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CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders.

ABSTRACT: CD13/aminopeptidase N is a widely expressed ectoenzyme with multiple functions. As an enzyme, CD13 regulates activities of numerous cytokines by cleaving their N-terminals and is involved in Ag processing by trimming the peptides bound to MHC class II. Independent of its enzymatic activity, cell membrane CD13 functions by cross-linking-induced signal transduction, regulation of receptor recycling, enhancement of Fc?R-mediated phagocytosis, and acting as a receptor for cytokines. Moreover, soluble CD13 has multiple proinflammatory roles mediated by binding to G-protein-coupled receptors. CD13 not only modulates development and activities of immune-related cells, but also regulates functions of inflammatory mediators. Therefore, CD13 is important in the pathogenesis of various inflammatory disorders. Inhibitors of CD13 have shown impressive anti-inflammatory effects, but none of them has yet been used for clinical therapy of human inflammatory diseases. We reevaluate CD13's regulatory role in inflammation and suggest that CD13 could be a potential therapeutic target for inflammatory disorders.

SUBMITTER: Lu C

PROVIDER: S-EPMC6997018 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders.

Lu Chenyang C Amin Mohammad A MA Fox David A DA

Journal of immunology (Baltimore, Md. : 1950) 20200101 1

CD13/aminopeptidase N is a widely expressed ectoenzyme with multiple functions. As an enzyme, CD13 regulates activities of numerous cytokines by cleaving their N-terminals and is involved in Ag processing by trimming the peptides bound to MHC class II. Independent of its enzymatic activity, cell membrane CD13 functions by cross-linking-induced signal transduction, regulation of receptor recycling, enhancement of FcγR-mediated phagocytosis, and acting as a receptor for cytokines. Moreover, solubl ...[more]

PMID: 31848300

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Project description:BackgroundAminopeptidase N (CD13) is a zinc-binding protease that has functional effects on both cancerogenesis and tumor angiogenesis. Since CD13 is an antigen suitable for molecular targeted therapies (e.g. tTF-NGR induced tumor vascular infarction), we evaluated its impact in NSCLC patients, and tested the effects of the CD13-targeted fusion protein tTF-NGR (truncated tissue factor (tTF) containing the NGR motif: asparagine-glycine-arginine) in vivo in nude mice.MethodsExpression of both CD13 and CD31 was studied in 270 NSCLC patients by immunohistochemistry. Clinical correlations and prognostic effects of the expression profiles were analyzed using univariate and multivariate analyses. In addition, a microarray-based analysis on the basis of the KM plotter database was performed. The in vivo effects of the CD13-targeted fusion protein tTF-NGR on tumor growth were tested in CD1 nude mice carrying A549 lung carcinoma xenotransplants.ResultsCD13 expression in tumor endothelial and vessel associated stromal cells was found in 15% of the investigated samples, while expression in tumor cells was observed in 7%. Although no significant prognostic impact was observed in the full NSCLC study cohort, both univariate and multivariate models identified vascular CD13 protein expression to correlate with poor overall survival in stage III and pN2+ NSCLC patients. Microarray-based mRNA analysis for either adenocarcinomas or squamous cell carcinomas did not reveal any significant effect. However, the analysis of CD13 mRNA expression for all lung cancer histologies demonstrated a positive prognostic effect. In vivo, systemic application of CD13-targeted tissue factor tTF-NGR significantly reduced CD13+ A549 tumor growth in nude mice.ConclusionsOur results contribute a data basis for prioritizing clinical testing of tTF-NGR and other antitumor molecules targeted by NGR-peptides in NSCLC. Because CD13 expression in NSCLC tissues was found only in a specific subset of NSCLC patients, rigorous pre-therapeutic testing will help to select patients for these studies.

Dataset Information

CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders.

Publications

CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders.

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