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Article

Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis

1
Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic
2
Department of Pathology, Military University Hospital, 169 02 Prague, Czech Republic
3
Departments of Neurosurgery, Na Homolce Hospital, 150 00 Prague, Czech Republic
4
Department of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University and Military University Hospital, 168 02 Prague, Czech Republic
5
Center of Oncocytogenomics, Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic
6
Institute of Computer Science, The Czech Academy of Sciences, 128 00 Prague, Czech Republic
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Ignacio Ochoa and José María Ayuso-Dominguez
Cancers 2021, 13(13), 3304; https://doi.org/10.3390/cancers13133304
Received: 31 May 2021 / Revised: 25 June 2021 / Accepted: 26 June 2021 / Published: 1 July 2021
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.
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. View Full-Text
Keywords: glioblastoma; angiogenesis; microenvironment; fibroblast activation protein; seprase; angiopoietin; vessel destabilisation glioblastoma; angiogenesis; microenvironment; fibroblast activation protein; seprase; angiopoietin; vessel destabilisation
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MDPI and ACS Style

Balaziova, E.; Vymola, P.; Hrabal, P.; Mateu, R.; Zubal, M.; Tomas, R.; Netuka, D.; Kramar, F.; Zemanova, Z.; Svobodova, K.; Brabec, M.; Sedo, A.; Busek, P. Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis. Cancers 2021, 13, 3304. https://doi.org/10.3390/cancers13133304

AMA Style

Balaziova E, Vymola P, Hrabal P, Mateu R, Zubal M, Tomas R, Netuka D, Kramar F, Zemanova Z, Svobodova K, Brabec M, Sedo A, Busek P. Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis. Cancers. 2021; 13(13):3304. https://doi.org/10.3390/cancers13133304

Chicago/Turabian Style

Balaziova, Eva, Petr Vymola, Petr Hrabal, Rosana Mateu, Michal Zubal, Robert Tomas, David Netuka, Filip Kramar, Zuzana Zemanova, Karla Svobodova, Marek Brabec, Aleksi Sedo, and Petr Busek. 2021. "Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis" Cancers 13, no. 13: 3304. https://doi.org/10.3390/cancers13133304

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