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.

Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas

“…There was a wide intertumoral variability in the expression of both molecules, possibly reflecting their differential expression in individual molecular subtypes of glioblastoma (ref. 12 and our unpublished data) and our unpublished data. FAP immunopositivity was detectable by WB in most of the high-grade glioma samples, but was absent in the DPP-IV negative gliomas.…”

“…Both proteases are involved in the regulation of cell differentiation, adhesion and migration by their proteolytic activity and also non-hydrolytic interactions 9,10 . Our previous reports demonstrated that the expression DPP-IV and FAP is increased in glioblastomas 11,12 . The data on their pathogenetic role in brain tumors is limited-DPP-IV inhibits glioma cell growth, in large part independently of its enzymatic activity 13 , and FAP likely influences the interaction of glioma cells with the surrounding extracellular matrix (our unpublished results and ref.…”

“…Brain tissue samples were collected from 51 patients undergoing astrocytic tumor resection, non-tumorous brain specimens were obtained from 15 patients in whom brain surgery was performed for drug-resistant temporal lobe epilepsy 12 . Written informed consent was obtained from the patients before their entry into the study according to the guidelines of institutional Ethics Committee conducted in accordance with the Declaration of Helsinki.…”

“…Interestingly, the isoforms detected in glioblastoma tissues exhibited more alkaline pI compared to the glioma cell lines. Similarly to DPP-IV, these isoforms may originate from the stromal cells expressing FAP in glioblastomas 12 or reflect the differences in FAP isoforms expressed by glioma cells in vitro and in situ.…”

FAP overexpression induce Epithelial-Mesenchymal Transition (EMT) in oral squamous cell carcinoma by down-regulating DPP9 gene

“…Human cancer FAP expression is reported to correlate to higher tumor grade and worse survival across a worldwide range(11),like cancer on the breast, colon, stomach, etc(12–15). Some studies(15, 16) indicated that FAP can induce EMT.…”