigated the potential of metabolomics to discover blood-based biomarkers relevant to lung cancer screening and early detection. An untargeted metabolomics approach was applied to identify biomarker candidates using prediagnostic sera from the Beta-Carotene and Retinol Efficacy Trial (CARET) study. PATIENTS AND METHODS A liquid chromatography/mass spectrometry hydrophilic interaction method designed to profile a wide range of metabolites was applied to prediagnostic serum samples from CARET participants (current or former heavy smokers), consisting of 100 patients who subsequently developed non-small-cell lung cancer (NSCLC) and 199 matched controls. A separate aliquot was used to quantify levels of pro-surfactant protein B (pro-SFTPB), a previously established protein biomarker for NSCLC. On the basis of the results from the discovery set, blinded validation of a metabolite, identified as N(1),N(12)-diacetylspermine (DAS), and pro-SFTPB was performed using an independent set of CARET prediagnostic sera from 108 patients with NSCLC and 216 matched controls. RESULTS Serum DAS was elevated by 1.9-fold, demonstrating significant specificity and sensitivity in the discovery set for samples collected up to 6 months before diagnosis of NSCLC. In addition, DAS significantly complemented performance of pro-SFTPB in both the discovery and validations sets, with a combined area under the curve in the validation set of 0.808 (P < .001 v pro-SFTPB). CONCLUSION DAS is a novel serum metabolite with significant performance in prediagnostic NSCLC and has additive performance with pro-SFTPB.
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Affiliation(s)
- William R Wikoff
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Samir Hanash
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Brian DeFelice
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Suzanne Miyamoto
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Matt Barnett
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Yang Zhao
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Gary Goodman
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Ziding Feng
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - David Gandara
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
| | - Oliver Fiehn
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
| | - Ayumu Taguchi
- William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA
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Saulnier Sholler GL, Gerner EW, Bergendahl G, MacArthur RB, VanderWerff A, Ashikaga T, Bond JP, Ferguson W, Roberts W, Wada RK, Eslin D, Kraveka JM, Kaplan J, Mitchell D, Parikh NS, Neville K, Sender L, Higgins T, Kawakita M, Hiramatsu K, Moriya SS, Bachmann AS. A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma. PLoS One 2015; 10:e0127246. [PMID: 26018967 PMCID: PMC4446210 DOI: 10.1371/journal.pone.0127246] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 04/11/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB. METHODS AND FINDINGS Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). CONCLUSIONS DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. TRIAL REGISTRATION Clinicaltrials.gov NCT#01059071.
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Affiliation(s)
- Giselle L. Saulnier Sholler
- Helen DeVos Children’s Hospital, Grand Rapids, Michigan, United States of America
- College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America
| | - Eugene W. Gerner
- Cancer Prevention Pharmaceuticals, Tucson, Arizona, United States of America
| | - Genevieve Bergendahl
- Helen DeVos Children’s Hospital, Grand Rapids, Michigan, United States of America
| | - Robert B. MacArthur
- Cancer Prevention Pharmaceuticals, Tucson, Arizona, United States of America
| | - Alyssa VanderWerff
- Helen DeVos Children’s Hospital, Grand Rapids, Michigan, United States of America
| | - Takamaru Ashikaga
- Medical Biostatistics, University of Vermont, Burlington, Vermont, United States of America
| | - Jeffrey P. Bond
- Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, United States of America
| | - William Ferguson
- Cardinal Glennon Children's Hospital, St. Louis, Missouri, United States of America
| | - William Roberts
- University of California San Diego School of Medicine and Rady Children's Hospital, San Diego, California, United States of America
| | - Randal K. Wada
- Kapiolani Medical Center for Women and Children, Honolulu, Hawaii, United States of America
| | - Don Eslin
- Arnold Palmer Hospital for Children, Orlando, Florida, United States of America
| | - Jacqueline M. Kraveka
- Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Joel Kaplan
- Levine Children's Hospital, Charlotte, North Carolina, United States of America
| | - Deanna Mitchell
- Helen DeVos Children’s Hospital, Grand Rapids, Michigan, United States of America
| | - Nehal S. Parikh
- Connecticut Children's Medical Center, Hartford, Connecticut, United States of America
| | - Kathleen Neville
- Children's Mercy Hospitals and Clinics, Kansas City, Missouri, United States of America
| | - Leonard Sender
- Children’s Hospital of Orange County, Orange, California, United States of America
| | - Timothy Higgins
- Medical Biostatistics, University of Vermont, Burlington, Vermont, United States of America
| | - Masao Kawakita
- Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Kyoko Hiramatsu
- Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | | | - André S. Bachmann
- College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America
- University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, Hawaii, United States of America
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Takahashi Y, Horio H, Sakaguchi K, Hiramatsu K, Kawakita M. Significant correlation between urinary N(1), N(12)-diacetylspermine and tumor invasiveness in patients with clinical stage IA non-small cell lung cancer. BMC Cancer 2015; 15:65. [PMID: 25884987 PMCID: PMC4391126 DOI: 10.1186/s12885-015-1068-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 02/03/2015] [Indexed: 01/15/2023] Open
Abstract
Background To select optimal candidates for limited lung resection, it is necessary to accurately differentiate the non-invasive tumors from other small-sized lung cancer. Urinary N1, N12-diacetylspermine (DiAcSpm) has been reported to be a useful tumor marker for various cancers. We aimed to examine the correlation between preoperative urinary DiAcSpm levels and specific clinicopathological characteristics such as the histological tumor invasiveness in patients with clinical stage IA non-small cell lung cancer (NSCLC). Methods We defined non-invasive tumors as NSCLC showing no vascular invasion, lymphatic permeation, pleural invasion, or lymph node metastasis. Preoperative urine samples were obtained from 516 consecutive patients with NSCLC resected at our institution between April 2008 and January 2013. Urinary DiAcSpm values were determined for all preoperative urine samples using the colloid gold aggregation procedure. Among these patients, 171 patients with clinical stage IA NSCLC met the criteria of our study cohort. Finally, we investigated the correlation between non-invasive tumor and urinary DiAcSpm levels. Results The median urine DiAcSpm for males was 147.2 nmol/g creatinine and 161.8 nmol/g creatinine in females. These median values were set as the cut-off values for each gender. Patients with higher urinary DiAcSpm levels frequently had significantly elevated serum CEA (p = 0.023) and greater lymph node metastasis (p = 0.048), lymphatic permeation (p = 0.046), and vascular invasion (p = 0.010). Compared with patients with non-invasive tumors, patients with invasive tumors had a tumor size >2.0 cm (p = 0.001), serum CEA >5.0 mg/dL (p < 0.001), high urinary DiAcSpm (p = 0.002), and a tumor disappearance rate (TDR) <0.75 (p < 0.001). Multivariate analysis revealed that a tumor size < 2.0 cm (RR = 2.901, 95% CI; 1.372-6.136, p = 0.005), high urinary DiAcSpm (RR = 3.374, 95% CI; 1.547-7.361, p = 0.002), and TDR < 0.75 (RR = 4.673, 95% CI; 2.178-10.027, p < 0.001) were independent predictors for invasive tumors. Conclusions We successfully showed that there was a significant correlation between urinary DiAcSpm levels and pathological tumor invasiveness in patients with clinical stage IA NSCLC. Further research would elucidate the clinical usefulness of DiAcSpm levels as a predictor of tumor invasiveness. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1068-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yusuke Takahashi
- Department of Thoracic Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo, Japan. .,Department of General Thoracic Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.
| | - Hirotoshi Horio
- Department of Thoracic Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo, Japan.
| | - Koji Sakaguchi
- Department of Thoracic Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo, Japan. .,Department of Thoracic Surgery, Nagano Prefectural Suzaka Hospital, 1332 Oaza-suzaka, Suzaka, Nagano, Japan.
| | - Kyoko Hiramatsu
- Center for Medical Research Cooperation, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kami-kitazawa, Setagaya-ku, Tokyo, Japan.
| | - Masao Kawakita
- Center for Medical Research Cooperation, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kami-kitazawa, Setagaya-ku, Tokyo, Japan.
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Moriya S, Hiramatsu K, Kimura E, Matsumoto K, Kawakita M. Construction of an immunochromatographic determination system for N¹,N¹²-diacetylspermine. J Clin Lab Anal 2014; 28:452-60. [PMID: 24659188 PMCID: PMC6807589 DOI: 10.1002/jcla.21709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 10/02/2013] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND N(1),N(12)-diacetylspermine (DiAcSpm) is a recently identified tumor marker. Its concentration increases in the urine of cancer patients at early clinical stages. To utilize this characteristic feature and thus contribute to the early detection of cancer, we developed an immunochromatographic determination system for DiAcSpm. METHODS We examined the factors that affect the performance and stability of our determination system, including antibody selection and the conditions for the formation of stably dispersed antibody-coated gold nanoparticles. We then tested the performance of the system by determining the DiAcSpm concentration in human urine samples. RESULTS We constructed an immunochromatographic strip using anti-DiAcSpm antibody-coated gold nanoparticles in the conjugate pad and an acetylspermine-protein conjugate (a DiAcSpm mimic) immobilized on the analyzing membrane. The use of the immunochromatographic strip and an immunochromato-reader allowed for the quantitative determination of DiAcSpm in the range of 20 to 700 nM. The analytical values obtained by this method were well correlated with those determined by a colloidal gold aggregation procedure using an automatic biochemical analyzer. The immunochromatographic strip was stable for at least 8 weeks at 50°C. CONCLUSIONS A competitive immunochromatographic device for DiAcSpm determination was developed in this study. This simple device will contribute to increasing the opportunities for early cancer detection and timely care.
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Affiliation(s)
- Shun‐suke Moriya
- Translational Medical Research CenterTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Kyoko Hiramatsu
- Translational Medical Research CenterTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Emi Kimura
- Mikuri Immunological LaboratoriesOsakaJapan
| | | | - Masao Kawakita
- Translational Medical Research CenterTokyo Metropolitan Institute of Medical ScienceTokyoJapan
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Polyamines metabolism and breast cancer: state of the art and perspectives. Breast Cancer Res Treat 2014; 148:233-48. [PMID: 25292420 DOI: 10.1007/s10549-014-3156-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/30/2014] [Indexed: 12/11/2022]
Abstract
Breast cancer (BC) is a common disease that generally occurs in women over the age of 50, and the risk is especially high for women over 60 years of age. One of the major BC therapeutic problems is that tumors initially responsive to chemotherapeutic approaches can progress to more aggressive forms poorly responsive to therapies. Polyamines (PAs) are small polycationic alkylamines, naturally occurring and essential for normal cell growth and development in eukaryotes. The intracellular concentration of PA is maintained within strongly controlled contents, while a dysregulation occurs in BC cells. Polyamines facilitate the interactions of transcription factors, such as estrogen receptors with their specific response element, and are involved in the proliferation of ER-negative and highly invasive BC tumor cells. Since PA metabolism has a critical role in cell death and proliferation, it represents a potential target for intervention in BC. The goal of this study was to perform a literature search reviewing the association between PA metabolism and BC, and the current evidence supporting the BC treatment targeting PA metabolism. We here describe in vitro and in vivo models, as well as the clinical trials that have been utilized to unveil the relationship between PA metabolism and BC. Polyamine pathway is still an important target for the development of BC chemotherapy via enzyme inhibitors. Furthermore, a recent promising strategy in breast anticancer therapy is to exploit the self-regulatory nature of PA metabolism using PA analogs to affect PA homeostasis. Nowadays, antineoplastic compounds targeting the PA pathway with novel mechanisms are of great interest and high social impact for BC chemotherapy.
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Vargas AJ, Ashbeck EL, Thomson CA, Gerner EW, Thompson PA. Dietary polyamine intake and polyamines measured in urine. Nutr Cancer 2014; 66:1144-53. [PMID: 25204413 DOI: 10.1080/01635581.2014.949801] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Dietary polyamines have recently been associated with increased risk of pre-malignant colorectal lesions. Because polyamines are synthesized in cells and taken up from dietary sources, development of a biomarker of exposure is challenging. Excess polyamines are primarily excreted in the urine. This pilot study seeks to identify dietary correlates of excreted urinary polyamines as putative biomarkers of exposure. Dietary polyamines/other nutrients were estimated from a food frequency questionnaire (FFQ) and correlated with urinary levels of acetylated polyamines in 36 men using 24-h urine samples. Polyamines, abundant in cheese and citrus, were highly positively correlated with urinary N(8)-acetylspermidine (correlation coefficient; r = 0.37, P = 0.03), but this correlation was attenuated after adjustment for total energy intake (r = 0.07, P = 0.68). Dietary energy intake itself was positively correlated with urinary total acetylated polyamine output (r = .40, P = 0.02). In energy-adjusted analyses, folic acid and folate from food were associated with urinary N(1),N(12)-diacetylspermine (r = 0.34, P = 0.05 and r = -0.39, P = 0.02, respectively). Red meat negatively correlated with total urinary acetylated polyamines (r = -0.42, P = 0.01). Our findings suggest that energy, folate, folic acid, saturated fat, and red meat intake, as opposed to FFQ-estimated dietary polyamines, are correlated with urinary polyamines.
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Affiliation(s)
- Ashley J Vargas
- a Department of Nutritional Sciences , University of Arizona , Tucson , Arizona , USA
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Park MH, Igarashi K. Polyamines and their metabolites as diagnostic markers of human diseases. Biomol Ther (Seoul) 2014; 21:1-9. [PMID: 24009852 PMCID: PMC3762300 DOI: 10.4062/biomolther.2012.097] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 01/04/2013] [Indexed: 01/31/2023] Open
Abstract
Polyamines, putrescine, spermidine and spermine, are ubiquitous in living cells and are essential for eukaryotic cell growth. These polycations interact with negatively charged molecules such as DNA, RNA, acidic proteins and phospholipids and modulate various cellular functions including macromolecular synthesis. Dysregulation of the polyamine pathway leads to pathological conditions including cancer, inflammation, stroke, renal failure and diabetes. Increase in polyamines and polyamine synthesis enzymes is often associated with tumor growth, and urinary and plasma contents of polyamines and their metabolites have been investigated as diagnostic markers for cancers. Of these, diacetylated derivatives of spermidine and spermine are elevated in the urine of cancer patients and present potential markers for early detection. Enhanced catabolism of cellular polyamines by polyamine oxidases (PAO), spermine oxidase (SMO) or acetylpolyamine oxidase (AcPAO), increases cellular oxidative stress and generates hydrogen peroxide and a reactive toxic metabolite, acrolein, which covalently incorporates into lysine residues of cellular proteins. Levels of protein-conjuagated acrolein (PC-Acro) and polyamine oxidizing enzymes were increased in the locus of brain infarction and in plasma in a mouse model of stroke and also in the plasma of stroke patients. When the combined measurements of PC-Acro, interleukin 6 (IL-6), and C-reactive protein (CRP) were evaluated, even silent brain infarction (SBI) was detected with high sensitivity and specificity. Considering that there are no reliable biochemical markers for early stage of stroke, PC-Acro and PAOs present promising markers. Thus the polyamine metabolites in plasma or urine provide useful tools in early diagnosis of cancer and stroke.
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Affiliation(s)
- Myung Hee Park
- Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, MD, 20892, USA
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Min JZ, Morota Y, Jiang YZ, Li G, Kang D, Yu HF, Inoue K, Todoroki K, Toyo'oka T. Rapid and sensitive determination of diacetylpolyamines in human fingernail by ultraperformance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. EUROPEAN JOURNAL OF MASS SPECTROMETRY (CHICHESTER, ENGLAND) 2014; 20:477-486. [PMID: 25905872 DOI: 10.1255/ejms.1301] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
A rapid and sensitive ultraperformance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method has been developed and validated for quantitatively determining diacetylpolyamines in the human fingernail. N(1),N(8)-diacetylspermidine (DiAct-Spd), N(1),N(12)- diacetylspermine (DiAct-Spm) and 1,6-diaminohexane (DAH) the [internal standard (IS)] were extracted from human fingernail samples by MeOH: 5 M HCl solution, followed by 4-(N,N-dimethylaminosulfonyl)-7-fluoro- 2,1,3-benzoxadiazole (DBD-F) derivatization, and then separated on an ACQUITY BEH C18 column with a gradient elution of acetonitrile and water containing 0.1% formic acid. The derivatives of the diacetylpolyamines were fully separated within a short run time (3.0 min). The triple quadrupole mass spectrometric detection was performed in the multiple reactions monitoring (MRM) mode by the UPLC-ESI- MS/MS system in the positive ionization mode. MRM using the fragmentation transitions of m/z 455.20→ 100.07, 737.25 → 100.07 and 567.10 → 479.07 in the positive ESI mode was performed to quantify DiAct-Spd, DiAct-Spm and IS, respectively. The calibration curve is between 0.04 ng mL(-1) for DiAct-Spd and DiAct-Spm. The detection limits (signal to noise ratio of five) were 5-10 pg mL(-1). A good linearity was achieved from the calibration curves (r(2) >0.9999), and the intra-day and inter-day assay precisions were less than 7.06%. Furthermore, the recoveries (%) of the diacetylpolyamines spiked in the human fingernails were 79.18-97.11. The present method proved that the high sensitivity is characterized by the specificity and feasibility of the sample analysis. Consequently, the proposed method was used to analyze human fingernail samples from 15 lung- cancer patients and 22 healthy volunteers. Diacetylpolyamines were detected from the fingernails of the lung- cancer patients for the first time. The concentration of DiAct-Spd in the lung-cancer patient group tended to be higher than those in the healthy volunteers.
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Affiliation(s)
- Jun Zhe Min
- Labo ratory of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
| | - Yuka Morota
- Laboratory of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
| | - Ying-Zi Jiang
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
| | - Gao Li
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
| | - Dongzhou Kang
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
| | - Hai-fu Yu
- Fengxian Branch of Shanghai Sixth People's Hospital, Shanghai 201400, China.
| | - Koichi Inoue
- Laboratory of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
| | - Kenichiro Todoroki
- Laboratory of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga- ku, Shizuoka 422-8526, Japan.
| | - Toshimasa Toyo'oka
- Laboratory of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
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Hiramatsu K, Sakaguchi K, Fujie N, Saitoh F, Takahama E, Moriya SS, Iwasaki K, Sakaguchi M, Takahashi KI, Kawaikta M. Excretion of N1, N12-diacetylspermine in the urine of healthy individuals. Ann Clin Biochem 2013; 51:459-67. [DOI: 10.1177/0004563213496978] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background Urinary N 1 ,N12-diacetylspermine (DiAcSpm) is a novel tumour marker that can be used to detect early cancers. In this study, we examined whether spot urine samples could represent the daily excretion of DiAcSpm after creatinine normalization and which factors should be taken into account in determining reference values for this biomarker. Methods We collected the following urine samples: (1) samples from seven healthy volunteers collected on each day of two 2-day sessions to examine the circadian variation of DiAcSpm excretion; (2) samples from 3952 male and 1782 female volunteers to estimate the DiAcSpm concentrations in apparently healthy adults and (3) samples from 16 female volunteers collected every morning over a 3-month period to examine the menstruation-related variation in DiAcSpm excretion. The DiAcSpm concentrations were determined by enzyme-linked immunosorbent assay or a colloidal gold aggregation procedure using DiAcSpm-specific antibodies. Results (1) The circadian variation of DiAcSpm in the urine was greatly diminished after creatinine normalization. (2) DiAcSpm was higher in females than in males, and the creatinine-normalized medians (95th percentile) of the urinary DiAcSpm concentrations were 149 (305) and 100 (192) nmol/g creatinine for females and males, respectively. (3) The mean concentrations of urinary DiAcSpm were lower after menstruation than before menstruation by approximately 30 nmol/g creatinine. Conclusion Spot urine samples obtained at any time of a day may be used to estimate the daily excretion of DiAcSpm in nmol DiAcSpm per gram creatinine. Sex, age and menstrual condition should be considered when determining the reference values for urinary DiAcSpm.
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Affiliation(s)
- Kyoko Hiramatsu
- Department of Molecular Medicine, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan
| | - Kouji Sakaguchi
- Department of Thoracic Surgery, Nagano Prefectural Suzaka Hospital, Suzaka, Japan
| | - Nana Fujie
- Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, Hachiouji, Japan
| | - Fumie Saitoh
- Department of Molecular Medicine, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan
| | - Emi Takahama
- Department of Molecular Medicine, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan
| | - Shun-suke Moriya
- Department of Molecular Medicine, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan
| | - Kaori Iwasaki
- Department of Molecular Medicine, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan
| | - Masayoshi Sakaguchi
- Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, Hachiouji, Japan
| | - Kei-ichi Takahashi
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Masao Kawaikta
- Department of Molecular Medicine, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan
- Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, Hachiouji, Japan
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Kuwata G, Hiramatsu K, Samejima K, Iwasaki K, Takahashi KI, Koizumi K, Horiguchi SI, Moriya SS, Kobayashi M, Kawakita M. Increase of N1, N12-diacetylspermine in tissues from colorectal cancer and its liver metastasis. J Cancer Res Clin Oncol 2013; 139:925-32. [PMID: 23443255 DOI: 10.1007/s00432-013-1405-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 02/13/2013] [Indexed: 10/27/2022]
Abstract
PURPOSE N (1),N (12)-Diacetylspermine (DiAcSpm) is a tumor marker featured by increase in the urine of patients with cancers, including early colorectal cancer, but where and how DiAcSpm is made remains unclear. We aimed to clarify whether colorectal cancer tissues produce increased amounts of DiAcSpm, and if they do, to examine whether tissue DiAcSpm level may serve as a criterion of tissue malignancy. METHODS Tissue samples were obtained from 140 patients (13 low-grade intraepithelial neoplasia, 98 high-grade intraepithelial neoplasia and 29 colorectal cancer) treated for colorectal cancer and intraepithelial neoplasia at Tokyo Metropolitan Komagome Hospital between November 2007 and April 2011. The DiAcSpm level in cancer and adjacent normal tissue extracts was compared, and its relationship with clinical stages of the diseases was analyzed. RESULTS DiAcSpm levels were higher in colorectal cancer tissue (p < 0.01, n = 12) and its liver metastasis (p < 0.05, n = 5) than in adjacent normal tissues. The tumor/normal ratio of tissue DiAcSpm content was examined for endoscopically obtained tumor and adjacent normal tissues from patients with intraepithelial neoplasia. The ratio was greater than 1.5 in 38 % (5/13) and 78 % (84/108) of low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia, respectively. CONCLUSIONS Tissue DiAcSpm levels increase in the tissue of colorectal cancer and also in precancerous lesion, such as high-grade intraepithelial neoplasia. The increase is considered a sign that a tissue is acquiring malignant characteristics. It is likely that the DiAcSpm produced by cancer cells is responsible for the frequent increase in urinary DiAcSpm in early cancer patients.
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Affiliation(s)
- Go Kuwata
- Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo, 113-8677, Japan
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Gerner EW. Abstract CN04-03: Development of NSAID eflornithine combinations for treating cancer risk factors. Cancer Prev Res (Phila) 2012. [DOI: 10.1158/1940-6207.prev-12-cn04-03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDS) have been found to be potent inhibitors of carcinogenesis in both preclinical models and in randomized controlled prospective clinical trials in humans. NSAIDS exert their anti-carcinogenic effects by inhibiting cyclooxygenases (COXs) involved in arachidonic acid metabolism and by COX-independent mechanisms. Empirical data indicates eflornithine (difluoromethylornithine or DFMO), an enzyme-activated inhibitor of ornithine decarboxylase (ODC) (Meyskens and Gerner, 1999), is one of the most potent agents known acting in combination with NSAIDS to inhibit carcinogenesis in rodent models (Steele and Lubet, 2010). At least part of the rationale for combining NSAIDS with eflornithine for inhibition of carcinogenesis is that eflornithine inhibits the activity of ODC, the first enzyme in polyamine synthesis, while NSAIDS activate the spermidine/spermine acetyltransferase (SAT1), which targets polyamines for export by specific solute carrier transporters (Gerner and Meyskens, 2009). Thus, NSAIDS and eflornithine both reduce tissue levels of the growth-associated polyamines, but by complementary mechanisms. A clinical trial of the combination of eflornithine and the NSAID sulindac showed dramatic treatment-associated reductions of metachronous colorectal adenomas in patients with prior sporadic colorectal polyps (Meyskens et al., 2008). Several clinical trials in progress or soon to commence will further test the hypothesis that NSAID eflornithine combinations can successfully treat cancer risk factors in patients with specific cancers, or risk of cancer. One group of clinical trials involves patients with neuroblastoma (NB). Patients with poor prognosis NB often have tumors in which MYCN is overexpressed. Preclinical data indicates that MYCN as well as c-MYC drive expression of ODC and other genes in the polyamine pathway, and that inhibiting this pathway with eflornithine suppressed carcinogenesis in mouse models of NB (Hogarty et al., 2008). Likewise, COX-2 is expressed in NB tumors and cell lines, and COX-2 inhibitors such as celecoxib can suppress the growth of NB xenografts (Ponthan et al., 2007). The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) and the New Approaches to Neuroblastoma Therapy (NANT) group are conducting clinical trials to evaluate the safety and efficacy of eflornithine alone or in combination with NSAIDS and other agents in patients with high risk NB. The NMTRC is conducting an especially novel prevention trial of eflornithine in patients with high risk NB in remission (NCT01586260). Eflornithine NSAID combinations are also being evaluated in other MYC-associated diseases. Familial adenomatous polyposis (FAP) is a genetic syndrome associated with increased risk of colon cancer and other neoplasia and is caused by mutation/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. MYC mediates intestinal tumorigenesis (Ignatenko et al., 2006) and combinations of eflornithine and NSAIDS are potent inhibitors of intestinal carcinogenesis (Ignatenko et al., 2008) in murine models of FAP. Notable is the change in clinical management of FAP patients over the past two decades. FAP is now managed primarily by surgery, with duodenal polyposis and desmoid disease constituting two current significant clinical problems. An international consortium will be evaluating the combination of eflornithine and sulindac in adult patients with FAP, using time to FAP-related events as the primary outcome (NCT01483144). This same combination will be evaluated in patients with prior sporadic colon cancer in a study to be conducted by a national cooperative group (S0820, Adenoma and second primary prevention trial, NCT01349881) (Rial et al., 2012). These and other trials have been designed to include assessment of a range of biological correlates, including genetic (Zell et al., 2010), tissue (Thompson et al., 2010) and urinary markers (Hiramatsu et al., 2005) of disease prognosis and prediction of treatment responses, including therapy-associated toxicities.
Citation Format: Eugene W. Gerner. Development of NSAID eflornithine combinations for treating cancer risk factors. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN04-03.
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NAKAYAMA YOSHIFUMI, TORIGOE TAKAYUKI, MINAGAWA NORITAKA, YAMAGUCHI KOJI. The clinical usefulness of urinary N(1),N(12)-diacetylspermine (DiAcSpm) levels as a tumor marker in patients with colorectal cancer. Oncol Lett 2012; 3:970-974. [PMID: 22783374 PMCID: PMC3389634 DOI: 10.3892/ol.2012.625] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 02/24/2012] [Indexed: 11/05/2022] Open
Abstract
The aim of this study was to evaluate the usefulness of urinary N(1),N(12)-diacetylspermine (DiAcSpm) measured by the colloidal gold aggregation method as a tumor marker for colorectal cancer (CRC). The preoperative urine of 113 CRC patients was collected, and the urinary DiAcSpm was measured by a reagent kit for DiAcSpm determination based on colloidal gold aggregation using automatic biochemical analyzers. The urinary DiAcSpm levels significantly correlated with distant metastasis and Tumor-Node-Metastasis (TNM) stage. The positive rates of urinary DiAcSpm were significantly higher than those of serum carcinoembryonic antigen (CEA) or cancer antigen 19-9 (CA19-9) in stages 0+I, II, III and IV. The positive rates of urinary DiAcSpm were also significantly higher than those of serum CEA or CA19-9 in the early and advanced CRC groups according to the Japan Classification of Colorectal Cancer. Therefore, urinary DiAcSpm, measured by a reagent kit for DiAcSpm determination based on colloidal gold aggregation, may be useful as a non-invasive tumor marker in patients with CRC.
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Affiliation(s)
- YOSHIFUMI NAKAYAMA
- Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kita-Kyushu, Fukuoka 807-8555, Japan
- Department of Gastroenterological and General Surgery, Wakamatsu Hospital of the University of Occupational and Environmental Health, Kita-Kyushu, Fukuoka 807-8555, Japan
| | - TAKAYUKI TORIGOE
- Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kita-Kyushu, Fukuoka 807-8555, Japan
| | - NORITAKA MINAGAWA
- Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kita-Kyushu, Fukuoka 807-8555, Japan
| | - KOJI YAMAGUCHI
- Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kita-Kyushu, Fukuoka 807-8555, Japan
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