gms | German Medical Science

Objective: Malignant gliomas are characterized by invasion, angiogenesis and recruitment of bone marrow derived progenitor cells. In non-glial tumors, CD146 was shown to serve as a key cell adhesion protein in vascular endothelial cell activity but also as a membrane signal receptor in tumor-induced angiogenesis. CD146 promotes tumor progression of cancers including melanoma and prostate, but its expression is frequently lost in breast carcinoma cells. We describe grade dependent CD146 expression in gliomas for the first time and characterize the underlying cell type in malignant gliomas based on their contribution to the entire tumor mass, surface marker expression and differentiation capabilities.

Methods: Microarray based gene expression data on CD146 were acquired from publicly available data bases for non-neoplastic brain as well as glial tumors to predict a possible differential expression in brain tumors. IHC staining of different astrocytomas (WHO°II, °III, °IV) were analyzed for expression of CD146. Staining was judged for its cellular localization and intensity was evaluated in a multi-level score. Flow cytometry for CD146 expression was performed. Applying a novel isolation protocol, mesenchymal progenitor cells derived from glioblastomas (gb-hMSC) were analyzed as well as bone marrow derived mesenchymal stem cells (bm-hMSC) and, as a control, human umbilical cord endothelial cells (HUVEC).

Results: Expression of CD146 was increased from low-grade gliomas to glioblastomas, demonstrating a grade dependency in glial brain tumors according to systems biological data. This was confirmed by IHC of gliomas from different WHO grades. Low-grade gliomas (LGG) displayed a weak staining for CD146, whereas expression was strong in GBM. CD146 expression in LGG was seen only in endothelial cells and was strongest in the tumor vasculature. Cells of the tumor stroma were positive for CD146 only in GBM, but could not be detected in LGG. FACS analysis revealed different staining intensities in gb-hMSC, bm-hMSC and HUVECs in rising order.

Conclusions: For the first time, we show a grade-dependent expression of the endothelial cell adhesion molecule CD146 in malignant gliomas, consistently expressed not only in tumor vasculature but also in the stroma of high grade tumors. The underlying cell type shows characteristics of mesenchymal lines as well as endothelial differentiation. Future work will focus on the exact role of CD146 in tumor angiogenesis, and its potential function of mediating downstream signalling.