RESUMEN
The transmembrane chemokine CX3CL1 and its receptor CX3CR1 are thought to be involved in the trafficking of immune cells during an immune response and in the pathology of various human diseases including cancer. However, little is known about the expression and function of CX3CR1 in human glioma-infiltrating microglia/macrophages (GIMs), representing the major cellular stroma component of highly malignant gliomas. Here, we show that CX3CR1 is overexpressed at both the mRNA and protein level in solid human astrocytomas of different malignancy grades and in glioblastomas. CX3CR1 was localized in ionized calcium-binding adapter molecule 1 (Iba1) and CD11b/c positive GIMs in situ as shown by fluorescence microscopy. In accordance with this, freshly isolated human GIM-enriched fractions separated by CD11b MACS technology displayed high Iba1 and CX3CR1 mRNA expression levels in vitro. Moreover, cultured human GIMs responded to CX3CL1-triggered activation of CX3CR1 with adhesion and migration in vitro. Besides an increase in motility, CX3CL1 also enhanced expression of matrix metalloproteases 2, 9, and 14 in GIM fractions in vitro. These data indicate that the CX3CL1/CX3CR1 system has a crucial tumor-promoting role in human glioblastomas via its impact on glioma-infiltrating immune subsets.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Macrófagos/metabolismo , Microglía/metabolismo , Receptores de Quimiocina/metabolismo , Western Blotting , Encéfalo/citología , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Receptor 1 de Quimiocinas CX3C , Proteínas de Unión al Calcio , Estudios de Casos y Controles , Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Glioma/genética , Glioma/patología , Humanos , Macrófagos/patología , Masculino , Metaloproteinasas de la Matriz/metabolismo , Proteínas de Microfilamentos , Microglía/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Quimiocina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esferoides Celulares/metabolismoRESUMEN
OBJECTIVE: Polysialic acid (PSA) is a carbohydrate binding on the neural cell adhesion molecule NCAM and impedes cell-cell interactions. It prevents neural progenitor cell differentiation and promotes their migration. Highly malignant tumours like small cell lung carcinoma (SCLC) also overexpress PSA and this correlates with a negative prognosis. METHODS: Intra-operatively collected biopsies from 30 patients with different astrocytoma grades were immuno-histochemically examined to identify expression of PSA. RESULTS: Astrocytoma grade I and II had 4% PSA expressing cells whereas in grade III and IV the number of PSA expressing cells was 45%. This difference was statistically highly significant. CONCLUSION: In this short communication we show that highly malignant astrocytomas express significantly more PSA compared to less malignant astrocytomas. Cleavage of PSA could be used in future therapeutic approaches.