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Tran MT. Identification of TIMP1-induced dysregulation of epithelial-mesenchymal transition as a key pathway in inflammatory bowel disease and small intestinal neuroendocrine tumors shared pathogenesis. Front Genet 2024; 15:1376123. [PMID: 39233736 PMCID: PMC11371700 DOI: 10.3389/fgene.2024.1376123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
Inflammatory Bowel Disease (IBD) is believed to be a risk factor for Small Intestinal Neuroendocrine Tumors (SI-NET) development; however, the molecular relationship between IBD and SI-NET has yet to be elucidated. In this study, we use a systems biology approach to uncover such relationships. We identified a more similar transcriptomic-wide expression pattern between Crohn's Disease (CD) and SI-NET whereas a higher proportion of overlapping dysregulated genes between Ulcerative Colitis (UC) and SI-NET. Enrichment analysis indicates that extracellular matrix remodeling, particularly in epithelial-mesenchymal transition and intestinal fibrosis mediated by TIMP1, is the most significantly dysregulated pathway among upregulated genes shared between both IBD subtypes and SI-NET. However, this remodeling occurs through distinct regulatory molecular mechanisms unique to each IBD subtype. Specifically, myofibroblast activation in CD and SI-NET is mediated through IL-6 and ciliary-dependent signaling pathways. Contrarily, in UC and SI-NET, this phenomenon is mainly regulated through immune cells like macrophages and the NCAM signaling pathway, a potential gut-brain axis in the context of these two diseases. In both IBD and SI-NET, intestinal fibrosis resulted in significant metabolic reprogramming of fatty acid and glucose to an inflammatory- and cancer-inducing state. This altered metabolic state, revealed through enrichment analysis of downregulated genes, showed dysfunctions in oxidative phosphorylation, gluconeogenesis, and glycogenesis, indicating a shift towards glycolysis. Also known as the Warburg effect, this glycolytic switch, in return, exacerbates fibrosis. Corresponding to enrichment analysis results, network construction and subsequent topological analysis pinpointed 7 protein complexes, 17 hub genes, 11 microRNA, and 1 transcription factor related to extracellular matrix accumulation and metabolic reprogramming that are candidate biomarkers in both IBD and SI-NET. Together, these biological pathways and candidate biomarkers may serve as potential therapeutic targets for these diseases.
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Stormezand GN, Schreuder RSBH, Brouwers AH, Slart RHJA, Elsinga PH, Walenkamp AME, Dierckx RAJO, Glaudemans AWJM, Luurtsema G. The effects of molar activity on [ 18F]FDOPA uptake in patients with neuroendocrine tumors. EJNMMI Res 2021; 11:88. [PMID: 34495420 PMCID: PMC8426426 DOI: 10.1186/s13550-021-00829-z] [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: 06/18/2021] [Accepted: 08/23/2021] [Indexed: 11/10/2022] Open
Abstract
Background 6-[18F]fluoro-l-3,4-dihydroxyphenyl alanine ([18F]FDOPA) is a commonly used PET tracer for the detection and staging of neuroendocrine tumors. In neuroendocrine tumors, [18F]FDOPA is decarboxylated to [18F]dopamine via the enzyme amino acid decarboxylase (AADC), leading to increased uptake when there is increased AADC activity. Recently, in our hospital, a new GMP compliant multi-dose production of [18F]FDOPA has been developed, [18F]FDOPA-H, resulting in a higher activity yield, improved molar activity and a lower administered mass than the conventional method ([18F]FDOPA-L). Aims This study aimed to investigate whether the difference in molar activity affects the [18F]FDOPA uptake at physiological sites and in tumor lesions, in patients with NET. It was anticipated that the specific uptake of [18F]FDOPA-H would be equal to or higher than [18F]FDOPA-L. Methods We retrospectively analyzed 49 patients with pathologically confirmed NETs and stable disease who underwent PET scanning using both [18F]FDOPA-H and [18F]FDOPA-L within a time span of 5 years. A total of 98 [18F]FDOPA scans (49 [18F]FDOPA-L and 49 [18F]FDOPA-H with average molar activities of 8 and 107 GBq/mmol) were analyzed. The SUVmean was calculated for physiological organ uptake and SUVmax for tumor lesions in both groups for comparison, and separately in subjects with low tumor load (1–2 lesions) and higher tumor load (3–10 lesions). Results Comparable or slightly higher uptake was demonstrated in various physiological uptake sites in subjects scanned with [18F]FDOPA-H compared to [18F]FDOPA-L, with large overlap being present in the interquartile ranges. Tumor uptake was slightly higher in the [18F]FDOPA-H group with 3–10 lesion (SUVmax 6.83 vs. 5.19, p < 0.001). In the other groups, no significant differences were seen between H and L. Conclusion [18F]FDOPA-H provides a higher activity yield, offering the possibility to scan more patients with one single production. Minor differences were observed in SUV’s, with slight increases in uptake of [18F]FDOPA-H in comparison to [18F]FDOPA-L. This finding is not a concern for clinical practice, but could be of importance when quantifying follow-up scans while introducing new production methods with a higher molar activity of [18F]FDOPA.
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Affiliation(s)
- Gilles N Stormezand
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
| | - Romano S B H Schreuder
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Adrienne H Brouwers
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Riemer H J A Slart
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Philip H Elsinga
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Annemiek M E Walenkamp
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - R A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Andor W J M Glaudemans
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - Gert Luurtsema
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
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Huang X, Lan Y, Li E, Li J, Deng Q, Deng X. Diagnostic values of MMP-7, MMP-9, MMP-11, TIMP-1, TIMP-2, CEA, and CA19-9 in patients with colorectal cancer. J Int Med Res 2021; 49:3000605211012570. [PMID: 33942633 PMCID: PMC8144491 DOI: 10.1177/03000605211012570] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/30/2021] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE Colorectal cancer (CRC) is one of the most common and lethal malignancies. The identification of precise and noninvasive biomarkers is urgently needed to aid the early diagnosis and clinical management of CRC. METHODS A total of 112 patients with CRC and 115 healthy control subjects were included in this study. Serum levels of matrix metalloproteinase (MMP)-7, MMP-9, MMP-11, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were analyzed by enzyme-linked immunosorbent assay, and carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 levels were measured using an automatic immunoassay analyzer. RESULTS MMP-7, MMP-9, MMP-11, TIMP-1, TIMP-2, CEA, and CA19-9 levels were all significantly higher in CRC patients compared with healthy controls. MMP-7, TIMP-1, and CEA levels were also closely related to clinicopathologic features in patients with CRC. The combination of serum CEA, MMP-7, and TIMP-1 significantly improved the diagnostic value compared with any single marker (area under the curve 0.858-0.890). Furthermore, a combined detection model including MMP-7, TIMP-1, and CEA improved both the specificity and sensitivity for detecting CRC. CONCLUSIONS The results showed that combined detection of CEA, MMP-7, and TIMP-1 in serum could provide a specific and sensitive biomarker for the diagnosis of CRC.
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Affiliation(s)
- Xiwen Huang
- Department of Oncology, Cancer Center, Meizhou People’s Hospital
(Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital
Affiliated to Sun Yat-sen University, Meizhou, China
| | - Yongquan Lan
- Department of Oncology, Cancer Center, Meizhou People’s Hospital
(Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital
Affiliated to Sun Yat-sen University, Meizhou, China
| | - En Li
- Department of Oncology, Cancer Center, Meizhou People’s Hospital
(Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital
Affiliated to Sun Yat-sen University, Meizhou, China
| | - Jiaquan Li
- Department of Oncology, Cancer Center, Meizhou People’s Hospital
(Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital
Affiliated to Sun Yat-sen University, Meizhou, China
| | - Qiaoting Deng
- Research and Experimental Center, Meizhou People’s Hospital
(Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital
Affiliated to Sun Yat-sen University, Meizhou, China
- Guangdong Provincial Key Laboratory of Precision Medicine and
Clinical Translational Research of Hakka Population, Meizhou, China
| | - Xunwei Deng
- Research and Experimental Center, Meizhou People’s Hospital
(Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital
Affiliated to Sun Yat-sen University, Meizhou, China
- Guangdong Provincial Key Laboratory of Precision Medicine and
Clinical Translational Research of Hakka Population, Meizhou, China
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Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, Martinez-Avila N, Martinez-Fierro ML. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int J Mol Sci 2020; 21:E9739. [PMID: 33419373 PMCID: PMC7767220 DOI: 10.3390/ijms21249739] [Citation(s) in RCA: 866] [Impact Index Per Article: 173.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/10/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM. The degradation of the ECM is of great importance, since it is related to embryonic development and angiogenesis. It is also involved in cell repair and the remodeling of tissues. When the expression of MMPs is altered, it can generate the abnormal degradation of the ECM. This is the initial cause of the development of chronic degenerative diseases and vascular complications generated by diabetes. In addition, this process has an association with neurodegeneration and cancer progression. Within the ECM, the tissue inhibitors of MMPs (TIMPs) inhibit the proteolytic activity of MMPs. TIMPs are important regulators of ECM turnover, tissue remodeling, and cellular behavior. Therefore, TIMPs (similar to MMPs) modulate angiogenesis, cell proliferation, and apoptosis. An interruption in the balance between MMPs and TIMPs has been implicated in the pathophysiology and progression of several diseases. This review focuses on the participation of both MMPs (e.g., MMP-2 and MMP-9) and TIMPs (e.g., TIMP-1 and TIMP-3) in physiological processes and on how their abnormal regulation is associated with human diseases. The inclusion of current strategies and mechanisms of MMP inhibition in the development of new therapies targeting MMPs was also considered.
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Affiliation(s)
| | - Idalia Garza-Veloz
- Molecular Medicine Laboratory, Unidad Académica de Medicina Humana y Ciencias de la Salud, Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, Zacatecas 98160, Mexico; (G.AC.-P.); (C.C.-D.l.R.); (J.MR.-A.); (B.AP.-R.); (J.FG.-R.); (N.M.-A.)
| | | | | | | | | | | | - Margarita L Martinez-Fierro
- Molecular Medicine Laboratory, Unidad Académica de Medicina Humana y Ciencias de la Salud, Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, Zacatecas 98160, Mexico; (G.AC.-P.); (C.C.-D.l.R.); (J.MR.-A.); (B.AP.-R.); (J.FG.-R.); (N.M.-A.)
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Cives M, Pelle' E, Quaresmini D, Rizzo FM, Tucci M, Silvestris F. The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications. Neuroendocrinology 2019; 109:83-99. [PMID: 30699437 DOI: 10.1159/000497355] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 01/30/2019] [Indexed: 12/12/2022]
Abstract
Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor β primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.
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Affiliation(s)
- Mauro Cives
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Eleonora Pelle'
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Davide Quaresmini
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Francesca Maria Rizzo
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Marco Tucci
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy,
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Malcherczyk D, Heyse TJ, El-Zayat BF, Kunzke V, Moll R, Fuchs-Winkelmann S, Paletta JRJ. Expression of MMP-9 decreases metastatic potential of Chondrosarcoma: an immunohistochemical study. BMC Musculoskelet Disord 2018; 19:9. [PMID: 29316907 PMCID: PMC5761152 DOI: 10.1186/s12891-017-1920-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 12/21/2017] [Indexed: 01/07/2023] Open
Abstract
Background Chondrosarcoma is the second most common primary malignant bone tumor. Because of their heterogeneity, with differences in invasive and metastatic behavior, it is important to identify biological markers that will allow for a more accurate estimation of prognosis in patients with these tumors. Matrix metalloproteinases (MMP) play a crucial role in tumor progression, invasion and metastasis. The mechanism of tumor progression dependent of MMPs is complex and influences malignant transformation, angiogenesis and tumor growth at the primary and metastatic sites. The purpose of this study was to investigate immunohistochemicaly the influence of MMP-1, MMP-3, MMP-9 and MMP-13 expression on prognostic parameter in chondrosarcoma. Methods We investigated tissue samples of 28 patients with chondrosarcoma. Immunohistochemical staining to evaluate the expression of MMP-1, MMP-3, MMP-9 and MMP-13 was performed. Subsequently, the expression level was correlated with metastatic potential, histological grading and overall survival in patients with this neoplasm. Results In consideration of semi quantitative scoring 64% of chondrosarcoma were scored as positive for MMP-1, 46% for MMP-3, 61% for MMP-9. The specimens had shown no expression of MMP-13. High expression of MMP-9 was associated with better histological differentiation, decreased metastatic potential and favourable overall survival. No correlation was found for expression of MMP-1, MMP-3 or MMP-13. Conclusions MMP-1, MMP-3 and MMP-9 are expressed in chondrosarcoma. Our findings suggest that the expression of MMP-9 is associated with clinical outcome parameters in chondrosarcoma.
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Affiliation(s)
- Dominik Malcherczyk
- Center for Orthopedics and Trauma Surgery, University Hospital Marburg, Baldingerstrasse, 35043, Marburg, Germany.
| | - Thomas J Heyse
- Center for Orthopedics and Trauma Surgery, University Hospital Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Bilal F El-Zayat
- Center for Orthopedics and Trauma Surgery, University Hospital Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Vanessa Kunzke
- Center for Orthopedics and Trauma Surgery, University Hospital Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Roland Moll
- Department of Pathology, University Hospital Marburg, Marburg, Germany
| | - Susanne Fuchs-Winkelmann
- Center for Orthopedics and Trauma Surgery, University Hospital Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Jürgen R J Paletta
- Center for Orthopedics and Trauma Surgery, University Hospital Marburg, Baldingerstrasse, 35043, Marburg, Germany
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Niederle B, Pape UF, Costa F, Gross D, Kelestimur F, Knigge U, Öberg K, Pavel M, Perren A, Toumpanakis C, O'Connor J, O'Toole D, Krenning E, Reed N, Kianmanesh R. ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum. Neuroendocrinology 2016; 103:125-38. [PMID: 26758972 DOI: 10.1159/000443170] [Citation(s) in RCA: 331] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- B Niederle
- Department of Surgery, Medical University of Vienna, Vienna, Austria
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Kuik WJ, Kema IP, Brouwers AH, Zijlma R, Neumann KD, Dierckx RAJO, DiMagno SG, Elsinga PH. In vivo biodistribution of no-carrier-added 6-18F-fluoro-3,4-dihydroxy-L-phenylalanine (18F-DOPA), produced by a new nucleophilic substitution approach, compared with carrier-added 18F-DOPA, prepared by conventional electrophilic substitution. J Nucl Med 2014; 56:106-12. [PMID: 25500826 DOI: 10.2967/jnumed.114.145730] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
UNLABELLED A novel synthetic approach to 6-(18)F-fluoro-3,4-dihydroxy-L-phenylalanine ((18)F-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added (18)F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method, involving an electrophilic substitution of a trialkylstannane precursor with (18)F2. We performed a direct comparison of high- and low-specific-activity (18)F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of (18)F-DOPA. METHODS (18)F-DOPA was produced via the novel synthesis method, yielding (18)F-DOPA-H with a high specific activity (35,050 ± 4,000 GBq/mmol). This product was compared in several experiments with conventional (18)F-DOPA-L with a low specific activity (11 ± 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0 °C and 37 °C and at 37 °C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of (18)F-DOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft. RESULTS At 37 °C, the uptake of both (18)F-DOPA-H and (18)F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0 °C, the uptake of (18)F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of (18)F-DOPA-H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of (18)F-DOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of (18)F-DOPA-H and (18)F-DOPA-L in carbidopa-pretreated mice. CONCLUSION The advantages of the novel synthesis of (18)F-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active (19)F-DOPA. (18)F-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than (18)F-DOPA-L.
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Affiliation(s)
- Willem-Jan Kuik
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ido P Kema
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Adrienne H Brouwers
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rolf Zijlma
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Kiel D Neumann
- Ground Fluor Pharmaceuticals, Inc., Lincoln, Nebraska; and
| | - Rudi A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Philip H Elsinga
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Chen YX, Fang JY. Current Perspective on the Pathogenesis of Small Intestinal Neuroendocrine Tumors: Progress in Biomarkers and Molecular Events. Gastrointest Tumors 2014; 1:2-8. [DOI: 10.1159/000354993] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
<b><i>Background:</i></b> Neuroendocrine tumors of the gastrointestinal tract differ in their histopathologic and clinical presentation. Small intestinal neuroendocrine tumors (SI-NETs), representing only a small portion within gastrointestinal malignancies, are often associated with a delayed diagnosis due to their non-specific symptoms. The increased incidence of SI-NETs during the last decades demands earlier diagnosis and more effective treatment, which both rely on a better understanding on the underlying molecular mechanisms. <b><i>Summary:</i></b> The purpose of this review is to discuss the biomolecular changes responsible for the pathogenesis of SI-NETs, and potential biomarkers in the diagnostic and prognostic evaluation. <b>Key Message</b> A greater understanding of the molecular mechanisms that underpin the pathogenesis of small intestinal neuroendocrine tumors (SI-NETs) facilitates the classification, diagnosis and treatment of these relatively rare gastrointestinal malignancies. <b>Practical Implications</b> Currently, SI-NETs are diagnosed using histological examination and staining for various neuroendocrine markers. Genetically, SI-NETs are characterized by an absence of alterations to K-ras, p53 and DNA mismatch repair genes. Loss of chromosome 18, deletion of Smad2 and Smad4, and amplification of SRC, EGFR and PDGFR have been reported. Abnormal DNA methylation status, reflected by overexpression of DNA methyltransferase, higher methylation of the RASSF1A promoter and overexpression of histone H1x are also associated with SI-NETs. These tumors are also associated with fibrosis, possibly due to the high levels of serotonin and other fibrotic factors produced. Genetic studies have pinpointed genes that can differentiate SI-NETs from other neuroendocrine tumors (oxytocin receptor, G protein-coupled receptor 113, VMAT-1, CDX-2), enabling more accurate diagnosis. Paraneoplastic antigen Ma2, neurokinin A and the CART peptide are under investigation as prognostic biomarkers. There is, however, still an unmet need for more sensitive biomarkers for earlier diagnosis and for a more specific classification system that encompasses tumor histology and reliable predictors of clinical response.
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Capelli P, Fassan M, Scarpa A. Pathology - grading and staging of GEP-NETs. Best Pract Res Clin Gastroenterol 2012; 26:705-717. [PMID: 23582914 DOI: 10.1016/j.bpg.2013.01.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 01/10/2013] [Indexed: 01/31/2023]
Abstract
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) constitute a heterogeneous group of neoplasms. In the last few decades, due to a substantial rise in incidence and prevalence, GEP-NETs have been included among the most common tumours of the gastrointestinal tract. Diagnosis could be challenging and a significant number of patients present with metastatic or unresectable disease. The development of appropriate tools for standardised prognostic stratification and the introduction of effective target therapies have opened new horizons for planning tailored surgical or medical management and follow-up programs for these complex neoplasms. An overview on the GEP-NETs' diagnostic and prognostic criteria proposed by the recently published WHO classification and ENETS and UICC TNM staging systems is presented, focussing on their impact on the clinical and therapeutical approaches.
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Affiliation(s)
- Paola Capelli
- Department of Pathology and Diagnostics & ARC-NET Research Centre, University of Verona, Verona, Italy.
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Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, Arnold R, Denecke T, Plöckinger U, Salazar R, Grossman A. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology 2012; 95:135-56. [PMID: 22262080 DOI: 10.1159/000335629] [Citation(s) in RCA: 298] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Ulrich-Frank Pape
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Campus Virchow-Klinikum, Berlin, Germany.
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Seiler R, Thalmann GN, Fleischmann A. MMP-2 and MMP-9 in lymph-node-positive bladder cancer. J Clin Pathol 2011; 64:1078-82. [DOI: 10.1136/jclinpath-2011-200153] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BackgroundMatrix metalloproteinases (MMP), particularly MMP-2 and MMP-9, participate in tumour progression and metastasis in various cancers. Their significance in urothelial cancer of the bladder (UCB) is unclear. Expression analysis of MMP-2 and MMP-9 in tissue microarrays (TMA) constructed of corresponding samples from histopathological normal urothelium, tumour centre and invasion front of primary tumours and lymph-node (LN) metastases might help to elucidate their relevance in UCB.MethodMMP-2 and MMP-9 expression was evaluated in TMA of 150 surgically treated LN-positive UCB patients. Biomarker expression was correlated with tumour characteristics (primary tumour and LN stage, number, total diameter and extracapsular extension of LN metastases) and overall survival.ResultsWhile there was a significant increase in MMP-9 expression from normal urothelium over primary tumours to metastases (median scores: 20, 50, 65; p<0.005), no such trend was observed in MMP-2 (median scores: 5, 22, 10; p<0.005). A comparison of expression in the tumour centre and the invasion front showed no difference in both MMP. No association between expression and histopathological tumour characteristics was identified. There was a non-significant trend for a more favourable outcome for patients with high MMP-2 expression in primary tumours.ConclusionIn LN-positive UCB, MMP-2 and MMP-9 expression was not increased at the invasion front, suggesting an infiltration strategy independent of MMP-2 and MMP-9 activity. Larger series are needed to detect a potential significant trend for favourable outcome in cancers with high MMP-2 expression.
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Langers AM, Verspaget HW, Hommes DW, Sier CF. Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer. World J Gastrointest Oncol 2011; 3:79-98. [PMID: 21731908 PMCID: PMC3124635 DOI: 10.4251/wjgo.v3.i6.79] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 05/27/2011] [Accepted: 06/03/2011] [Indexed: 02/05/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are implicated in cancer development and progression and are associated with prognosis. Single-nucleotide polymorphisms (SNPs) of MMPs, most frequently located in the promoter region of the genes, have been shown to influence cancer susceptibility and/or progression. SNPs of MMP-1, -2, -3, -7, -8, -9, -12, -13 and -21 and of the tissue inhibitor of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 have been studied in digestive tract tumors. The contribution of these polymorphisms to the cancer risk and prognosis of gastrointestinal tumors are reviewed in this paper.
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Affiliation(s)
- Alexandra Mj Langers
- Alexandra MJ Langers, Hein W Verspaget, Daniel W Hommes, Cornelis FM Sier, Department of Gastroenterology and Hepatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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Olszewski U, Zeillinger R, Geissler K, Hamilton G. Genome-wide gene expression analysis of chemoresistant pulmonary carcinoid cells. LUNG CANCER-TARGETS AND THERAPY 2010; 1:107-117. [PMID: 28210111 DOI: 10.2147/lctt.s12874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
PURPOSE Carcinoids are highly chemoresistant tumors associated with a dismal prognosis. This study involved a comparison of the genome-wide gene expression pattern of a chemoresistant and a chemosensitive pulmonary carcinoid cell line to reveal factors that contribute to the resistant phenotype. MATERIALS AND METHODS Gene expression of UMC-11 chemoresistant carcinoid cells as assessed by 32 K microarray was compared with H835 chemosensitive carcinoid cells, and the genes that were differentially expressed and expected to be related to chemoresistance were selected. RESULTS Drug-resistant UMC-11 cells exhibited increased expression of transcripts known to confer resistance to different cytostatics such as P-glycoprotein, multidrug resistance-associated proteins 2 and 3, effectors of the glutathione detoxification and xenobiotics degradation pathways, and ion transporters including Na+/K+-adenosine triphosphatase. In addition, enhanced transcription of several S100 proteins, capable of suppressing apoptosis, regulation of topoisomerase I (topo I) expression by antisense transcripts from TOPO1 pseudogenes, and alterations of the cytoskeleton seem to contribute to the multidrug-resistant phenotype. A multitude of epidermal growth factor (EGF)-related and neuropeptide growth factors, overexpression of proteases, and appearance of aerobic glycolytic metabolism complement the malignant phenotype of the UMC-11 cells. CONCLUSION The multidrug-resistant phenotype of the UMC-11 pulmonary carcinoid cell line seems to be mediated by classical efflux pumps, drug metabolization or conjugation systems, and, possibly, modulation of apoptotic cell death by S100 proteins and topo I expression by pseudogene transcripts. Autocrine or paracrine stimulation by a host of EGF-related and neuropeptide growth factors, as well as high metastatic potency indicated by increased expression of components of aerobic glycolysis and proteolytic enzymes, may furthermore account for the failure of therapeutic interventions.
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Affiliation(s)
- Ulrike Olszewski
- Ludwig Boltzmann Cluster of Translational Oncology, Ludwig Boltzmann Society, Vienna, Austria
| | - Robert Zeillinger
- Ludwig Boltzmann Cluster of Translational Oncology, Ludwig Boltzmann Society, Vienna, Austria
| | - Klaus Geissler
- Ludwig Boltzmann Cluster of Translational Oncology, Ludwig Boltzmann Society, Vienna, Austria
| | - Gerhard Hamilton
- Ludwig Boltzmann Cluster of Translational Oncology, Ludwig Boltzmann Society, Vienna, Austria
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