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.

Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image

“…Tumor biomarkers in circulating liquid would thus be useful as tracers that could aid in diagnosis and contribute to the evaluation of patients' therapeutic effects. Circulating proteins released by tumor cells or cancer-associated cells have recently been identi ed as potential biomarkers for glioma, whereas existing markers show insu cient sensitivity or patient coverage for broad clinical applicability [15]. So far, little progress has been made in developing effective blood-based methods for tracking glioma.…”

Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments

“…Secondly, upregulated cell pathways can be targeted [ 83 , 84 , 85 ], for example, using miRNAs that disrupt those pathways [ 86 , 87 ]. Similarly, the tumour microenvironment can be a site of therapeutic interest [ 88 , 89 , 90 , 91 , 92 ]: one example is exploiting the high concentration of Reactive Oxygen Species (ROS) with ROS-sensitive NMeds that would release the drug only in the presence of ROS [ 93 , 94 ]. However, major limitations to these strategies lay in the poor stability of sensitive molecules, such as RNAs and the lack of cell specificity that could still lead to off-target effects.…”

86Y-Labeled Albumin-Binding Fibroblast Activation Protein Inhibitor for Late-Time-Point Cancer Diagnosis

“…Fibroblast activation protein (FAP) belongs to the dipeptidyl peptidase family and is overexpressed in cancer-associated fibroblasts (CAFs), which suppresses antitumor immunity, promotes tumor growth, and drives epithelial–mesenchymal transition . FAP is highly and selectively expressed in more than 90% of epithelial carcinomas but rarely in normal tissues, , making it a promising diagnostic and therapeutic target for a large variety of malignancies.…”

“…Fibroblast activation protein (FAP) belongs to the dipeptidyl peptidase family and is overexpressed in cancer-associated fibroblasts (CAFs), which suppresses antitumor immunity, promotes tumor growth, and drives epithelial−mesenchymal transition. 1 FAP is highly and selectively expressed in more than 90% of epithelial carcinomas but rarely in normal tissues, 2,3 making it a promising diagnostic and therapeutic target for a large variety of malignancies. In recent years, quinoline-based aromatic small-molecule radiopharmaceuticals have been developed as FAP inhibitors (FAPIs), 4 and with either diagnostic (e.g., 18 F, 68 Ga, 86 Y) or therapeutic (e.g., 90 Y, 177 Lu, 225 Ac) radionuclide labeling, FAPIs have been investigated for theranostics in oncology.…”