Fibroblast Activation Protein-α as a Target in the Bench-to-Bedside Diagnosis and Treatment of Tumors: A Narrative Review

Abstract

Fibroblast activation protein-α (FAP) is a type II integral serine protease that is specifically expressed by activated fibroblasts. Cancer-associated fibroblasts (CAFs) in the tumor stroma have an abundant and stable expression of FAP, which plays an important role in promoting tumor growth, invasion, metastasis, and immunosuppression. For example, in females with a high incidence of breast cancer, CAFs account for 50–70% of the cells in the tumor’s microenvironment. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signaling, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. This review discusses the basic biological characteristics of FAP and its applications in the diagnosis and treatment of various cancers. We review the emerging basic and clinical research data regarding the use of nanomaterials that target FAP.

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

“…However, MIP-1232, a UAMC-1110-based probe radiolabeled with I 125 , appeared to be highly correlated with tumour tissue imaging [120]. Based on their selective and strong binding to FAP, a multitude of radiolabeled FAP inhibitors (FAPI) have been generated and are now widely used in experimental tumour diagnosis (reviewed in [10,14]). Several FAPI tracers recently entered the clinical phase for pan-tumour imaging, diagnosis, and staging examinations (Table S1) [121].…”

“…Among them, sibrotuzumab was tested in phase I/II clinical trials in patients with metastatic colorectal cancer, albeit without therapeutic response, and some patients developed antihuman Abs [133,134]. Thereafter, FAP Abs have been conjugated with toxins, radioisotopes, immunomodulatory cytokines, or costimulatory molecules (reviewed in [10,14]). Based on the role of the costimulatory receptor 4-1BB (CD137, TNFRSF9) in sustaining effective T cell immune responses, a bispecific FAP antibody-fusion protein combining a trimeric 4-1BB ligand (4-1BBL) and a Fab moiety recognizing fibroblast FAP was developed [135].…”

“…As mentioned above for DPP4, several anti-FAP CAR-T models based on MO36 and F19 mAbs were constructed (reviewed in [10,14]). A blockade of tumour growth by anti-FAP CAR-T cells was validated in human lung cancer xenografts and syngeneic murine pancreatic cancers [147].…”

“…The roles of ectoproteases within neoplastic sites have been investigated actively. Attention has been peculiarly focused on dipeptidyl peptidase 4 (DPP4, CD26), fibroblast activation protein alpha (FAP, Seprase), aminopeptidase N (APN, CD13), and ADAM17 (also known as tumour necrosis factor-α-converting enzyme/TACE), whose deregulated expression in the tumour microenvironment (TME) is correlated with a malignant cancer phenotype (tumour cell growth, survival, metastasis, and tumour-associated angiogenesis) [2][3][4][5][6][7][8][9][10][11][12][13][14] (Figure 1). Through their enzymatic activities, DPP4, FAP, APN, and ADAM17 mediate the proteolysis of bioactive peptides and cytokines, components of the extracellular matrix, and transmembrane proteins (receptors and adhesion molecules) [8,[10][11][12][13][15][16][17][18][19][20][21][22].…”

“…The enzymatic activity of DPP4, FAP, APN, and ADAM17, even if it contributes, is not essential for signal transduction. Indeed, these entities have a short intracytoplasmic tail, and inhibitor or mAb binding to the ectoenzyme initiates lateral membrane interactions with transmembrane proteins (including β1 integrins) for downstream signalling [14,18,28,[30][31][32].…”