RESUMO
CD157/BST1 glycosylphosphatidylinositol-anchored glycoprotein is an evolutionary conserved dual-function receptor and ß-NAD+-metabolizing ectoenzyme of the ADP-ribosyl cyclases gene family. Identified as bone marrow stromal cell and myeloid cell differentiation antigen, CD157 turned out to have a wider expression than originally assumed. The functional significance of human CD157 as an enzyme remains unclear, while it was well established in mouse models. Conversely, the receptor role of CD157 has been clearly delineated. In physiological conditions, CD157 is a key player in regulating leukocyte adhesion, migration and diapedesis. Underlying these functional roles is the ability of CD157 to bind with high affinity selected extracellular matrix components within their heparin-binding domains. CD157 binding to extracellular matrix promotes its interaction with ß1 and ß2-integrins and induces the organization of a multimolecular complex that is instrumental to the delivery of synergistic outside-in signals leading to optimal cell adhesion and migration, both in physiological and in pathological situations. CD157 also regulates cell adhesion and migration and is a marker of adverse prognosis in epithelial ovarian cancer and pleural mesothelioma. This review focuses on human CD157 expression and functions and provides an overview on its role in human pathology and its emerging potential as target for antibody-mediated immunotherapy.
Assuntos
ADP-Ribosil Ciclase/imunologia , Antígenos CD/imunologia , Inflamação/terapia , Neoplasias/terapia , ADP-Ribosil Ciclase/genética , ADP-Ribosil Ciclase/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Adesão Celular , Matriz Extracelular/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunidade Inata , Imunoterapia , Inflamação/imunologia , Inflamação/metabolismo , Leucócitos/fisiologia , NAD/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismoRESUMO
: Human CD157/BST-1 and CD38 are dual receptor-enzymes derived by gene duplication that belong to the ADP ribosyl cyclase gene family. First identified over 30 years ago as Mo5 myeloid differentiation antigen and 10 years later as Bone Marrow Stromal Cell Antigen 1 (BST-1), CD157 proved not to be restricted to the myeloid compartment and to have a diversified functional repertoire ranging from immunity to cancer and metabolism. Despite being a NAD+-metabolizing ectoenzyme anchored to the cell surface through a glycosylphosphatidylinositol moiety, the functional significance of human CD157 as an enzyme remains unclear, while its receptor role emerged from its discovery and has been clearly delineated with the identification of its high affinity binding to fibronectin. The aim of this review is to provide an overview of the immunoregulatory functions of human CD157/BST-1 in physiological and pathological conditions. We then focus on CD157 expression in hematological tumors highlighting its emerging role in the interaction between acute myeloid leukemia and extracellular matrix proteins and its potential utility for monoclonal antibody targeted therapy in this disease.
Assuntos
ADP-Ribosil Ciclase/metabolismo , Antígenos CD/metabolismo , Células Mieloides/citologia , Células Mieloides/metabolismo , ADP-Ribosil Ciclase/antagonistas & inibidores , ADP-Ribosil Ciclase/química , Imunidade Adaptativa , Antígenos CD/química , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Suscetibilidade a Doenças , Ativação Enzimática , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunidade Inata , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Modelos Moleculares , Terapia de Alvo Molecular , Células Mieloides/efeitos dos fármacos , Conformação Proteica , Relação Estrutura-Atividade , Especificidade por Substrato , Distribuição TecidualRESUMO
BACKGROUND: CD157/Bst1 glycoprotein is expressed in >85% of malignant pleural mesotheliomas and is a marker of enhanced tumor aggressiveness. RESULTS: In vitro, mesothelial cells (malignant and non-malignant) released CD157 in soluble form or as an exosomal protein. In vivo, sCD157 is released and can be measured in pleural effusions by ELISA. Significantly higher levels of effusion sCD157 were detected in patients with malignant pleural mesothelioma than in patients with non-mesothelioma tumors or with non-malignant conditions. In our patient cohort, the area under the receiver-operating characteristic curve for sCD157 that discriminated malignant pleural mesothelioma from all other causes of pleural effusion was 0.685, cut-off (determined by the Youden Index) = 23.66 ng/ml (62.3% sensitivity; 73.93% specificity). Using a cut-off that yielded 95.58% specificity, measurement of sCD157 in cytology-negative effusions increased sensitivity of malignant pleural mesothelioma diagnosis from 34.42% to 49.18%. CONCLUSIONS: Evaluation of soluble CD157 in pleural effusions provides a diagnostic aid in malignant mesothelioma. METHODS: Soluble CD157 (sCD157) was detected biochemically in culture supernatants of malignant and non-malignant mesothelial cells, and in pleural effusions from various pathological conditions. An ELISA system was established to measure the concentration of sCD157 in fluids, and extended to analyze sCD157 in pleural effusions from a cohort of 295 patients.