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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.

Cancer-associated fibroblasts (CAFs) significantly influence biological properties of many tumors. The role of these mesenchymal cells is also anticipated in human gliomas. To evaluate the putative role of CAFs in glioblastoma, we tested the effect of CAF conditioned media on the proliferation and chemotaxis of glioma cells. The proliferation of glioma cells was stimulated to similar extent by both the normal fibroblasts (NFs) and CAF-conditioned media. Nevertheless, CAF-conditioned media enhanced the chemotactic migration of glioma cells significantly more potently than the media from normal fibroblasts. In order to determine whether CAF-like cells are present in human glioblastomas, immunofluorescence staining was performed on tissue samples from 20 patients using markers typical for CAFs. This analysis revealed regular presence of mesenchymal cells expressing characteristic CAF markers α-smooth muscle actin and TE-7 in human glioblastomas. These observations indicate the potential role of CAF-like cells in glioblastoma biology.

Fibroblast activation protein (FAP, seprase) is a serine protease with post-proline dipeptidyl peptidase and endopeptidase enzymatic activity. FAP is upregulated in several tumor types, while its expression in healthy adult tissues is scarce. FAP molecule itself and FAP+ stromal cells play an important although probably context-dependent and tumor type-specific pathogenetic role in tumor progression. We provide an overview of FAP expression under both physiological and pathological conditions with focus on human malignancies. We also review and critically analyze the results of studies which used various strategies for the therapeutic targeting of FAP including the use of low molecular weight inhibitors, FAP activated prodrugs, anti-FAP antibodies and their conjugates, FAP-CAR T cells, and FAP vaccines. A unique enzymatic activity and selective expression in tumor microenvironment make FAP a promising therapeutic target. A better understanding of its role in individual tumor types, careful selection of patients, and identification of suitable combinations with currently available anticancer treatments will be critical for a successful translation of preclinically tested approaches of FAP targeting into clinical setting.

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Dipeptidyl peptidase-IV (DPP-IV) represents a unique proteolytic activity cleaving N-terminal X-Pro dipeptides. In addition to canonical DPP-IV/CD26, a number of other molecules have been discovered which exhibit DPP-IV-like enzymatic activity and various degree of structural similarity. These comprise enzymatically active fibroblast activation protein-alpha, DPP-II, DPP8, DPP9 and enzymatically inactive DPP6 and DPP10 that have been grouped as "DPP-IV activity and/or structure homologues" (DASH). Because the enzymatically active DASH can share similar sets of biologically active substrates and are frequently coexpressed within single cell or on tissue level, it is tempting to consider their participation on biological function(s) previously attributed to DPP-IV/CD26. It is speculated that disrupted expression and enzymatic activity of some DASH might corrupt the message carried by their substrates, with consequent promotion of abnormal cell behavior. Thus, modulation of activity of a particular enzyme using e.g. inhibitors, specific antibodies or modifying its expression may be an attractive therapeutic concept in cancer treatment. This review summarizes current knowledge of the expression and possible function of DPP-IV enzymatic activity bearing molecules in human brain tumors.

Glioblastoma stem-like cells (GSCs) are critical for the aggressiveness and progression of glioblastoma (GBM) and contribute to its resistance to adjuvant treatment. MicroRNAs (miRNAs) are small, non-coding RNAs controlling gene expression at the post-transcriptional level, which are known to be important regulators of the stem-like features. Moreover, miRNAs have been previously proved to be promising diagnostic biomarkers in several cancers including GBM. Using global expression analysis of miRNAs in 10 paired in-vitro as well as in-vivo characterized primary GSC and non-stem glioblastoma cultures, we identified a miRNA signature associated with the stem-like phenotype in GBM. 51 most deregulated miRNAs classified the cell cultures into GSC and non-stem cell clusters and identified a subgroup of GSC cultures with more pronounced stem-cell characteristics. The importance of the identified miRNA signature was further supported by demonstrating that a Risk Score based on the expression of seven miRNAs overexpressed in GSC predicted overall survival in GBM patients in the TCGA dataset independently of the IDH1 status. In summary, we identified miRNAs differentially expressed in GSCs and described their association with GBM patient survival. We propose that these miRNAs participate on GSC features and could represent helpful prognostic markers and potential therapeutic targets in GBM.

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