title: Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma.
abstract: Glioblastomas are deadly neoplasms resistant to current treatment modalities. Fibroblast activation protein (FAP) is a protease which is not expressed in most of the normal adult tissues but is characteristically present in the stroma of extracranial malignancies. FAP is considered a potential therapeutic target and is associated with a worse patient outcome in some cancers. The FAP localization in the glioma microenvironment and its relation to patient survival are unknown. By analyzing 56 gliomas and 15 non-tumorous brain samples, we demonstrate increased FAP expression in a subgroup of high-grade gliomas, in particular on the protein level. FAP expression was most elevated in the mesenchymal subtype of glioblastoma. It was neither associated with glioblastoma patient survival in our patient cohort nor in publicly available datasets. FAP was expressed in both transformed and stromal cells; the latter were frequently localized around dysplastic blood vessels and commonly expressed mesenchymal markers. In a mouse xenotransplantation model, FAP was expressed in glioma cells in a subgroup of tumors that typically did not express the astrocytic marker GFAP. Endogenous FAP was frequently upregulated and part of the FAP+host cells coexpressed the CXCR4 chemokine receptor. In summary, FAP is expressed by several constituents of the glioblastoma microenvironment, including stromal non-malignant mesenchymal cells recruited to and/or activated in response to glioma growth. The limited expression of FAP in healthy tissues together with its presence in both transformed and stromal cells suggests that FAP may be a candidate target for specific delivery of therapeutic agents in glioblastoma.
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53, Prague 2, Czech Republic. busekpetr@seznam.cz.
authors: Petr
authors: P
authors: Busek
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53, Prague 2, Czech Republic.
authors: Eva
authors: E
authors: Balaziova
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53, Prague 2, Czech Republic.
authors: Ivana
authors: I
authors: Matrasova
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53, Prague 2, Czech Republic.
authors: Marek
authors: M
authors: Hilser
authors: Department of Neurosurgery, Na Homolce Hospital, Roentgenova 2, 150 30, Prague 5, Czech Republic.
authors: Robert
authors: R
authors: Tomas
authors: Department of Pathology, Na Homolce Hospital, Roentgenova 2, 150 30, Prague 5, Czech Republic.
authors: Martin
authors: M
authors: Syrucek
authors: Institute of Clinical Biochemistry and Laboratory Diagnostics of the First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, U Nemocnice 2, 128 01, Prague 2, Czech Republic.
authors: Zuzana
authors: Z
authors: Zemanova
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53, Prague 2, Czech Republic.
authors: Evzen
authors: E
authors: Krepela
authors: Institute of Biophysics and Bioinformatics, First Faculty of Medicine, Charles University in Prague, Salmovská 1, 120 00, Prague 2, Czech Republic.
authors: Jaromir
authors: J
authors: Belacek
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53, Prague 2, Czech Republic. aleksi@cesnet.cz.
authors: Aleksi
authors: A
authors: Sedo
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002461:Cell Line, Transformed / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005500:Follow-Up Studies; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: Fibroblast activation protein α; Glioma; Seprase; Serine protease; Stromal cells