Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.

Center of Oncocytogenomics Institute of Clinical Biochemistry and Laboratory Diagnostics General University Hospital and 1st Faculty of Medicine Charles University 128 00 Prague Czech Republic

Department of Neurosurgery and Neurooncology 1st Faculty of Medicine Charles University and Military University Hospital 168 02 Prague Czech Republic

Department of Pathology Military University Hospital 169 02 Prague Czech Republic

Departments of Neurosurgery Na Homolce Hospital 150 00 Prague Czech Republic

Institute of Computer Science The Czech Academy of Sciences 128 00 Prague Czech Republic

Laboratory of Cancer Cell Biology Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University 128 00 Prague Czech Republic

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