Tumor Biology

, Volume 37, Issue 10, pp 13961–13971 | Cite as

Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma

  • Petr Busek
  • Eva Balaziova
  • Ivana Matrasova
  • Marek Hilser
  • Robert Tomas
  • Martin Syrucek
  • Zuzana Zemanova
  • Evzen Krepela
  • Jaromir Belacek
  • Aleksi Sedo
Original Article

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.

Keywords

Fibroblast activation protein α Seprase Glioma Serine protease Stromal cells 

Supplementary material

13277_2016_5274_MOESM1_ESM.rtf (151 kb)
ESM 1(RTF 151 kb)
13277_2016_5274_MOESM2_ESM.pptx (786 kb)
Supplementary Figure S1Characteristics of the glioma stem-like cell cultures a) GSC57 and b) GSC48. Expression of Sox2 (Sox2-PerCP, RD Systems) and CD133 (CD133-APC, Miltenyi Biotech) was determined by flow cytometry, detection of the differentiation markers glial fibrillary acidic protein (GFAP) and beta III tubulin was performed in cells grown on laminin in defined stem-cell serum free media (undifferentiated) or in the presence of 10 % fetal calf serum (differentiated). (PPTX 785 kb)
13277_2016_5274_MOESM3_ESM.pptx (146 kb)
Supplementary Figure S2Fibroblast activation protein (FAP) and survival in gliomas. The Kaplan-Meier survival plots for glioma patients and the proportion of individual tumor grades in the subgroups based on FAP expression in studies comprising grade I-IV tumors. A) Greavendeel [9] dataset, b) Data from REMBRANDT. Patients were divided into groups based on FAP mRNA expression: ∆ low expression = 1st quartile, □ medium expression = 2nd + 3rd quartile, ○ high expression = 4th quartile. + = censored data. Log rank test p < 0.05 for all intergroup comparisons in A), and p < 0.05 for downregulated vs. intermediate and downregulated vs. upregulated in B). (PPTX 146 kb)
13277_2016_5274_MOESM4_ESM.xlsx (37 kb)
Table S1(XLSX 36 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Petr Busek
    • 1
  • Eva Balaziova
    • 1
  • Ivana Matrasova
    • 1
  • Marek Hilser
    • 1
  • Robert Tomas
    • 2
  • Martin Syrucek
    • 3
  • Zuzana Zemanova
    • 4
  • Evzen Krepela
    • 1
  • Jaromir Belacek
    • 5
  • Aleksi Sedo
    • 1
  1. 1.Institute of Biochemistry and Experimental Oncology, First Faculty of MedicineCharles University in PraguePrague 2Czech Republic
  2. 2.Department of NeurosurgeryNa Homolce HospitalPrague 5Czech Republic
  3. 3.Department of PathologyNa Homolce HospitalPrague 5Czech Republic
  4. 4.Institute of Clinical Biochemistry and Laboratory Diagnostics of the First Faculty of MedicineCharles University in Prague and General University Hospital in PraguePrague 2Czech Republic
  5. 5.Institute of Biophysics and Bioinformatics, First Faculty of MedicineCharles University in PraguePrague 2Czech Republic

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