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FAP (fibroblast activation protein alpha)

Written2020-08Sinem Tunçer, Sreeparna Banerjee
Vocational School of Health Services, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey Biotechnology Application and Research Center, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey; (ST); Department of Biology, Middle East Technical University, 06800 Ankara, Turkey; (SB)

Abstract FAP is a cell surface glycoprotein serine protease that has been shown to participate in cellular processes such as wound healing, tissue remodeling, fibrosis, and inflammation and may contribute to tumor growth.

Keywords FAP, Fibroblast Activation Protein Alpha, Cancer, Cancer Therapy

(Note : for Links provided by Atlas : click)


HGNC Alias symbDPPIV
HGNC Alias nameseprase
HGNC Previous namefibroblast activation protein, alpha
LocusID (NCBI) 2191
Atlas_Id 40530
Location 2q24.2  [Link to chromosome band 2q24]
Location_base_pair Starts at 162170684 and ends at 162243445 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping FAP.png]
Local_order According to the human genome assembly GRCh38.p13 (annotation release 109.20200522) from Genome Reference Consortium, the gene can be found on chromosome 2 at location: NC_000002.12 (162170684..162243472, complement) (Figure 1).
  Figure 1: Genomic location of human FAP
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Note FAP appears to be conserved among chordates, with especially high homology in many mammals (Table 1). In humans, both the FAP and DPPIV genes are located on the 2q24.2 location. This genomic proximity, coupled with their high degree of homology suggests that they have a common ancestry, and it is believed that FAP evolved from DPPIV via a gene duplication event (Brennen et al., 2012a).
Table 1: Pairwise alignment of FAP gene (in distance from human; NCBI)
GeneIdentity (%)
vs. P.troglodytesFAP10099,7
vs. M.mulattaFAP99,698,9
vs. C.lupusFAP93,394
vs. B.taurusFAP93,994
vs. M.musculusFap89,689,4
vs. R.norvegicusFap88,988,2
vs. G.gallusFAP73,675,1
vs. X.tropicalisfap61,266,6
vs. D.melanogasterome36,446
vs. A.gambiaeAgaP_AGAP01158439,145,3
vs. M.oryzaeMGG_0598934,143
  Figure 2: Regulators of FAP expression: Multiple environmental and soluble factors can modulate FAP transcription. A detailed explanation can be found in the text. The figure was modified from Puré and Blomberg, 2018.
Transcription Electronic Northern blot (eNorthern) analysis for transcriptional profiles of normal and cancer samples showed that FAP mRNA is expressed in a range of cancer types while normal tissues generally lack the mRNA signal (Dolznig et al., 2005). In the tumor microennvironment (TME), cancer-associated fibroblasts (CAFs) are the dominant cellular component, playing critical roles in promoting tumor progression. Although FAP is not detectable in normal adult human tissues, its expression is enhanced in the CAF (Jiang et al., 2016). For instance, in human breast cancer, FAP was found as one of the six CAF markers (Liu et al., 2019). In colorectal cancer patients, enhanced FAP expression was also reported as a marker of activated CAFs (Son et al., 2019).
The main regulatory mechanism that controls FAP expression is at the level of mRNA transcription (Figure 2). The region located approximately 750-250 bp upstream from the transcription start site was identified as the core promoter that controls the expression in various FAP+ cell lines. In humans and rats, this region contains the canonical TATA box and putative binding sites for transcription factors EGR1 (Early Growth Response 1), E2F1 (E2F Transcription Factor 1), SP1 (Sp1 Transcription Factor), HOXA4 (Homeobox A4), JUN (Activator protein 1), CEBPA (c/EBP, CCAAT-enhancer-binding protein), Ets proteins, SMAD3 and an E-box as well as several TGFB1 (Transforming Growth Factor Beta)-responsive cis-regulatory elements (Busek et al., 2018; Lindner et al., 2019; Puré and Blomberg, 2018; Tulley and Chen, 2014).
Human TERT (telomerase reverse transcriptase), which contributes to cancer development and progression through several mechanisms, might also regulate FAP expression through EGR1. Other possible FAP regulators in the context of cancer and embryogenesis include mesenchymal transcription factors TWIST1 (Twist-related protein 1) and TCF15 (PARAXIS) (Busek et al., 2018). Several other factors have been also suggested to play roles in tumor-mediated up-regulation of FAP. In breast cancer cell lines, high doses of TNF (Tumor Necrosis Factor Alpha) treatment has been shown to enhance MAPK3 / MAPK6 (misnamed ERK1 and ERK2, Extracellular Signal-Regulated Protein Kinases 1 and 2) phosphorylation along with a modest increase in FAP expression while TNF treatment of bone-marrow mesenchymal stem cells (BM-MSCs) did not yield significant up-regulation of FAP; instead, in BM-MSCs, FAP was up-regulated in response to IL1B (Interleukin-1beta) and TGFB1 (Puré and Blomberg, 2018). UVR-induced and cathepsin mediated release of TGFB1 in primary melanoma cells could also enhance FAP expression. Moreover, TGFB1-dependent FAP expression was reported in fibroblast cells co-cultured with melanoma cells or incubated with the conditioned media obtained from melanoma cultures (Wäster et al., 2017) suggesting that TGFB1 could activate fibroblasts. LPS stimulation was also shown to enhance FAP, TGFB1, and collagen I expression through the activation of TLR4/NF-kB signaling (Guo et al., 2015). Therefore, TGFB1 seems to be an important player in the signaling pathways that have been implicated in FAP expression. In addition to TGFB1, phorbol ester, retinol, or retinoic acid treatment was also reported to induce FAP expression in FAP-negative fetal leptomeningeal fibroblasts (Busek et al., 2018).
ERK signaling pathway was also reported to contribute to FAP expression. In a mouse transplant model of melanoma, treatment with an inhibitor of the A2BR adenosine ( ADO) receptor reduced the number of FAP+ cells while A2BR stimulation increased FAP+ cells and enhanced ERK1/2 phosphorylation (Sorrentino et al., 2016). In vitro studies showed that GRN (progranulin), a well-known secreted glycoprotein that promotes proliferation and angiogenesis of colorectal cancer cells, also stimulates FAP expression in fibroblasts through the activation of TNFRSF1B (TNFR2, Tumor Necrosis Factor Receptor 2)/AKT and ERK signaling pathways (Wang et al., 2017).
On the other hand, not much known about the factors that suppress FAP expression; either acutely or as part of basal regulation. Estrogen signaling through ESR1 (Estrogen Receptor Alpha) was observed to inhibit FAP expression in prostate CAFS where ERα levels were found to lower than the normal fibroblasts (Jia et al., 2016). FAP mRNA together with several miRNAs have been detected in Ago (Argonaute) complexes isolated from pancreatic islets and bioinformatics prediction tools have suggested that several miRNAs might regulate FAP expression post-transcriptionally (Busek et al., 2018). In breast phyllodes tumors, MIR21 was shown to induce the expression of FAP by down-regulating PTEN (Phosphatase And Tensin Homolog) expression (Gong et al., 2014). In an in vitro model of oral squamous cell carcinoma, MIR30A (miR-30a-5p) was reported to target FAP mRNA directly (Ruan et al., 2018).
FAP expression was also shown to be affected by the culture conditions and the surface adhesion properties can modulate FAP expression (Puré and Blomberg, 2018). Ha et al. showed that in contrast with the mice fibroblasts cultured on flat silicon which rarely express FAP, silicon nanowires cultivated fibroblasts exhibited FAP levels similar to those found in cancerous tissue (Ha et al., 2014). Wäster et al. reported decreased levels of FAP in the senescent cultures of human melanocytes and Avery et al. claimed that FAP expression was downregulated in primary murine adult pulmonary fibroblasts cultured on plastic surface (Avery et al., 2018).
Finally, a natural variant of FAP (dbSNP: rs762738740 ; Ser363LeuFAP) decreased plasma membrane expression of FAP and caused the loss of homodimerization and dipeptidyl peptidase activity, mislocalization with the calnexin ( CANX) in the endoplasmic reticulum and induction of the unfolded protein response (UPR) (Keane et al., 2014; Osborne et al., 2014). The transcript variants for the gene can be found in


Note FAP (EC 3.4.21.B28) is a cell-surface type II transmembrane glycoprotein serine protease that acts on various hormones and extracellular matrix (ECM) components. The protein is involved in many cellular processes including tissue remodeling, wound healing, inflammation, fibrosis, and tumor growth (Dimitrova et al., 2015; Hamson et al., 2014; Puré and Blomberg, 2018). This atypical serine protease, belonging to the S9b family of post-proline cleaving enzymes, has both dipeptidyl peptidase and endopeptidase activities (Dimitrova et al., 2015; Hamson et al., 2014). Substrates of FAP include natural bioactive peptides containing the X-Pro sequence (Keane et al., 2014). Although gelatin and heat-denatured type I collagen were recognized as biological substrates of FAP, the enzyme cannot degrade native collagen type I and IV, vitronectin, tenascin, laminin, fibronectin, fibrin, or casein (Juillerat-Jeanneret et al., 2017). The endopeptidase activity of soluble FAP cleaves α2-antiplasmin a proteinase that digests fibrin, the main component of blood clots (Lee et al., 2006). Neuropeptide Y, B-type natriuretic peptide, substance P, and peptide YY are natural neuropeptide hormones that were shown to be hydrolyzed by FAP (Keane et al., 2011).
FAP has a molecular weight of 170 kDa and consists of two 97 kDa glycoprotein subunits (Figure 3). The FAP monomer has five potential N-glycosylation sites, 13 cysteine residues, three segments corresponding to the highly conserved catalytic domains of serine proteases, a hydrophobic transmembrane segment and a short cytoplasmic tail of six amino acids (Liu et al., 2012). Based on its amino acid homology, FAP is considered to be very closely related to DPP4 (DPPIV, Dipeptidyl Peptidase IV; EC which is the best-studied member of the S9b family of enzymes. The major difference between these two enzymes is that FAP possesses Ala657 while DPPIV contains Asp663 at their active sites. Substrates and inhibitors for FAP have been developed based on this difference between FAP and DPPIV. This variation proves to be enough to lessen the acidity and increase the size of the active center pocket, thus making FAP capable of endopeptidase activity (Dimitrova et al., 2015).
A soluble truncated form of FAP lacking the transmembrane domain has been reported in human plasma. In this form, FAP cleaves alpha-2-antiplasmin, the main inhibitor of the fibrinolytic system, at prolyl bonds Pro3-Leu4 and Pro12-Asn13. Tissue repair relies on the formation of a fibrin clot in which fibrin is deposited. During scar resolution, the fibrin clot is dissolved by plasmin in a process called fibrolysis. However, cleavage of alpha-2-antiplasmin by FAP converts alpha-2-antiplasmin into a more potent inhibitor of plasmin. Thus, enhanced FAP activity can lead to a reduction in fibrinolysis (Hamson et al., 2014).
More recently, natural substrates of FAP were identified using degradomic and proteomic techniques. Terminal amine isotopic labeling of substrates (TAILS) based degradomics technique identified FAP cleavage sites in collagens, and many other ECM and ECM associated proteins in a mouse model. Cleavages of LOXL1 (Lysyl Oxidase-Like-1), CXCL5 (C-X-C Motif Chemokine 5), CSF1 (Colony Stimulating Factor 1), and C1QTNF6 (Complement C1q Tumor Necrosis factor-related Protein 6) by FAP were confirmed in in vitro. Differential metabolic labeling coupled with quantitative proteomic analysis showed that its broad substrate repertoire enables FAP to play important roles in many different biological processes (Zhang et al., 2019).
Description Immunohistochemical analyses using specific monoclonal antibodies revealed that FAP has a distinctive tissue distribution and is usually absent in normal adult tissues. The enzyme activity of FAP was shown to be restricted to single reactive fibroblasts, glucagon producing A-cells in pancreatic islets, and endometrial cells in healthy human tissues (Dimitrova et al., 2015). The expression of FAP is weak in the cervix and the uterine stroma, while the expression reaches the highest levels during the proliferative phase. FAP is also present in multipotent bone marrow stromal cells (BM-MSC) in both mice and humans. Independent of its enzymatic activity, FAP was shown to promote the motility of human BM-MSC, possibly via RHOA (Ras Homolog Family Member A) activity. It has also been detected in the human placenta and some cases in dermal fibroblasts surrounding hair follicles (Busek et al., 2018). More recently FAP was shown to promote epithelial-mesenchymal transition (EMT) in human oral squamous cell carcinoma by down-regulating DPP9 (Dipeptidyl Peptidase 9) in a non-enzymatic manner (Wu et al., 2020). The non-enzymatic function of FAP was also shown in lung cancer: FAP was reported to promote the growth, adhesion, and migration of lung cancer cells by regulating the SHH (Sonic Hedgehog Signaling Molecule) and PI3K (Phosphoinositide 3-Kinase) signaling pathways (Jia et al., 2018).
In mice, the highest FAP enzymatic activity was detected in the uterus, pancreas, submaxillary gland, and skin, whereas the lowest levels were in brain, prostate, leukocytes, and testis and some activity was also present in the skeletal muscles and lymph nodes (Keane et al., 2014). Roberts et al. showed that FAP+ stromal cells were found in several mouse tissues and suggested that FAP+ cells are important in sustaining muscle mass and hemopoiesis. Besides, cancer-induced cachexia was associated with a depletion of these FAP+ stromal cells from normal tissues. The authors claimed that the acquisition of FAP+ stromal cells by tumors may cause the failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia (Roberts et al., 2013). On the other hand, although high enzyme levels of FAP have been detected during embryogenesis in mesenchymal cells, FAP knockout mice had a normal phenotype in histological and hematological analysis and Fap-/- animals showed no overt developmental defects. In addition, these animals showed no difference in their susceptibility to cancer when compared to their wildtype littermates (Niedermeyer et al., 2000). Tan et al. showed that although the expression of Fap was high in the lungs and lung-draining lymph nodes in influenza infection, absence of Fap did not alter the antiviral CD8+ T cell and B cell responses, nor did it affect the course of recovery in infected mice. In more general terms, Fap deficiency by itself did not cause abnormalities in immune cell subsets or abnormal anti-influenza immune response. This study is important for FAP targeting anti-cancer strategies since cancer patients are highly susceptible to the long-term complications of influenza infection (Tan et al., 2017). Fan et al. found increased mortality and increased lung fibrosis in Fap-deficient mice compared to wild-type mice. In the same study, intermediate-sized collagen fragments were found to be accumulated in the lungs of Fap-deficient mice. This observation was consistent with in vitro studies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products (Fan et al., 2016). Besides, in human idiopathic pulmonary fibrosis (IPF), FAP was shown to be selectively induced in fibrotic foci, but not in the normal or emphysematous lung (Acharya et al., 2006). FAP may play a role in metabolic syndrome. Administration of the FAP inhibitor talabostat (TB) to diet-induced obese animals led to a profound decrease in body weight, reduced food consumption and adiposity, increased energy expenditure, improved glucose tolerance, and insulin sensitivity, and lowered cholesterol levels probably due to increased bioavailability of FGF21 (Fibroblast Growth Factor 21) (Sánchez-Garrido et al., 2016), demonstrating a metabolic benefit of FAP inhibition for treating diabetes.
The expression of FAP may also change under some pathological conditions. FAP is undetectable in a healthy liver but is markedly elevated in liver cirrhosis and the intensity of FAP immunoreactivity was found to be correlated with the severity of liver fibrosis in hepatitis C infected patients. Serum FAP levels were higher in patients with alcoholic liver disease (Busek et al., 2018). In rheumatoid arthritis and osteoarthritis, FAP expression has been detected in fibroblast-like synovial cells (Yu et al., 2010). Expression of active FAP on the chondrocyte membrane and elevated levels in cartilage from osteoarthritis patients were also detected. The pro-inflammatory cytokines IL1 (Interleukin 1) and OSM (oncostatin M), which promote cartilage destruction, were found to enhance FAP expression on the chondrocyte membrane (Milner et al., 2006). Supporting these findings, Fap knockout mice exhibited a decrease in cartilage destruction in inflammatory destructive arthritis. Therefore, these results suggest that FAP expressing cells contribute to joint destruction and FAP can be considered as a potential target to prevent cartilage degradation (Wäldele et al., 2015).
Increased FAP expression is also involved in tissue remodeling. FAP expression was shown to be induced in fibroblasts during skin wound healing and enhanced FAP expression was also detected in keloids and scleroderma. During the healing process after myocardial infarction, FAP was reported to contribute to the migratory potential of FAP+ activated fibroblasts. FAP expression was detected in the submucosal and muscularis layers in intestinal strictured regions in Crohn's disease, in advanced aortic atherosclerotic plaques, and in thin-cap human coronary fibroatheromata, where FAP was proposed to contribute to type I collagen breakdown in the fibrous caps (Busek et al., 2018).
  Figure 3: Structure of human FAP: Secondary structure of human FAP is shown. Crystal structure was obtained by Aertgeerts et al. using X-ray diffraction (PDB ID: 1Z68) (Aertgeerts et al., 2005).
Expression FAP is highly upregulated in many tumor cells and tumor-associated stromal cells. In basal cell carcinoma, squamous cell carcinoma of the skin, hepatocellular carcinoma, renal cancer, prostate cancer, thyroid cancer, and myeloma, FAP expression was found to be upregulated in stromal cells (mesenchymal cells and/or fibroblasts), but not in tumor cells. In oral squamous cell carcinoma, esophageal cancer, gastric cancer, colorectal cancer, pancreatic adenocarcinoma, mesothelioma, breast tumors, cervical cancer, ovarian cancer, glioma, and sarcomas, both malignant and stromal cells showed increased expression of FAP (Busek et al., 2018). In addition, depending on the tumor type, FAP has been detected in other cell types in the TME including endothelial cells (Coto-Llerena et al., 2020; Tunçer et al., 2017), macrophages, monocytes, and Tregs (Coto-Llerena et al., 2020), and osteoclasts, osteogenic cells, fibrotic stroma, certain adipocytes and vascular endothelial cells (Ge et al., 2006).
Localisation FAP is located on the plasma membrane but in certain types of carcinomas, intracellular cytoplasmic pools have also been reported (Dolznig et al., 2005).
Function A meta-analysis consisting of 15 studies that assessed FAP expression in 11 solid cancers by immunohistochemistry revealed that FAP positivity was found in 50-100% of patients. Enhanced FAP expression was associated with 1) a higher local tumor invasion, 2) increased risk of lymph node metastases, and 3) decreased survival, particularly in cases where FAP was expressed in the malignant cells. Worse survival was reported for hepatocellular, ovarian, non-small cell lung carcinoma, and osteosarcoma, but a stronger association was demonstrated for colorectal and pancreatic carcinoma (Busek et al., 2018). Park et al. showed that although FAP was significantly increased in the intratumoral stroma of pancreatic ductal adenocarcinomas, low intratumoral FAP+ CAF counts were associated with a significantly reduced overall survival compared to those with high FAP+ cancer-associated fibroblast counts (Park et al., 2017). Kelly et al. reported that FAP was overexpressed in invasive ductal carcinoma cells of human breast cancers (Kelly et al., 1998). Contrary to these data, Ariga et al. revealed that FAP expression was restricted to stromal fibroblasts adjacent to breast tumor-cell nests but not cancer cells, and more abundant FAP expression was associated with longer overall and disease-free survival (Ariga et al., 2001). Such discrepant results can be due to differences in the methodology for FAP quantification as well as differences in the specificity of the antibodies that recognize different FAP epitopes (Busek et al., 2018).
The tumorigenic role of FAP has been attributed to enhanced proliferation of transformed cells, ECM remodeling, enhanced tumor vascularization, support of invasion and metastasis, and favoring escape from immunosurveillance (Busek et al., 2018; Koczorowska et al., 2016; Liu et al., 2012). In an endogenous mouse model of lung adenocarcinoma, Fap deficiency was associated with a lower tumor burden, decreased tumor cell proliferation, and increased survival of the animals. Similarly, in a Fap knockout mouse model of endogenous pancreatic ductal adenocarcinoma, occurrence tumor was delayed and animal survival was increased (Lo et al., 2017). FAP can increase the proliferation of tumor cells and decrease the exogenous growth factor dependency of transformed cells at least in part through decreasing PTEN activity and stimulating PI3K/AKT and RAS-ERK pathways (Lv et al., 2016; H. Wang et al., 2014). Interestingly, breast cancer cells expressing a catalytically inactive form of FAP were also shown to degrade the ECM extensively and increase the secretion of MMP9 (Matrix Metalloproteinase-9) in the conditioned medium compared to cells transfected with a control vector (Y. Huang et al., 2011). Similarly, enhanced cellular growth and motility were detected in breast cancer cells expressing the enzymatically inactive form of FAP via the activation of the PI3K/AKT and MMP2 /MMP9 signaling pathways (Lv et al., 2016). In the TME, FAP-expressing stromal cells can support tumor growth by providing growth factors such as HGF (Hepatocyte Growth Factor), IL6, IL11, EGF, FGF1 (Fibroblast Growth Factor 1), FGF2, and TGFB1. Correspondingly, depleted Fap expression and/or elimination of Fap-expressing cells in mouse models resulted in a lower proliferation of tumor cells (Busek et al., 2018).
FAP can also promote the migration of non-malignant stromal cells, including endothelial cells and fibroblasts by stimulating pericellular proteolysis and enhancing the production of motility-promoting factors and modifying ECM organization (Cai et al., 2013; Fang et al., 2016; Goodman et al., 2003; Lee et al., 2011; Santos et al., 2009). ECM remodeling is closely associated with tumor neovascularization (Busek et al., 2018). FAP expressing human breast cancer cells had a 3-fold higher microvessel density compared to tumors from cells that did not express FAP indicating a pro-angiogenic function for FAP. Analysis of the endothelial cells showed that FAP mRNA was upregulated by endothelial cells undergoing reorganization and capillary morphogenesis. Tumor xenograft models showed that FAP depletion decreased blood vessel density. IFNG (Interferon gamma) and TNF were shown to be involved in the proangiogenic action of FAP (Liu et al., 2012). Besides, FAP expression in fibroblasts was associated with the secretion of pro-angiogenic factors, such as vascular endothelial growth factor ( VEGFA) and angiopoetin-1 ( ANGPT1), and negatively associated with the expression of anti-angiogenic factors such as SERPINF1 (PEDF, Pigment Epithelium-Derived Factor) (Koczorowska et al., 2016). On the other hand, the ablation of FAP+ cells in in vivo tumor models resulted in a decreased intratumoral VEGFA amount and a reduced vascular density (Liao et al., 2009; Lo et al., 2015).
FAP also has immune-suppressive functions in the TME (Jiang et al., 2016). FAP-expressing cells were shown to be important sources of immunosuppressive molecules including HMOX1 (heme oxygenase 1), PTGES (prostaglandin E synthase), CXCL12, and CCL2 (C-C Motif Chemokine Ligand 2). In addition, FAP-expressing stromal cells were reported to contribute to the switch from cytotoxic antitumor immunity to a tumor-promoting pro-inflammatory state characterized by an abundance of various immunosuppressive cells, such as tumor-associated macrophages or myeloid-derived suppressor cells (Busek et al., 2018). However, since most of the studies aimed to investigate mechanistically whether the immune suppressor action of FAP on stromal cells relies on the use of the inhibitors such as PT100 (talabostat), which target both FAP and DPPIV, the observed effects may not be specific to FAP (Chen et al., 2017; Wen et al., 2017; Wu et al., 2017).
FAP has been reported as a tumor suppressor in some tumor types. In vitro analyses revealed that FAP expression in normal fibroblasts, normal melanocytes, and osteosarcoma cells, was downregulated once these cells were transformed into malignant cells and acquired tumorigenic potential (Rettig et al., 1993). Fap expression in mouse melanoma cell lines was shown to abrogate their tumorigenicity, restore contact inhibition, induce cell cycle arrest, and enhanced their susceptibility to stress-induced apoptosis (Ramirez-Montagut et al., 2004). Of note, the observed anti-tumor effects were even more pronounced when an enzymatically inactive form of Fap was used (Ramirez-Montagut et al., 2004). Immunohistochemical analysis of human skin lesions showed that FAP was expressed in only a fraction of melanocytic nevi and expression was scarce in both primary and metastatic melanoma lesions (Huber et al., 2003). In another study, Tsujimoto et al. analyzed differentially expressed genes in the fusion cells of tumorigenic HeLa cells and normal human skin fibroblasts. The authors reported that FAP was one of the proteins downregulated in the tumorigenic hybrids (Tsujimoto et al., 1999).
Homology The FAP gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, fruit fly, mosquito, M.oryzae, and frog. Conserved domains are shown in Figure 4.
  Figure 4: FAP proteins and their conserved domain architectures (NCBI).


Note The distribution of different types of mutations for FAP can be found in and a table for the FAP gene mutations can be found in
Epigenetics Colorectal cancers can be distinguished into two distinct subtypes: tumors with either microsatellite stability (MSS) or microsatellite instability (MSI). MSI tumors are generally less aggressive than MSS cancers and the lymph node metastases or distant spread are less often in MSI tumors. Therefore, patients with MSI tumors have a better prognosis than stage-matched MSS patients. MSI is highly associated with the CpG island methylator phenotype (CIMP), in which gene promoter regions are frequently hypermethylated with resultant gene silencing. FAP expression was shown to be more common in MSI specimens and patients with high CpG CIMP status. On the other hand, the inclusion of MSI screening status and CIMP status in a multivariate analysis strengthened the risk estimates for high FAP expression in the tumor center (HR = 1.89; 95 % CI 1.13-3.14; p = 0.014) and emphasized the role of FAP as an independent prognostic factor (Wikberg et al., 2013). Hypo and hypermethylation status of FAP in different cancer tissue samples can be found in the complete methylation data for the gene can be found in

Implicated in

Note The relatively selective expression of FAP in tumors and/or tumor-associated stromal cells and its presumed direct role in various aspects of cancer progression including the re-modeling of the tumor microenvironment make FAP attractive as a therapeutic target.
As mentioned above, FAP has both collagenase and dipeptidase activities which can degrade gelatin, collagen, and other substrates of dipeptidase, and can promote tumor growth, migration, invasion, metastasis, and ECM degradation. Therefore, it was hypothesized that selective blocking of the enzymatic activity of FAP can be a strategy to prevent tumor development. Val-boroPro, also known as Talabostat (PT100), is a broad S9 protease inhibitor and currently is the only non-specific FAP inhibitor that has been tested in cancer patients in clinical trials (Bainbridge et al., 2017) It was well tolerated in a phase I study in solid tumor patients who were receiving myelosuppressive chemotherapy and it accelerated neutrophil recovery. However, despite the promising results in phase I tests, PT100 failed in phase II clinical trials performed in patients with metastatic colon cancer, non-small cell lung cancer, and melanoma (Busek et al., 2018; Jiang et al., 2016). There is still no consistent conclusion to explain why the drug was not successful during the phase II trial, but reports suggest that the enzymatic activity of FAP has little to do with increased tumor growth. Another explanation for this failure is that serine proteases can function as tumor suppressors (Jiang et al., 2016). However, after this disappointing clinical outcome of PT100, studies concentrated on the investigation of FAP inhibitor antibodies. An inhibitory scFv antibody, named E3 was identified, which could modify the FAP-mediated rearrangement of the fibronectin fibers in vitro, but its effect on cancer growth still needs to be determined (Zhang et al., 2013). In another study, rabbits were immunized with recombinant murine FAP to develop polyclonal anti-FAP antibodies. The antibodies significantly inhibited murine FAP dipeptidyl peptidase activity in vitro and slowed tumor growth in a mouse xenotransplantation model (Cheng et al., 2002).
131-labeled monoclonal antibody (131I-mAbF19) was the first monoclonal antibody against FAP that was used in patients with hepatic metastases from colorectal carcinoma. The 131I-mAbF19 was administered by intravenous injection and no toxicity was observed (Jiang et al., 2016). Sibrotuzumab, a humanized version of the F19 antibody, was tested in phase I clinical trial in metastatic cancer patients. It was found to be non-toxic, did not accumulate in healthy tissues, and was successful in targeting the tumor stroma. However, no therapeutic response was observed in either phase I or the subsequent phase II trial in metastatic colorectal cancer; moreover, some of the patients developed anti-human antibodies (Busek et al., 2018). Despite these disappointing results, the search for more efficient FAP antibodies continues. Novel human-mouse cross-reactive antibodies, ESC11, and ESC14 labeled with the radionuclide (177) Lu were designed and tested for their capacity to accumulate in tumors. In a melanoma xenograft model, (177)Lu-labeled ESC11 was found to be specific to tumor tissue, suggesting these antibodies can be potent radioimmunoconjugates or antibody-drug conjugates for diagnostic and therapeutic use in patients with FAP-expressing tumors (Fischer et al., 2012).
To selectively activate apoptotic pathways in tumor cells, a bispecific antibody (RG7386) binding to both FAP and TNFRSF10B (DR5, Death Receptor 5) was designed. The binding of this antibody to FAP on stromal cells caused a hyperclustering of DR5 which resulted in the induction of apoptosis in tumor cells in in vitro co-culture systems and reduced tumor growth in vivo. When combined with irinotecan, a chemotherapeutic drug to inhibit topoisomerase I, an enzyme involved in DNA replication, this bispecific antibody led to complete tumor eradication in a colorectal cancer mouse model (Brünker et al., 2016). As another approach, a dimeric anti-FAP-TNF protein was designed to activate TNF receptor signaling only when bound to FAP. The protein delayed tumor growth and enhanced macrophage recruitment to the tumor in immunodeficient mice xenografted with FAP-transfected fibrosarcoma HT1080 cells (Bauer et al., 2006, 2004). Other studies have aimed for specific stimulation of local antitumor immune response using FAP targeting antibodies. For instance, in a 3D heterotypic spheroid model containing colon cancer cells, fibroblasts, and peripheral blood mononuclear cells, a bispecific antibody targeting FAP and CD3E (CD3 Cluster of Differentiation 3 epsilon) resulted in a decrease in FAP expressing fibroblasts and this inhibitory effect was more pronounced when variant IL2 (IL-2v) was applied simultaneously (Herter et al., 2017). Hornig et al. reported the construction of a bispecific FAP-CD3 antibody by using the FAP targeting antibodies MO33, MO36, and a costimulatory ligand B7.2. The B7.2 containing antibody was next combined with another costimulatory ligand 4-1BBL fused to an anti-endoglin antibody to induce T cell activation and the release of IL-2 and IFNγ in the presence of target cells expressing both FAP and ENG (endoglin). By the costimulation of CD28 and 4-1BB, the overall T-cell population was strongly increased in activation-experienced memory phenotype accompanied by a decrease in naive phenotype (Hornig et al., 2012). In another study, an antibody cytokine fusion protein (scFv_RD_IL-15), composed of an antibody moiety targeting FAP, an extended IL-15Rα sushi domain (RD) and IL15 was generated to improve the efficiency of IL15. The fusion protein exhibited antibody-mediated specific binding and cytokine activity in both soluble and targeted form and improved the antitumor effect of IL15 in a mouse B16F10/lung metastasis model (Kermer et al., 2012).
Anti-FAP antibody fragments were also immobilized on liposomes to create nanocarriers for therapeutically active agents to specifically target tumor tissue. Immunoliposomes presenting single-chain Fv molecules targeting FAP were able to bind to FAP-expressing cells and were internalized. When loaded with the fluorescent dye DY-676-COOH, these immunoliposomes could be used for the visualization of FAP+ cells in vitro and in a mouse xenograft model (Rüger et al., 2014). The immunoliposomes were also used to detect the metastatic spread of tumors. Bispecific immunliposomes recognizing FAP and endoglin exhibited a higher binding to target stromal cells compared to monospecific liposomes that targeted FAP or endoglin separately. More importantly, these bispecific immunoliposomes showed robust interaction with target cells and upon loading with doxorubicin, showed enhanced cytotoxicity (Rabenhold et al., 2015). Tansi et al. designed bispecific liposomes containing single-chain antibody fragments specific for FAP and ERBB2 (HER2, Human Epidermal Growth Factor Receptor 2) to target both stromal and transformed cells. In a mouse breast cancer model, these bispecific immunoliposomes accumulated in fibroblasts, perivascular cells, as well as in HER2+ tumor elements and were successful in delivering the encapsulated therapeutic cargo to tumor cells and tumor stromal fibroblasts (Tansi et al., 2017). In summary, although the available studies are promising, preclinical and clinical experiments are needed to investigate the efficiency of diagnostic and therapeutic effects of the FAP antibody conjugates in patients with FAP-expressing tumors.
FAP is also a candidate target for DNA vaccines for cancer treatment. An oral DNA vaccine was constructed to target FAP, which could successfully suppress primary tumor cell growth and metastasis of multidrug-resistant murine colon and breast carcinoma. Furthermore, tumor tissue of Fap-vaccinated mice revealed markedly decreased collagen type I expression and up to 70% greater uptake of chemotherapeutic drugs. More importantly, Fap-vaccinated mice treated with chemotherapy showed prolonged lifespan and marked suppression of tumor growth, with half of the animals completely overcoming a tumor cell challenge (Loeffler et al., 2006). Similarly, in in vivo models of melanoma, carcinoma, and lymphoma, tumor growth was inhibited by immunization against FAP using dendritic cells transfected with FAP mRNA. The magnitude of the antitumor response was comparable to that of vaccination against tumor cell-expressed antigens (Lee et al., 2005). To enhance the immunogenicity of the mRNA-translated FAP product, a lysosomal targeting signal derived from LAMP1 (Lysosome-Associated Membrane Protein-1) was fused to the COOH terminus of FAP to redirect the translated product into the MHC class II presentation pathway. Dendritic cells transfected with mRNA encoding the FAP-LAMP fusion product was shown to stimulate CD4+ and CD8+ T-cell responses (Fassnacht et al., 2005).
Cancer immunotherapy by chimeric antigen receptor-modified T (CAR-T) cells has shown robust clinical efficacy for hematological malignancies. Nonetheless, challenges remain for the use of CAR-T cell therapy to treat solid tumors (Yu et al., 2017). In 2013, Kakarla et al. constructed a FAP-CAR, based on an anti-FAP antibody MO36. The resulting FAP-specific T cells recognized and killed FAP+ cancer target cells as determined by proinflammatory cytokine release and target cell lysis. In an A549 lung cancer model, the adoptive transfer of FAP-specific T cells significantly reduced FAP+ stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EPHA2 (EPH Receptor A2) antigen on the A549 cancer cells significantly enhanced overall antitumor activity and conferred a survival advantage (Kakarla et al., 2013). In another study, CD8+ human T cells were retrovirally transduced with a CAR based on the anti-FAP F19 antibody. When contacted with FAP+ mesothelioma cells, these CAR-T cells released IFNγ and specifically lysed the target cells in vitro. In an in vivo mesothelioma model, these CAR-T cells delayed tumor growth and significantly prolonged the survival of mice (Schuberth et al., 2013). Wang et al. developed a retroviral CAR construct specific for mouse Fap, comprising of a single-chain Fv FAP with the CD8A (CD8α) hinge and transmembrane regions, and the human CD247 (CD3ζ) and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFNγ and killed FAP-expressing 3T3 target cells specifically. In in vivo studies, these CAR-T cells reduced the number of FAP+ stromal fibroblasts and leukocytes, thus slowing tumor growth in several syngeneic mouse models. To a large extent, the observed effects were dependent on the augmentation of endogenous CD8+ T cell antitumor responses (L. C. S. Wang et al., 2014). On the other hand, Tran et al. showed that FAP-targeting CAR-T cells may lead to severe side effects. Two CAR constructs were generated using the scFv from FAP-specific monoclonal antibodies FAP5 and sibrotuzumab (F19; humanized monoclonal antibody directed against FAP). The resulting CAR-T cells were capable of specific degranulation and could produce effector cytokines in the presence of FAP-expressing cell lines. Nonetheless, their effect on tumor growth in a broad panel of mouse models was limited. More importantly, the injection of FAP5-CAR-T cells led to morbidity and mortality in most of the mice. Severe bone marrow hypocellularity and cachexia caused by the targeting of FAP+ osteogenic cells, including BMSC and possibly mesenchymal stromal cells in other organs were observed in FAP5-CAR-T cell treated animals. Similar toxic effects were observed in a pancreatic adenocarcinoma model rich in FAP expressing stroma (Busek et al., 2018; Tran et al., 2013). Tran et al. reported that some tumor stromal cells may simply be multipotent MSCs recruited into the tumor microenvironment. Thus, the promising strategy of targeting these normal tumor components must be approached with great care to avoid potentially life-threatening collateral damage to essential regenerative cells (Tran et al., 2013). Therefore, the use of FAP as a universal target antigen in cell-based immunotherapy should be further investigated particularly in light of the life-threatening side-effects.
The design of the FAP-activated prodrugs is another approach for tumor therapy. A non-toxic prodrug can be selectively activated to a highly potent form by the enzymatic activity of FAP (Busek et al., 2018; Puré and Blomberg, 2018). As cytotoxic drugs, melittin, doxorubicin, and thapsigargin were used as activable prodrugs coupled to FAP substrates (Akinboye et al., 2016; Brennen et al., 2012a, 2012b; S. Huang et al., 2011; Ke et al., 2017; LeBeau et al., 2009). Additionally, by linking multiple drugs with a FAP-cleavable linker enhanced efficacy could be achieved (Ke et al., 2017). Such a concept of FAP-mediated activation can also be applied to imaging techniques for cancer detection by using reporter constructs (Bainbridge et al., 2017; Feng et al., 2017). However, no clinical success has been reported with FAP based prodrug formulations.
Entity Breast cancer
Note FAP was identified in the reactive stroma of breast cancer and epithelial tumor cells in ductal carcinomas (Kelly et al., 2012). However, data on the possible association of FAP expression with breast cancer survival are conflicting (Ariga et al., 2001; Jia et al., 2014; Jung et al., 2015).
Entity Oral squamous cell carcinoma
Note FAP is a negative prognostic marker in oral squamous cell carcinoma (H. Wang et al., 2014).
Entity Basal cell carcinoma, squamous cell carcinoma of the skin
Note Enhanced expression of FAP was detected in fibroblasts located close to cancer cells. Although FAP expression was absent in benign epithelial tumors, its positivity in the stroma was reported to be a useful criterion for differentiating between morpheaform/infiltrative basal cell carcinomas and FAP-negative desmoplastic trichoepithelioma (Busek et al., 2018).
Entity Gastric cancer
Note FAP+ cells were shown to be accumulated in gastric cancer tissues (Song et al., 2017). Enhanced stromal FAP was associated with worse survival (Wen et al., 2017) as well as low tumor cell differentiation, more advanced TNM stage, serosal invasion, and poor survival (Shan et al., 2012). In intestinal-type gastric cancer, enhanced stromal FAP expression was associated with the presence of liver and lymph node metastases (Okada et al., 2003).
Entity Melanoma
Note FAP expression was detected in in 30% of benign melanocytic nevi (a subset of melanocytes), but the expression was not detectable in malignant melanoma cells in melanoma tissues (Huber et al., 2006, 2003). A positive correlation was detected between ECM composition and inflammatory cell infiltration and the number of FAP+ stromal cells (Samaniego et al., 2013). On the other hand, there are also studies in which several human melanoma cell lines were shown to express FAP, which in turn, contributed to their invasiveness in vitro (Aoyama and Chen, 1990; Monsky et al., 1994; Tulley and Chen, 2014).
Entity Esophageal cancer
Note FAP is expressed in cancer cells as well as in premalignant metaplastic cells of the esophagus in both adenocarcinoma and squamous cell carcinoma (Busek et al., 2018).
Entity Colorectal cancer
Note Wikberg et al. reported that stromal FAP expression is common in colorectal cancer, and FAP expression was high in the tumor center, but not the tumor front. A high FAP expression in the tumor center was suggested as a negative prognostic factor (Wikberg et al., 2013). In patients with stage IV tumors, high FAP was associated with worse survival (Henry et al., 2007).
Entity Pancreatic adenocarcinoma
Note FAP+ cells were reported to enhance pancreatic ductal adenocarcinoma progression (Lo et al., 2017). Its expression in carcinoma cells was associated with larger tumor size, presence of a fibrotic focus, perineural invasion, and a worse prognosis (Shi et al., 2012). Although stromal FAP expression was shown to be correlated with reduced survival and lymph node metastasis (Cohen et al., 2008; Kawase et al., 2015; Lo et al., 2017; Patsouras et al., 2015; Shi et al., 2012), Park et al. claimed an association between a lower number of FAP+ fibroblasts and a decreased overall survival (Park et al., 2017).
Entity Hepatocellular carcinoma
Note In hepatocellular carcinoma, the over-expression of FAP has been reported in CAFs rather than hepatocellular carcinoma cells. Zou et al. showed that FAP can be induced in hepatocellular cancer cells under hypoxia and its expression was correlated with poor clinical outcomes (Zou et al., 2018). FAP expression was detected especially in tumors with abundant fibrous stroma (Kim et al., 2014).
Entity Non-small cell lung cancer
Note FAP was found to be highly expressed in cancer stroma and it was also a predictor of poor survival of non-small cell lung cancer patients (Liao et al., 2013)
Entity Mesothelioma
Note FAP expression has been detected in all subtypes (Schuberth et al., 2013).
Entity Multiple myeloma
Note FAP expression was not detected in multiple myeloma cells, but its expression was found in osteoclasts, endothelial cells, adipocytes, and fibrotic stroma (Ge et al., 2006).
Entity Renal cancer
Note Stromal FAP expression was shown to be associated with worse survival in clear cell renal cell carcinoma and FAP was defined as a marker of aggressiveness and metastasis (Errarte et al., 2016; López et al., 2016).
Entity Prostate cancer
Note The expression of FAP in stromal cells was reported (Tuxhorn et al., 2002).
Entity Cervical cancer
Note Enhanced expression of FAP was found in cervical cancer cells and subepithelial stromal cells in some of the micro-invasive and all of the invasive carcinomas (Jin et al., 2003).
Entity Ovarian carcinoma
Note FAP+ cells were detected in cancer cells in 21% of tumors and stromal positivity was detected in 61% of tumors (Mhawech-Fauceglia et al., 2015). FAP expressing malignant cells were present in malignant pleural and peritoneal effusions and associated with worse survival (Zhang et al., 2007). FAP+ cells were also found to be positively correlated with tumor stage and negative FAP expression was reported to be associated with longer disease-free survival (Zhang et al., 2015).
Entity Thyroid cancer
Note In aggressive papillary thyroid carcinomas, FAP was found to be one of the upregulated genes (Fluge et al., 2006). FAP expression in the peritumoral and intratumoral stromal compartment in medullary thyroid carcinoma was shown to be correlated with the degree of desmoplasia and presence of lymph node metastases (Koperek et al., 2007).
Entity Glioma
Note Enhanced FAP expression was detected in glioblastoma; however, the overall FAP quantity was not found to be associated with patient survival (Busek et al., 2016).
Entity Sarcomas
Note FAP expression was detected in malignant cells in fibrosarcomas, leiomyosarcoma, malignant fibrous histiocytoma (Rettig et al., 1988), low-grade myofibroblastic sarcoma, fibroblastic areas in osteosarcomas, osteoid osteoma (Dohi et al., 2009), and in osteosarcoma (Ding et al., 2014). In osteosarcoma, enhanced FAP expression was associated with a more advanced clinical stage, presence of metastasis, high histological grade, and a worse progression-free and overall survival (Yuan et al., 2013).

To be noted

Clinical development of FAP inhibitors is challenging since this therapeutic agent should have a strict FAP selectivity over highly related dipeptidyl peptidases such as DPPIV as well as more distally related endopeptidases. In addition, a selective assay format is also needed to determine both membrane-bound and circulating levels and activity of FAP, especially for clinical drug development studies, clinical trials, and personalized medicine applications.


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Koczorowska MM, Tholen S, Bucher F, Lutz L, Kizhakkedathu JN, De Wever O, Wellner UF, Biniossek ML, Stahl A, Lassmann S, Schilling O
Mol Oncol 2016 Jan;10(1):40-58.
PMID 26304112
Molecular characterization of the desmoplastic tumor stroma in medullary thyroid carcinoma
Koperek O, Scheuba C, Puri C, Birner P, Haslinger C, Rettig W, Niederle B, Kaserer K, Garin Chesa P
Int J Oncol 2007 Jul;31(1):59-67.
PMID 17549405
Fibroblast activation protein predicts prognosis in clear cell renal cell carcinoma
López JI, Errarte P, Erramuzpe A, Guarch R, Cortés JM, Angulo JC, Pulido R, Irazusta J, Llarena R, Larrinaga G
Hum Pathol 2016 Aug;54:100-5.
PMID 27063470
Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin
LeBeau AM, Brennen WN, Aggarwal S, Denmeade SR
Mol Cancer Ther 2009 May;8(5):1378-86.
PMID 19417147
FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells
Lee HO, Mullins SR, Franco-Barraza J, Valianou M, Cukierman E, Cheng JD
BMC Cancer 2011 Jun 13;11:245.
PMID 21668992
Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts
Lee J, Fassnacht M, Nair S, Boczkowski D, Gilboa E
Cancer Res 2005 Dec 1;65(23):11156-63.
PMID 16322266
Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein
Lee KN, Jackson KW, Christiansen VJ, Lee CS, Chun JG, McKee PA
Blood 2006 Feb 15;107(4):1397-404.
PMID 16223769
Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model
Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA
PLoS One 2009 Nov 23;4(11):e7965.
PMID 19956757
Clinical implications of fibroblast activation protein-α in non-small cell lung cancer after curative resection: a new predictor for prognosis
Liao Y, Ni Y, He R, Liu W, Du J
J Cancer Res Clin Oncol 2013 Sep;139(9):1523-8.
PMID 23835897
Targeting of activated fibroblasts for imaging and therapy
Lindner T, Loktev A, Giesel F, Kratochwil C, Altmann A, Haberkorn U
EJNMMI Radiopharm Chem 2019 Jul 25;4(1):16.
PMID 31659499
Fibroblast activation protein: A potential therapeutic target in cancer
Liu R, Li H, Liu L, Yu J, Ren X
Cancer Biol Ther 2012 Feb 1;13(3):123-9.
PMID 22236832
Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment
Liu T, Zhou L, Li D, Andl T, Zhang Y
Front Cell Dev Biol 2019 Apr 24;7:60.
PMID 31106200
Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma
Lo A, Li CP, Buza EL, Blomberg R, Govindaraju P, Avery D, Monslow J, Hsiao M, Puré E
JCI Insight 2017 Oct 5;2(19):e92232.
PMID 28978805
Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells
Lo A, Wang LS, Scholler J, Monslow J, Avery D, Newick K, O', Brien S, Evans RA, Bajor DJ, Clendenin C, Durham AC, Buza EL, Vonderheide RH, June CH, Albelda SM, Puré E
Cancer Res 2015 Jul 15;75(14):2800-2810.
PMID 25979873
Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
Loeffler M, Krüger JA, Niethammer AG, Reisfeld RA
J Clin Invest 2006 Jul;116(7):1955-62.
PMID 16794736
Promotion of Cellular Growth and Motility Is Independent of Enzymatic Activity of Fibroblast Activation Protein-α
Lv B, Xie F, Zhao P, Ma X, Jiang WG, Yu J, Zhang X, Jia J
Cancer Genomics Proteomics May-Jun 2016;13(3):201-8.
PMID 27107062
Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer
Mhawech-Fauceglia P, Yan L, Sharifian M, Ren X, Liu S, Kim G, Gayther SA, Pejovic T, Lawrenson K
Cancer Microenviron 2015 Apr;8(1):23-31.
PMID 25331442
Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis
Milner JM, Kevorkian L, Young DA, Jones D, Wait R, Donell ST, Barksby E, Patterson AM, Middleton J, Cravatt BF, Clark IM, Rowan AD, Cawston TE
Arthritis Res Ther 2006;8(1):R23.
PMID 16507127
A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells
Monsky WL, Lin CY, Aoyama A, Kelly T, Akiyama SK, Mueller SC, Chen WT
Cancer Res 1994 Nov 1;54(21):5702-10.
PMID 7923219
Targeted disruption of mouse fibroblast activation protein
Niedermeyer J, Kriz M, Hilberg F, Garin-Chesa P, Bamberger U, Lenter MC, Park J, Viertel B, Püschner H, Mauz M, Rettig WJ, Schnapp A
Mol Cell Biol 2000 Feb;20(3):1089-94.
PMID 10629066
Seprase, a membrane-type serine protease, has different expression patterns in intestinal- and diffuse-type gastric cancer
Okada K, Chen WT, Iwasa S, Jin X, Yamane T, Ooi A, Mitsumata M
Oncology 2003;65(4):363-70.
PMID 14707457
A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation
Osborne B, Yao TW, Wang XM, Chen Y, Kotan LD, Nadvi NA, Herdem M, McCaughan GW, Allen JD, Yu DM, Topaloglu AK, Gorrell MD
Biochim Biophys Acta 2014 Jul;1844(7):1248-59.
PMID 24717288
The prognostic significance of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma
Park H, Lee Y, Lee H, Kim JW, Hwang JH, Kim J, Yoon YS, Han HS, Kim H
Tumour Biol 2017 Oct;39(10):1010428317718403.
PMID 29025374
Fibroblast activation protein and its prognostic significance in correlation with vascular endothelial growth factor in pancreatic adenocarcinoma
Patsouras D, Papaxoinis K, Kostakis A, Safioleas MC, Lazaris AC, Nicolopoulou-Stamati P
Mol Med Rep 2015 Jun;11(6):4585-90.
PMID 25625587
Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics
Puré E, Blomberg R
Oncogene 2018 Aug;37(32):4343-4357.
PMID 29720723
In vivo near-infrared fluorescence imaging of FAP-expressing tumors with activatable FAP-targeted, single-chain Fv-immunoliposomes
Rüger R, Tansi FL, Rabenhold M, Steiniger F, Kontermann RE, Fahr A, Hilger I
J Control Release 2014 Jul 28;186:1-10.
PMID 24810115
Bispecific single-chain diabody-immunoliposomes targeting endoglin (CD105) and fibroblast activation protein (FAP) simultaneously
Rabenhold M, Steiniger F, Fahr A, Kontermann RE, Rüger R
J Control Release 2015 Mar 10;201:56-67.
PMID 25617725
FAPalpha, a surface peptidase expressed during wound healing, is a tumor suppressor
Ramirez-Montagut T, Blachere NE, Sviderskaya EV, Bennett DC, Rettig WJ, Garin-Chesa P, Houghton AN
Oncogene 2004 Jul 15;23(32):5435-46.
PMID 15133496
Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin
Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, Albino AP, Old LJ
Cancer Res 1993 Jul 15;53(14):3327-35.
PMID 8391923
Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia
Roberts EW, Deonarine A, Jones JO, Denton AE, Feig C, Lyons SK, Espeli M, Kraman M, McKenna B, Wells RJ, Zhao Q, Caballero OL, Larder R, Coll AP, O', Rahilly S, Brindle KM, Teichmann SA, Tuveson DA, Fearon DT
J Exp Med 2013 Jun 3;210(6):1137-51.
PMID 23712428
Low expression of miR-30a-5p induced the proliferation and invasion of oral cancer via promoting the expression of FAP
Ruan P, Tao Z, Tan A
Biosci Rep 2018 Jan 25;38(1):BSR20171027.
PMID 29026005
Fibroblast activation protein (FAP) as a novel metabolic target
Sánchez-Garrido MA, Habegger KM, Clemmensen C, Holleman C, Müller TD, Perez-Tilve D, Li P, Agrawal AS, Finan B, Drucker DJ, Tschöp MH, DiMarchi RD, Kharitonenkov A
Mol Metab 2016 Jul 16;5(10):1015-1024.
PMID 27689014
Mesenchymal contribution to recruitment, infiltration, and positioning of leukocytes in human melanoma tissues
Samaniego R, Estecha A, Relloso M, Longo N, Escat JL, Longo-Imedio I, Avilés JA, del Pozo MA, Puig-Kröger A, Sánchez-Mateos P
J Invest Dermatol 2013 Sep;133(9):2255-64.
PMID 23446986
Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice
Santos AM, Jung J, Aziz N, Kissil JL, Puré E
J Clin Invest 2009 Dec;119(12):3613-25.
PMID 19920354
Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells
Schuberth PC, Hagedorn C, Jensen SM, Gulati P, van den Broek M, Mischo A, Soltermann A, Jüngel A, Marroquin Belaunzaran O, Stahel R, Renner C, Petrausch U
J Transl Med 2013 Aug 12;11:187.
PMID 23937772
Roles of fibroblasts from the interface zone in invasion, migration, proliferation and apoptosis of gastric adenocarcinoma
Shan LH, Sun WG, Han W, Qi L, Yang C, Chai CC, Yao K, Zhou QF, Wu HM, Wang LF, Liu JR
J Clin Pathol 2012 Oct;65(10):888-95.
PMID 22844068
Expression of fibroblast activation protein in human pancreatic adenocarcinoma and its clinicopathological significance
Shi M, Yu DH, Chen Y, Zhao CY, Zhang J, Liu QH, Ni CR, Zhu MH
World J Gastroenterol 2012 Feb 28;18(8):840-6.
PMID 22371645
Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer
Son GM, Kwon MS, Shin DH, Shin N, Ryu D, Kang CD
Medicine (Baltimore) 2019 May;98(18):e15164.
PMID 31045759
Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression
Sorrentino C, Miele L, Porta A, Pinto A, Morello S
Oncotarget 2016 Sep 27;7(39):64274-64288.
PMID 27590504
Fibroblast activation protein is dispensable in the anti-influenza immune response in mice
Tan SY, Chowdhury S, Polak N, Gorrell MD, Weninger W
PLoS One 2017 Feb 3;12(2):e0171194.
PMID 28158223
Activatable bispecific liposomes bearing fibroblast activation protein directed single chain fragment/Trastuzumab deliver encapsulated cargo into the nuclei of tumor cells and the tumor microenvironment simultaneously
Tansi FL, Rüger R, Böhm C, Steiniger F, Kontermann RE, Teichgraeber UK, Fahr A, Hilger I
Acta Biomater 2017 May;54:281-293.
PMID 28347861
Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia
Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee CC, Restifo NP, Rosenberg SA
J Exp Med 2013 Jun 3;210(6):1125-35.
PMID 23712432
Differential gene expression in tumorigenic and nontumorigenic HeLa x normal human fibroblast hybrid cells
Tsujimoto H, Nishizuka S, Redpath JL, Stanbridge EJ
Mol Carcinog 1999 Dec;26(4):298-304.
PMID 10569806
Transcriptional regulation of seprase in invasive melanoma cells by transforming growth factor-β signaling
Tulley S, Chen WT
J Biol Chem 2014 May 30;289(22):15280-96.
PMID 24727589
15-Lipoxygenase-1 re-expression in colorectal cancer alters endothelial cell features through enhanced expression of TSP-1 and ICAM-1
Tunçer S, Kesk AG, olakolu M, imen I, Yener C, Konu Ö, Banerjee S
Cell Signal 2017 Nov;39:44-54.
PMID 28757355
Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling
Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR
Clin Cancer Res 2002 Sep;8(9):2912-23.
PMID 12231536
Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis
Wäldele S, Koers-Wunrau C, Beckmann D, Korb-Pap A, Wehmeyer C, Pap T, Dankbar B
Arthritis Res Ther 2015 Jan 20;17(1):12.
PMID 25600705
UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins-TGF-β1-FAP-α
Wäster P, Orfanidis K, Eriksson I, Rosdahl I, Seifert O, Öllinger K
Br J Cancer 2017 Aug 8;117(4):535-544.
PMID 28697174
Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma
Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y, Zhang Y, Hua S, Fu Q, Zhao M, Chen Y, Fang W, Lv X
Cell Death Dis 2014 Apr 10;5(4):e1155.
PMID 24722280
Tumor necrosis factor receptor 2/AKT and ERK signaling pathways contribute to the switch from fibroblasts to CAFs by progranulin in microenvironment of colorectal cancer
Wang L, Yang D, Tian J, Gao A, Shen Y, Ren X, Li X, Jiang G, Dong T
Oncotarget 2017 Apr 18;8(16):26323-26333.
PMID 28412748
Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity
Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, Solomides CC, June CH, Puré E, Albelda SM
Cancer Immunol Res 2014 Feb;2(2):154-66.
PMID 24778279
Fibroblast Activation Protein-α-Positive Fibroblasts Promote Gastric Cancer Progression and Resistance to Immune Checkpoint Blockade
Wen X, He X, Jiao F, Wang C, Sun Y, Ren X, Li Q
Oncol Res 2017 Apr 14;25(4):629-640.
PMID 27983931
High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis
Wikberg ML, Edin S, Lundberg IV, Van Guelpen B, Dahlin AM, Rutegård J, Stenling R, Oberg A, Palmqvist R
Tumour Biol 2013 Apr;34(2):1013-20.
PMID 23328994
Fibroblast Activation Protein (FAP) Overexpression Induces Epithelial-Mesenchymal Transition (EMT) in Oral Squamous Cell Carcinoma by Down-Regulating Dipeptidyl Peptidase 9 (DPP9)
Wu QQ, Zhao M, Huang GZ, Zheng ZN, Chen Y, Zeng WS, Lv XZ
Onco Targets Ther 2020 Mar 27;13:2599-2611.
PMID 32273729
MM-BMSCs induce naïve CD4+ T lymphocytes dysfunction through fibroblast activation protein α
Wu X, Wang Y, Xu J, Luo T, Deng J, Hu Y
Oncotarget 2017 Apr 30;8(32):52614-52628.
PMID 28881756
The dipeptidyl peptidase IV family in cancer and cell biology
Yu DM, Yao TW, Chowdhury S, Nadvi NA, Osborne B, Church WB, McCaughan GW, Gorrell MD
FEBS J 2010 Mar;277(5):1126-44.
PMID 20074209
Chimeric antigen receptor T cells: a novel therapy for solid tumors
Yu S, Li A, Liu Q, Li T, Yuan X, Han X, Wu K
J Hematol Oncol 2017 Mar 29;10(1):78.
PMID 28356156
Overexpression of fibroblast activation protein and its clinical implications in patients with osteosarcoma
Yuan D, Liu B, Liu K, Zhu G, Dai Z, Xie Y
J Surg Oncol 2013 Sep;108(3):157-62.
PMID 23813624
Identification of Novel Natural Substrates of Fibroblast Activation Protein-alpha by Differential Degradomics and Proteomics
Zhang HE, Hamson EJ, Koczorowska MM, Tholen S, Chowdhury S, Bailey CG, Lay AJ, Twigg SM, Lee Q, Roediger B, Biniossek ML, O', Rourke MB, McCaughan GW, Keane FM, Schilling O, Gorrell MD
Mol Cell Proteomics 2019 Jan;18(1):65-85.
PMID 30257879
Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens
Zhang J, Valianou M, Simmons H, Robinson MK, Lee HO, Mullins SR, Marasco WA, Adams GP, Weiner LM, Cheng JD
FASEB J 2013 Feb;27(2):581-9.
PMID 23104982
Expression levels of seprase/FAPα and DPPIV/CD26 in epithelial ovarian carcinoma
Zhang M, Xu L, Wang X, Sun B, Ding J
Oncol Lett 2015 Jul;10(1):34-42.
PMID 26170973
Expression of seprase in effusions from patients with epithelial ovarian carcinoma
Zhang MZ, Qiao YH, Nesland JM, Trope C, Kennedy A, Chen WT, Suo ZH
Chin Med J (Engl) 2007 Apr 20;120(8):663-8.
PMID 17517181
Fibroblast activation protein α in tumor microenvironment: recent progression and implications (review)
Zi F, He J, He D, Li Y, Yang L, Cai Z
Mol Med Rep 2015 May;11(5):3203-11.
PMID 25593080
The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes
Zou B, Liu X, Zhang B, Gong Y, Cai C, Li P, Chen J, Xing S, Chen J, Peng S, Pokhrel B, Ding L, Zeng L, Li J
J Cancer 2018 Sep 7;9(18):3278-3286.
PMID 30271487


This paper should be referenced as such :
Tunçer S, Banerjee S
FAP (fibroblast activation protein alpha);
Atlas Genet Cytogenet Oncol Haematol. in press

External links


HGNC (Hugo)FAP   3590
Entrez_Gene (NCBI)FAP    fibroblast activation protein alpha
AliasesDPPIV; FAPA; FAPalpha; SIMP
GeneCards (Weizmann)FAP
Ensembl hg19 (Hinxton)ENSG00000078098 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000078098 [Gene_View]  ENSG00000078098 [Sequence]  chr2:162170684-162243445 [Contig_View]  FAP [Vega]
ICGC DataPortalENSG00000078098
TCGA cBioPortalFAP
Genatlas (Paris)FAP
SOURCE (Princeton)FAP
Genetics Home Reference (NIH)FAP
Genomic and cartography
GoldenPath hg38 (UCSC)FAP  -     chr2:162170684-162243445 -  2q24.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FAP  -     2q24.2   [Description]    (hg19-Feb_2009)
GoldenPathFAP - 2q24.2 [CytoView hg19]  FAP - 2q24.2 [CytoView hg38]
Genome Data Viewer NCBIFAP [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AK055327 AK297118 AK309260 AK310293 AK315448
RefSeq transcript (Entrez)NM_001291807 NM_004460
Consensus coding sequences : CCDS (NCBI)FAP
Gene ExpressionFAP [ NCBI-GEO ]   FAP [ EBI - ARRAY_EXPRESS ]   FAP [ SEEK ]   FAP [ MEM ]
Gene Expression Viewer (FireBrowse)FAP [ Firebrowse - Broad ]
GenevisibleExpression of FAP in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2191
GTEX Portal (Tissue expression)FAP
Human Protein AtlasENSG00000078098-FAP [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12884   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ12884  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ12884
Domains : Interpro (EBI)AB_hydrolase    FAP-alpha    Pept_S9_AS    Peptidase_S9    Peptidase_S9B_N    Peptidase_S9B_N_sf   
Domain families : Pfam (Sanger)DPPIV_N (PF00930)    Peptidase_S9 (PF00326)   
Domain families : Pfam (NCBI)pfam00930    pfam00326   
Conserved Domain (NCBI)FAP
PDB (RSDB)1Z68   
PDB Europe1Z68   
PDB (PDBSum)1Z68   
PDB (IMB)1Z68   
Structural Biology KnowledgeBase1Z68   
SCOP (Structural Classification of Proteins)1Z68   
CATH (Classification of proteins structures)1Z68   
AlphaFold pdb e-kbQ12884   
Human Protein Atlas [tissue]ENSG00000078098-FAP [tissue]
Protein Interaction databases
IntAct (EBI)Q12884
Ontologies - Pathways
Ontology : AmiGOangiogenesis  protease binding  endopeptidase activity  serine-type endopeptidase activity  integrin binding  protein binding  extracellular space  cytoplasm  plasma membrane  plasma membrane  plasma membrane  focal adhesion  proteolysis  proteolysis  proteolysis  cell adhesion  peptidase activity  serine-type peptidase activity  serine-type peptidase activity  serine-type peptidase activity  dipeptidyl-peptidase activity  dipeptidyl-peptidase activity  dipeptidyl-peptidase activity  cell surface  regulation of collagen catabolic process  negative regulation of extracellular matrix disassembly  integral component of membrane  lamellipodium  lamellipodium membrane  ruffle membrane  identical protein binding  protein homodimerization activity  endothelial cell migration  apical part of cell  basal part of cell  proteolysis involved in cellular protein catabolic process  regulation of cell cycle  regulation of fibrinolysis  negative regulation of cell proliferation involved in contact inhibition  melanocyte proliferation  positive regulation of execution phase of apoptosis  melanocyte apoptotic process  negative regulation of extracellular matrix organization  peptidase complex  
Ontology : EGO-EBIangiogenesis  protease binding  endopeptidase activity  serine-type endopeptidase activity  integrin binding  protein binding  extracellular space  cytoplasm  plasma membrane  plasma membrane  plasma membrane  focal adhesion  proteolysis  proteolysis  proteolysis  cell adhesion  peptidase activity  serine-type peptidase activity  serine-type peptidase activity  serine-type peptidase activity  dipeptidyl-peptidase activity  dipeptidyl-peptidase activity  dipeptidyl-peptidase activity  cell surface  regulation of collagen catabolic process  negative regulation of extracellular matrix disassembly  integral component of membrane  lamellipodium  lamellipodium membrane  ruffle membrane  identical protein binding  protein homodimerization activity  endothelial cell migration  apical part of cell  basal part of cell  proteolysis involved in cellular protein catabolic process  regulation of cell cycle  regulation of fibrinolysis  negative regulation of cell proliferation involved in contact inhibition  melanocyte proliferation  positive regulation of execution phase of apoptosis  melanocyte apoptotic process  negative regulation of extracellular matrix organization  peptidase complex  
NDEx NetworkFAP
Atlas of Cancer Signalling NetworkFAP
Wikipedia pathwaysFAP
Orthology - Evolution
GeneTree (enSembl)ENSG00000078098
Phylogenetic Trees/Animal Genes : TreeFamFAP
Homologs : HomoloGeneFAP
Homology/Alignments : Family Browser (UCSC)FAP
Gene fusions - Rearrangements
Fusion : QuiverFAP
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFAP [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FAP
Exome Variant ServerFAP
GNOMAD BrowserENSG00000078098
Varsome BrowserFAP
ACMGFAP variants
Genomic Variants (DGV)FAP [DGVbeta]
DECIPHERFAP [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFAP 
ICGC Data PortalFAP 
TCGA Data PortalFAP 
Broad Tumor PortalFAP
OASIS PortalFAP [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFAP  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DFAP
Mutations and Diseases : HGMDFAP
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)FAP
DoCM (Curated mutations)FAP
CIViC (Clinical Interpretations of Variants in Cancer)FAP
NCG (London)FAP
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry FAP
NextProtQ12884 [Medical]
Target ValidationFAP
Huge Navigator FAP [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDFAP
Pharm GKB GenePA28003
Clinical trialFAP
DataMed IndexFAP
PubMed148 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:17:47 CEST 2021

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