Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

SIMPLE SUMMARY: The perivascular niche in glioblastoma is crucial for maintaining a tumour- permissive microenvironment. In various extracranial cancers, mesenchymal cells that express fibroblast activation protein (FAP) are an important stromal component and a potential therapeutic target. In this study, we examine their functions in the glioblastoma microenvironment where their role is so far largely unexplored. Glioblastoma-associated FAP(+) mesenchymal cells are localised around activated endothelial cells and their presence positively correlates with vascular density. They represent a subpopulation of stromal, non-tumorigenic cells which mostly lack the chromosomal aberrations characteristic of glioma cells. By soluble factors they induce angiogenic sprouting, chemotaxis of endothelial cells, contribute to destabilisation of blood vessels, and increase the migration and growth of glioma cells. Taken together, we identified a subpopulation of FAP(+) mesenchymal cells in the perivascular niche in glioblastoma that may contribute to tumour progression by promoting angiogenesis and supporting dissemination of transformed cells into the surrounding tissue. ABSTRACT: 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.