FAP (fibroblast activation protein alpha)

2020-08-01   Sinem Tunçer , Sreeparna Banerjee 

Identity

HGNC
LOCATION
2q24.2
IMAGE
Atlas Image
LEGEND
Figure 1: Genomic location of human FAP
LOCUSID
ALIAS
DPPIV,FAPA,FAPalpha,SIMP
FUSION GENES

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.

DNA/RNA

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 (%)
SpeciesSymbolProteinDNA
H.sapiensFAP  
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
Atlas Image
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 https://www.ncbi.nlm.nih.gov/nuccore/NC_000002.12?report=genbank&from=162170684&to=162243472&strand=true

Proteins

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 3.4.14.5) 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 Crohns 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).
Atlas Image
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.
Atlas Image
Figure 4: FAP proteins and their conserved domain architectures (NCBI).

Mutations

Note

The distribution of different types of mutations for FAP can be found in https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=FAP#distribution and a table for the FAP gene mutations can be found in https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=FAP#variants

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 https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=FAP#tissueand the complete methylation data for the gene can be found in https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=FAP#variants

Implicated in

Top 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 name
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 name
Oral squamous cell carcinoma
Note
FAP is a negative prognostic marker in oral squamous cell carcinoma (H. Wang et al., 2014).
Entity name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
Mesothelioma
Note
FAP expression has been detected in all subtypes (Schuberth et al., 2013).
Entity name
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 name
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 name
Prostate cancer
Note
The expression of FAP in stromal cells was reported (Tuxhorn et al., 2002).
Entity name
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 name
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 name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
166133312006Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis.Acharya PS et al
158093062005Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha.Aertgeerts K et al
268358732016Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy.Akinboye ES et al
21729801990A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells.Aoyama A et al
112413142001Stromal expression of fibroblast activation protein/seprase, a cell membrane serine proteinase and gelatinase, is associated with longer survival in patients with invasive ductal carcinoma of breast.Ariga N et al
292485562018Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts.Avery D et al
289705662017Selective Homogeneous Assay for Circulating Endopeptidase Fibroblast Activation Protein (FAP).Bainbridge TW et al
168880042006Structure-activity profiles of Ab-derived TNF fusion proteins.Bauer S et al
270374122016RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis.Brünker P et al
229116692012Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug.Brennen WN et al
274924572016Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma.Busek P et al
297725382018Targeting fibroblast activation protein in cancer - Prospects and caveats.Busek P et al
237106352013Short hairpin RNA targeting of fibroblast activation protein inhibits tumor growth and improves the tumor microenvironment in a mouse model.Cai F et al
283024822017FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression.Chen L et al
121834362002Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model.Cheng JD et al
186650762008Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma.Cohen SJ et al
327337922020High Expression of FAP in Colorectal Cancer Is Associated With Angiogenesis and Immunoregulation Processes.Coto-Llerena M et al
245202912014Impact of fibroblast activation protein on osteosarcoma cell lines in vitro.Ding L et al
198178942009Histogenesis-specific expression of fibroblast activation protein and dipeptidylpeptidase-IV in human bone and soft tissue tumours.Dohi O et al
160760892005Characterization of cancer stroma markers: in silico analysis of an mRNA expression database for fibroblast activation protein and endosialin.Dolznig H et al
280334212016The Expression of Fibroblast Activation Protein in Clear Cell Renal Cell Carcinomas Is Associated with Synchronous Lymph Node Metastases.Errarte P et al
266630852016Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice.Fan MH et al
263347772016A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice.Fang J et al
160618742005Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy.Fassnacht M et al
287946282017A synthetic urinary probe-coated nanoparticles sensitive to fibroblast activation protein α for solid tumor diagnosis.Feng X et al
229925152012Radioimmunotherapy of fibroblast activation protein positive tumors by rapidly internalizing antibodies.Fischer E et al
166764022006Gene expression in poorly differentiated papillary thyroid carcinomas.Fluge Ø et al
165128332006Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival.Ge Y et al
249805532014miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors.Gong C et al
145245362003Seprase, a membrane-bound protease, alleviates the serum growth requirement of human breast cancer cells.Goodman JD et al
266177092015Lipopolysaccharide activated TLR4/NF-κB signaling pathway of fibroblasts from uterine fibroids.Guo J et al
249328602014Rapid fibroblast activation in mammalian cells induced by silicon nanowire arrays.Ha Q et al
244702602014Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy.Hamson EJ et al
173635262007Clinical implications of fibroblast activation protein in patients with colon cancer.Henry LR et al
278581012017A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents.Herter S et al
225763472012Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy.Hornig N et al
212845422011Evaluation of the tumor targeting of a FAPα-based doxorubicin prodrug.Huang S et al
216041852011Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions.Huang Y et al
164203102006Expression of stromal cell markers in distinct compartments of human skin cancers.Huber MA et al
271638432016GPR30 Promotes Prostate Stromal Cell Activation via Suppression of ERα Expression and Its Downstream Signaling Pathway.Jia B et al
291155732018Fibroblast activation protein-α promotes the growth and migration of lung cancer cells via the PI3K and sonic hedgehog pathways.Jia J et al
269857692016The application of the fibroblast activation protein α-targeted immunotherapy strategy.Jiang GM et al
129260532003Expression patterns of seprase, a membrane serine protease, in cervical carcinoma and cervical intraepithelial neoplasm.Jin X et al
288292112017Fibroblast activation protein-α in fibrogenic disorders and cancer: more than a prolyl-specific peptidase?Juillerat-Jeanneret L et al
260445622015Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer.Jung YY et al
237329882013Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma.Kakarla S et al
263303492015Fibroblast activation protein-α-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma.Kawase T et al
280633522017A tumor-targeted activatable phthalocyanine-tetrapeptide-doxorubicin conjugate for synergistic chemo-photodynamic therapy.Ke MR et al
213148172011Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α.Keane FM et al
243717212013Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs.Keane FM et al
226085582012Fibroblast activation protein-α: a key modulator of the microenvironment in multiple pathologies.Kelly T et al
97583651998Seprase, a membrane-bound protease, is overexpressed by invasive ductal carcinoma cells of human breast cancers.Kelly T et al
224918232012An antibody fusion protein for cancer immunotherapy mimicking IL-15 trans-presentation at the tumor site.Kermer V et al
251267472014Increased expression of CCN2, epithelial membrane antigen, and fibroblast activation protein in hepatocellular carcinoma with fibrous stroma showing aggressive behavior.Kim GJ et al
263041122016Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.Koczorowska MM et al
175494052007Molecular characterization of the desmoplastic tumor stroma in medullary thyroid carcinoma.Koperek O et al
270634702016Fibroblast activation protein predicts prognosis in clear cell renal cell carcinoma.López JI et al
194171472009Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin.LeBeau AM et al
216689922011FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells.Lee HO et al
163222662005Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts.Lee J et al
162237692006Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein.Lee KN et al
199567572009Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.Liao D et al
238358972013Clinical implications of fibroblast activation protein-α in non-small cell lung cancer after curative resection: a new predictor for prognosis.Liao Y et al
316594992019Targeting of activated fibroblasts for imaging and therapy.Lindner T et al
222368322012Fibroblast activation protein: A potential therapeutic target in cancer.Liu R et al
311062002019Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment.Liu T et al
289788052017Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma.Lo A et al
259798732015Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells.Lo A et al
167947362006Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake.Loeffler M et al
271070622016Promotion of Cellular Growth and Motility Is Independent of Enzymatic Activity of Fibroblast Activation Protein-α.Lv B et al
253314422015Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer.Mhawech-Fauceglia P et al
165071272006Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis.Milner JM et al
79232191994A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells.Monsky WL et al
106290662000Targeted disruption of mouse fibroblast activation protein.Niedermeyer J et al
147074572003Seprase, a membrane-type serine protease, has different expression patterns in intestinal- and diffuse-type gastric cancer.Okada K et al
247172882014A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation.Osborne B et al
290253742017The prognostic significance of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.Park H et al
256255872015Fibroblast activation protein and its prognostic significance in correlation with vascular endothelial growth factor in pancreatic adenocarcinoma.Patsouras D et al
297207232018Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics.Puré E et al
248101152014In vivo near-infrared fluorescence imaging of FAP-expressing tumors with activatable FAP-targeted, single-chain Fv-immunoliposomes.Rüger R et al
256177252015Bispecific single-chain diabody-immunoliposomes targeting endoglin (CD105) and fibroblast activation protein (FAP) simultaneously.Rabenhold M et al
151334962004FAPalpha, a surface peptidase expressed during wound healing, is a tumor suppressor.Ramirez-Montagut T et al
83919231993Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin.Rettig WJ et al
237124282013Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia.Roberts EW et al
290260052018Low expression of miR-30a-5p induced the proliferation and invasion of oral cancer via promoting the expression of FAP.Ruan P et al
276890142016Fibroblast activation protein (FAP) as a novel metabolic target.Sánchez-Garrido MA et al
234469862013Mesenchymal contribution to recruitment, infiltration, and positioning of leukocytes in human melanoma tissues.Samaniego R et al
199203542009Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice.Santos AM et al
239377722013Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells.Schuberth PC et al
228440682012Roles of fibroblasts from the interface zone in invasion, migration, proliferation and apoptosis of gastric adenocarcinoma.Shan LH et al
223716452012Expression of fibroblast activation protein in human pancreatic adenocarcinoma and its clinicopathological significance.Shi M et al
310457592019Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer.Son GM et al
275905042016Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression.Sorrentino C et al
281582232017Fibroblast activation protein is dispensable in the anti-influenza immune response in mice.Tan SY et al
283478612017Activatable 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 et al
237124322013Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia.Tran E et al
105698061999Differential gene expression in tumorigenic and nontumorigenic HeLa x normal human fibroblast hybrid cells.Tsujimoto H et al
247275892014Transcriptional regulation of seprase in invasive melanoma cells by transforming growth factor-β signaling.Tulley S et al
28757355201715-Lipoxygenase-1 re-expression in colorectal cancer alters endothelial cell features through enhanced expression of TSP-1 and ICAM-1.Tunçer S et al
122315362002Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling.Tuxhorn JA et al
256007052015Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis.Wäldele S et al
286971742017UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins-TGF-β1-FAP-α.Wäster P et al
247222802014Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma.Wang H et al
284127482017Tumor 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 et al
247782792014Targeting 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 et al
279839312017Fibroblast Activation Protein-α-Positive Fibroblasts Promote Gastric Cancer Progression and Resistance to Immune Checkpoint Blockade.Wen X et al
233289942013High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.Wikberg ML et al
322737292020Fibroblast Activation Protein (FAP) Overexpression Induces Epithelial-Mesenchymal Transition (EMT) in Oral Squamous Cell Carcinoma by Down-Regulating Dipeptidyl Peptidase 9 (DPP9).Wu QQ et al
288817562017MM-BMSCs induce naïve CD4+ T lymphocytes dysfunction through fibroblast activation protein α.Wu X et al
200742092010The dipeptidyl peptidase IV family in cancer and cell biology.Yu DM et al
283561562017Chimeric antigen receptor T cells: a novel therapy for solid tumors.Yu S et al
238136242013Overexpression of fibroblast activation protein and its clinical implications in patients with osteosarcoma.Yuan D et al
302578792019Identification of Novel Natural Substrates of Fibroblast Activation Protein-alpha by Differential Degradomics and Proteomics.Zhang HE et al
231049822013Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens.Zhang J et al
261709732015Expression levels of seprase/FAPα and DPPIV/CD26 in epithelial ovarian carcinoma.Zhang M et al
175171812007Expression of seprase in effusions from patients with epithelial ovarian carcinoma.Zhang MZ et al
255930802015Fibroblast activation protein α in tumor microenvironment: recent progression and implications (review).Zi F et al
302714872018The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes.Zou B et al

Other Information

Locus ID:

NCBI: 2191
MIM: 600403
HGNC: 3590
Ensembl: ENSG00000078098

Variants:

dbSNP: 2191
ClinVar: 2191
TCGA: ENSG00000078098
COSMIC: FAP

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000078098ENST00000188790Q12884
ENSG00000078098ENST00000422436H7C4D9
ENSG00000078098ENST00000443424B4DLR2
ENSG00000078098ENST00000447386C9J131
ENSG00000078098ENST00000450031F8WF29
ENSG00000078098ENST00000462608H0YG61
ENSG00000078098ENST00000627638A0A0D9SEN1

Expression (GTEx)

0
50
100
150

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
216689922011FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells.75
223234942012Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy.74
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
229116692012Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug.57
186650762008Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma.55
158093062005Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha.51
120239642002Regulation of fibroblast migration on collagenous matrix by a cell surface peptidase complex.46
157675442005Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth.43
162237692006Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein.42
162237692006Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein.42

Citation

Sinem Tunçer ; Sreeparna Banerjee

FAP (fibroblast activation protein alpha)

Atlas Genet Cytogenet Oncol Haematol. 2020-08-01

Online version: http://atlasgeneticsoncology.org/gene/40530/fap-(fibroblast-activation-protein-alpha)