Oncogenesis, Microenvironment Modulation and Clinical Potentiality of FAP in Glioblastoma: Lessons Learned from Other Solid Tumors

Abstract

Currently, glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults. Fibroblast activation protein (FAP) is a member of the dipeptidyl peptidase family, which has catalytic activity and is engaged in protein recruitment and scaffolds. Recent studies have found that FAP expression in different types of cells within the GBM microenvironment is typically upregulated compared with that in lower grade glioma and is most pronounced in the mesenchymal subtype of GBM. As a marker of cancer-associated fibroblasts (CAFs) with tumorigenic activity, FAP has been proven to promote tumor growth and invasion via hydrolysis of molecules such as brevican in the extracellular matrix and targeting of downstream pathways and substrates, such as fibroblast growth factor 21 (FGF21). In addition, based on its ability to suppress antitumor immunity in GBM and induce temozolomide resistance, FAP may be a potential target for immunotherapy and reversing temozolomide resistance; however, current studies on therapies targeting FAP are still limited. In this review, we summarized recent progress in FAP expression profiling and the understanding of the biological function of FAP in GBM and raised the possibility of FAP as an imaging biomarker and therapeutic target.

Keywords: fibroblast activation protein; glioblastoma; imaging biomarker; immunosuppression; therapeutic target; tumorigenesis.

Figure 1

The signaling pathway in FAP regulation. (a) Regulation of FAP expression via the TGFβ signaling pathway in GBM cells; (b) downstream signaling pathway regulated by activated FAP heterodimers leading to various effects on cancer cells, including proliferation and invasion, immunosuppression and epithelial-mesenchymal transition (EMT).

Figure 2

Magnetic resonance imaging (MRI) and FAPI PET/CT in GBM. An IDH-wildtype GBM from a 71-year-old woman displayed ring-like contrast enhancement with hypointense T1-weighted and hyperintense T2-weighted signals (a,b) from central tissue. ⁶⁸Ga-FAPI PET and merged PET/CT images (c,d) showed elevated radioactivity in the whole tumor area (including ring-like contrast enhancement and noncontrast-enhanced tissue).