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      Soluble intercellular adhesion molecule-1 is a prognostic marker in colorectal carcinoma

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          Abstract

          Purpose

          Serological tumor markers are routinely used to monitor tumor onset and progression. In colorectal carcinoma (CRC), the carcinoembryonic antigen (CEA) is roughly elevated in 50% of patients at initial diagnosis. Soluble ICAM-1 (sICAM-1) is elevated in different cancers. The aim of this study was to evaluate the prognostic relevance of sICAM-1 combined with CEA in patients with CRC.

          Methods

          In blood samples of 297 CRC patients, sICAM-1 was determined by ELISA and CEA by microparticle enzyme immunoassay the day before oncologic resection. Separation in patients with sICAM-1 high and sICAM-1 low was performed by minimum p value approach; separation in CEA normal and elevated was performed according to the established diagnostic cutoff. Clinical data were obtained from the prospective collected data from the Erlangen Registry for Colorectal Carcinomas.

          Results

          Cancer-related 5-year survival rate of patients with sICAM-1 low (< 290 ng/ml, n = 208) was significantly increased (83.4%) as compared to that of patients with sICAM-1 high (≥ 290 ng/ml, n = 89) (66.2%; p < 0.001). Patients with normal CEA concentrations ( n = 199; 90.8%) showed a significantly ( p < 0.001) improved cancer-related 5-year survival rate compared to patients with elevated CEA concentrations ( n = 98; 52.1%). Moreover, high sICAM-1 was an independent risk factor (hazard ratio 1.6) in multivariate analysis. Of note, increased sICAM-1 levels, either within normal or within elevated CEA, allowed to identify high-risk subgroups, both for overall ( < 0.001) and cancer-related survival ( p < 0.001).

          Conclusion

          Application of a novel risk score combining CEA/sICAM-1 serum concentrations allows the identification of high-risk groups for poor survival in CRC patients.

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          Most cited references28

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          Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use.

          The aim of this article is to present updated guidelines for the use of serum, tissue and faecal markers in colorectal cancer (CRC). Lack of specificity and sensitivity preclude the use of all existing serum markers for the early detection of CRC. For patients with stage II or stage III CRC who may be candidates for either liver resection or systemic treatment should recurrence develop, CEA should be measured every 2-3 months for at least 3 years after diagnosis. Insufficient evidence exists to recommend routine use of tissue factors such as thymidylate synthase, microsatellite instability (MSI), p53, K-ras and deleted in colon cancer (DCC) for either determining prognosis or predicting response to therapy in patients with CRC. Microsatellite instability, however, may be used as a pre-screen for patients with suspected hereditary non-polyposis colorectal cancer. Faecal occult blood testing but not faecal DNA markers may be used to screen asymptomatic subjects 50 years or older for early CRC.
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            Soluble intercellular adhesion molecule-1 (sICAM-1): an overview.

            Soluble intercellular adhesion molecule-1 (sICAM-1) represents a circulating form of ICAM-1 that is constitutively expressed or is inducible on the cell surface of different cell lines. It serves as a counter-receptor for the lymphocyte function-associated antigen (LFA-1). Interaction between ICAM-1, present on endothelial cells, and LFA-1 facilitates leukocyte adhesion and migration across the endothelium. ICAM-1 and its circulating form have been implicated in the development of any number of diseases.
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              Tumor necrosis factor-alpha-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1).

              Ectodomain shedding has emerged as an important regulatory step in the function of transmembrane proteins. Intercellular adhesion molecule-1 (ICAM-1), an adhesion receptor that mediates inflammatory and immune responses, undergoes shedding in the presence of inflammatory mediators and phorbol 12-myristate 13-acetate (PMA). The shedding of ICAM-1 in ICAM-1-transfected 293 cells upon PMA stimulation and in endothelial cells upon tumor necrosis factor-alpha stimulation was blocked by metalloproteinase inhibitors, whereas serine protease inhibitors were ineffective. p-Aminophenylmercuric acetate, a mercuric compound that is known to activate matrix metalloproteinases, up-regulated ICAM-1 shedding. TIMP-3 (but not TIMP-1 or -2) effectively blocked cleavage. This profile suggests the involvement of the ADAM family of proteases in the cleavage of ICAM-1. The introduction of enzymatically active tumor necrosis factor-alpha-converting enzyme (TACE) into ICAM-1-expressing cells up-regulated cleavage. Small interfering RNA directed against TACE blocked ICAM-1 cleavage. ICAM-1 transfected into TACE-/- fibroblasts did not show increased shedding over constitutive levels in the presence of PMA, whereas cleavage did occur in ICAM-1-transfected TACE+/+ cells. These results indicate that ICAM-1 shedding is mediated by TACE. Blocking the shedding of ICAM-1 altered the cell adhesive function, as ICAM-1-mediated cell adhesion was up-regulated in the presence of TACE small interfering RNA and TIMP-3, but not TIMP-1. However, cleavage was found to occur at multiple sites within the stalk domain of ICAM-1, and numerous point mutations within the region did not affect cleavage, indicating that TACE-mediated cleavage of ICAM-1 may not be sequence-specific.
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                Author and article information

                Contributors
                ++49 (0) 9131 85 42024 , vera.schellerer@uk-erlangen.de
                Journal
                Int J Colorectal Dis
                Int J Colorectal Dis
                International Journal of Colorectal Disease
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0179-1958
                1432-1262
                23 November 2018
                23 November 2018
                2019
                : 34
                : 2
                : 309-317
                Affiliations
                [1 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Department of Surgery, University Medical Center Erlangen, , Friedrich-Alexander-University Erlangen-Nürnberg, ; Krankenhausstr. 12, 91054 Erlangen, Germany
                [2 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, , Friedrich-Alexander-University Erlangen-Nürnberg, ; Erlangen, Germany
                [3 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Department of Medical Informatics, Biometry and Epidemiology, , Friedrich-Alexander- University of Erlangen-Nürnberg, ; Erlangen, Germany
                Author information
                http://orcid.org/0000-0002-6389-3040
                Article
                3198
                10.1007/s00384-018-3198-0
                6331741
                30470940
                ecd3eada-ca2c-4132-86e3-254e360a0c7a
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 12 November 2018
                Funding
                Funded by: Interdisziplinäres Zentrum für Klinische Forschung
                Award ID: D28
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: FOR 2438
                Award Recipient :
                Funded by: Doktor Robert Pfleger Stiftung
                Award ID: AZ
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Gastroenterology & Hepatology
                colorectal carcinoma,cea,sicam-1,survival
                Gastroenterology & Hepatology
                colorectal carcinoma, cea, sicam-1, survival

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