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Fibroblast Activation Protein (FAP): A Key Modulator of the Cancer Microenvironment

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Handbook of Cancer and Immunology

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Abstract

Fibroblast activation protein-α (FAP) is a type II transmembrane serine protease with extensive endonuclease activity that is almost undetectable in normal tissues. In contrast, it is particularly pronounced in a wide range of cancers, and an increased level of FAP is often associated with worse clinical outcomes. Here, we summarize and discuss the basic introduction of FAP, its biological features, and recent advances in understanding the role and clinical significance of FAP in a variety of cancers. In addition, the enzymatic activities of FAP and its different substrates, its nonenzymatic activities, and the key role in regulating different signaling pathways are reviewed. Finally, the high tremendous potential of FAP as an effective therapeutic target for the management of different inflammatory and oncologic conditions has been investigated.

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References

  • Adams S, Miller GT, Jesson MI, Watanabe T, Jones B, Wallner BP (2004) PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res 64:5471–5480

    Article  CAS  Google Scholar 

  • Aertgeerts K, Levin I, Shi L, Snell GP, Jennings A, Prasad GS, Zhang Y, Kraus ML, Salakian S, Sridhar V, Wijnands R, Tennant MG (2005) Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha. J Biol Chem 280:19441–19444

    Article  CAS  Google Scholar 

  • Aoyama A, Chen W-T (1990) A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells. Proc Natl Acad Sci 87:8296–8300

    Article  CAS  Google Scholar 

  • Ariga N, Sato E, Ohuchi N, Nagura H, Ohtani H (2001) Stromal 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. Int J Cancer 95:67–72

    Article  CAS  Google Scholar 

  • Arnold JN, Magiera L, Kraman M, Fearon DT (2014) Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1. Cancer Immunol Res 2:121–126

    Article  CAS  Google Scholar 

  • Artym VV, Kindzelskii AL, Chen W-T, Petty HR (2002) Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on β1 integrins and the cytoskeleton. Carcinogenesis 23:1593–1601

    Article  CAS  Google Scholar 

  • Babushkina EA, Belokopytova LV, Grachev AM, Meko DM, Vaganov EA (2017) Variation of the hydrological regime of Bele-Shira closed basin in Southern Siberia and its reflection in the radial growth of Larix sibirica. Reg Environ Chang 17:1725–1737

    Article  Google Scholar 

  • Badar T, Shah NN (2020) Chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Curr Treat Options in Oncol 21:1–11

    Article  Google Scholar 

  • Baird SK, Allan L, Renner C, Scott FE, Scott AM (2015) Fibroblast activation protein increases metastatic potential of fibrosarcoma line HT1080 through upregulation of integrin-mediated signaling pathways. Clin Exp Metastasis 32:507–516

    Article  CAS  Google Scholar 

  • Bauer S, Jendro MC, Wadle A, Kleber S, Stenner F, Dinser R, Reich A, Faccin E, Godde S, Dinges H, Muller-Ladner U, Renner C (2006) Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res Ther 8:R171

    Article  Google Scholar 

  • Boonacker E, Van Noorden CJ (2003) The multifunctional or moonlighting protein CD26/DPPIV. Eur J Cell Biol 82:53–73

    Article  CAS  Google Scholar 

  • Brown DD, Wang Z, Furlow JD, Kanamori A, Schwartzman RA, Remo BF, Pinder A (1996) The thyroid hormone-induced tail resorption program during Xenopus laevis metamorphosis. Proc Natl Acad Sci USA 93:1924–1929

    Article  CAS  Google Scholar 

  • Busek P, Mateu R, Zubal M, Kotackova L, Sedo A (2018) Targeting fibroblast activation protein in cancer – prospects and caveats. Front Biosci 23:1933–1968

    Article  CAS  Google Scholar 

  • Ceppi F, Gardner RA (2019) Chimeric antigen receptor T cells for B-cell acute lymphoblastic leukemia. Cancer J 25:191–198

    Article  CAS  Google Scholar 

  • Chen M, Xu G, Fan M, Jia H, Xiao L, Lang J (2019) Anti-tumour effects of a xenogeneic fibroblast activation protein-based whole cell tumour vaccine in murine tumour models. Artif Cells Nanomed Biotechnol 47:4182–4193

    Article  CAS  Google Scholar 

  • Cheng JD, Dunbrack RL, Valianou M, Rogatko A, Alpaugh RK, Weiner LM (2002) Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res 62:4767–4772

    CAS  Google Scholar 

  • Christiansen VJ, Jackson KW, Lee KN, McKee PA (2007) Effect of fibroblast activation protein and α2-antiplasmin cleaving enzyme on collagen types I, III, and IV. Arch Biochem Biophys 457:177–186

    Article  CAS  Google Scholar 

  • Cohen SJ, Alpaugh RK, Palazzo I, Meropol NJ, Rogatko A, Xu Z, Hoffman JP, Weiner LM, Cheng JD (2008) Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas 37:154–158

    Article  CAS  Google Scholar 

  • Dong R, Guo J, Zhang Z, Zhou Y, Hua Y (2018) Polyphyllin I inhibits gastric cancer cell proliferation by downregulating the expression of fibroblast activation protein alpha (FAP) and hepatocyte growth factor (HGF) in cancer-associated fibroblasts. Biochem Biophys Res Commun 497:1129–1134

    Article  CAS  Google Scholar 

  • Dunshee DR, Bainbridge TW, Kljavin NM, Zavala-Solorio J, Schroeder AC, Chan R, Corpuz R, Wong M, Zhou W, Deshmukh G, Ly J, Sutherlin DP, Ernst JA, Sonoda J (2016) Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J Biol Chem 291:5986–5996

    Article  CAS  Google Scholar 

  • Fan MH, Zhu Q, Li HH, Ra HJ, Majumdar S, Gulick DL, Jerome JA, Madsen DH, Christofidou-Solomidou M, Speicher DW, Bachovchin WW, Feghali-Bostwick C, Puré E (2016) Fibroblast activation protein (FAP) accelerates collagen degradation and clearance from lungs in mice. J Biol Chem 291:8070–8089

    Article  CAS  Google Scholar 

  • Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci 110:20212–20217

    Article  CAS  Google Scholar 

  • Fitzgerald AA, Weiner LM (2020) The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev 39:783–803

    Article  CAS  Google Scholar 

  • Garin-Chesa P, Old LJ, Rettig WJ (1990) Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci 87:7235–7239

    Article  CAS  Google Scholar 

  • Ge Y, Zhan F, Barlogie B, Epstein J, Shaughnessy J Jr, Yaccoby S (2006) Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival. Br J Haematol 133:83–92

    Article  CAS  Google Scholar 

  • Ghersi G, Dong H, Goldstein LA, Yeh Y, Hakkinen L, Larjava HS, Chen W-T (2002) Regulation of fibroblast migration on collagenous matrix by a cell surface peptidase complex. J Biol Chem 277:29231–29241

    Article  CAS  Google Scholar 

  • Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S, Chen W-T (2006) The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res 66:4652

    Article  CAS  Google Scholar 

  • Goldstein LA, Ghersi G, Piñeiro-Sánchez ML, Salamone M, Yeh Y, Flessate D, Chen WT (1997) Molecular cloning of seprase: a serine integral membrane protease from human melanoma. Biochim Biophys Acta 1361:11–19

    Article  Google Scholar 

  • Gong C, Nie Y, Qu S, Liao J-Y, Cui X, Yao H, Zeng Y, Su F, Song E, Liu Q (2014) miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors. Cancer Res 74:4341–4352

    Article  CAS  Google Scholar 

  • Goodman JD, Rozypal TL, Kelly T (2003) Seprase, a membrane-bound protease, alleviates the serum growth requirement of human breast cancer cells. Clin Exp Metastasis 20:459–470

    Article  CAS  Google Scholar 

  • Gunderson AJ, Yamazaki T, McCarty K, Phillips M, Alice A, Bambina S, Zebertavage L, Friedman D, Cottam B, Newell P (2019) Blockade of fibroblast activation protein in combination with radiation treatment in murine models of pancreatic adenocarcinoma. PLoS One 14:e0211117

    Article  CAS  Google Scholar 

  • Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD (2014) Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl 8:454–463

    Article  CAS  Google Scholar 

  • Henry LR, Lee H-O, Lee JS, Klein-Szanto A, Watts P, Ross EA, Chen W-T, Cheng JD (2007) Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res 13:1736–1741

    Article  CAS  Google Scholar 

  • Hu M, Qian C, Hu Z, Fei B, Zhou H (2017) Biomarkers in tumor microenvironment? Upregulation of fibroblast activation protein-α correlates with gastric cancer progression and poor prognosis. OMICS 21:38–44

    Article  CAS  Google Scholar 

  • Huang Y, Simms AE, Mazur A, Wang S, León NR, Jones B, Aziz N, Kelly T (2011a) Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clin Exp Metastasis 28:567–579

    Article  CAS  Google Scholar 

  • Huang CH, Suen CS, Lin CT, Chien CH, Lee HY, Chung KM, Tsai TY, Jiaang WT, Hwang MJ, Chen X (2011b) Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full-length protein substrate. J Biochem 149:685–692

    Article  CAS  Google Scholar 

  • Huber MA, Schubert RD, Peter RU, Kraut N, Park JE, Rettig WJ, Garin-Chesa P (2003) Fibroblast activation protein: differential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors. J Investig Dermatol 120:182–188

    Article  CAS  Google Scholar 

  • Irwin DM (2002) Ancient duplications of the human proglucagon gene. Genomics 79:741–746

    Article  CAS  Google Scholar 

  • Iwasa S, Jin X, Okada K, Mitsumata M, Ooi A (2003) Increased expression of seprase, a membrane-type serine protease, is associated with lymph node metastasis in human colorectal cancer. Cancer Lett 199:91–98

    Article  CAS  Google Scholar 

  • Jia J, Martin TA, Ye L, Jiang WG (2014a) FAP-α (fibroblast activation protein-α) is involved in the control of human breast cancer cell line growth and motility via the FAK pathway. BMC Cell Biol 15:16

    Article  Google Scholar 

  • Jia J, Martin TA, Ye L, Jiang WG (2014b) FAP-α (fibroblast activation protein-α) is involved in the control of human breast cancer cell line growth and motility via the FAK pathway. BMC Cell Biol 15:1–14

    Article  Google Scholar 

  • Jia J, Martin TA, Ye L, Meng L, Xia N, Jiang WG, Zhang X (2018) Fibroblast activation protein-α promotes the growth and migration of lung cancer cells via the PI3K and sonic hedgehog pathways. Int J Mol Med 41:275–283

    CAS  Google Scholar 

  • Jung YY, Lee YK, Koo JS (2015) Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer. Tumor Biol 36:8685–8695

    Article  CAS  Google Scholar 

  • Kakarla S, Chow KK, Mata M, Shaffer DR, Song X-T, Wu M-F, Liu H, Wang LL, Rowley DR, Pfizenmaier K (2013) Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther 21:1611–1620

    Article  CAS  Google Scholar 

  • Kawase T, Yasui Y, Nishina S, Hara Y, Yanatori I, Tomiyama Y, Nakashima Y, Yoshida K, Kishi F, Nakamura M (2015) Fibroblast activation protein-α-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. BMC Gastroenterol 15:1–9

    Article  Google Scholar 

  • Keane FM, Nadvi NA, Yao T-W, Gorrell MD (2011) Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α. FEBS J 278:1316–1332

    Article  CAS  Google Scholar 

  • Kelly T (1999) Evaluation of seprase activity. Clin Exp Metastasis 17:67–72

    Article  Google Scholar 

  • Kelly T, Huang Y, Simms AE, Mazur A (2012) Chapter 3 – fibroblast activation protein-α: a key modulator of the microenvironment in multiple pathologies. In: Jeon KW (ed) International review of cell and molecular biology, vol 297. Academic Press, pp 83–116

    Google Scholar 

  • Lai D, Ma L, Wang F (2012) Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells. Int J Oncol 41:541–550

    Article  CAS  Google Scholar 

  • Lang J, Zhao X, Qi Y, Zhang Y, Han X, Ding Y, Guan J, Ji T, Zhao Y, Nie G (2019) Reshaping prostate tumor microenvironment to suppress metastasis via cancer-associated fibroblast inactivation with peptide-assembly-based nanosystem. ACS Nano 13:12357–12371

    Article  CAS  Google Scholar 

  • Lawrence DA, Palaniappan S, Stefansson S, Olson ST, Francis-Chmura AM, Shore JD, Ginsburg D (1997) Characterization of the binding of different conformational forms of plasminogen activator inhibitor-1 to vitronectin: implications for the regulation of pericellular proteolysis*. J Biol Chem 272:7676–7680

    Article  CAS  Google Scholar 

  • Lee KN, Jackson KW, Christiansen VJ, Chung KH, McKee PA (2004) A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion. Blood 103:3783–3788

    Article  CAS  Google Scholar 

  • Lee KN, Jackson KW, Christiansen VJ, Lee CS, Chun JG, McKee PA (2006) Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein. Blood 107:1397–1404

    Article  CAS  Google Scholar 

  • Li M, Li M, Yin T, Shi H, Wen Y, Zhang B, Chen M, Xu G, Ren K, Wei Y (2016) Targeting of cancer-associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment. Mol Med Rep 13:2476–2484

    Article  CAS  Google Scholar 

  • Li L, Zhou S, Lv N, Zhen Z, Liu T, Gao S, Xie J, Ma Q (2018) Photosensitizer-encapsulated ferritins mediate photodynamic therapy against cancer-associated fibroblasts and improve tumor accumulation of nanoparticles. Mol Pharm 15:3595–3599

    Article  CAS  Google Scholar 

  • Liu F, Qi L, Liu B, Liu J, Zhang H, Che D, Cao J, Shen J, Geng J, Bi Y (2015) Fibroblast activation protein overexpression and clinical implications in solid tumors: a meta-analysis. PLoS One 10:e0116683

    Article  Google Scholar 

  • Lo A, Li C-P, Buza EL, Blomberg R, Govindaraju P, Avery D, Monslow J, Hsiao M, Puré E (2017) Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma. JCI insight 2:e92232

    Article  Google Scholar 

  • Loeffler M, Krüger JA, Niethammer AG, Reisfeld RA (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 116:1955–1962

    Article  CAS  Google Scholar 

  • Loktev A, Lindner T, Burger E-M, Altmann A, Giesel F, Kratochwil C, Debus J, Marmé F, Jäger D, Mier W (2019) Development of fibroblast activation protein–targeted radiotracers with improved tumor retention. J Nucl Med 60:1421–1429

    Article  CAS  Google Scholar 

  • Luo Y, Ye S, Chen X, Gong F, Lu W, Li X (2017) Rush to the fire: FGF21 extinguishes metabolic stress, metaflammation and tissue damage. Cytokine Growth Factor Rev 38:59–65

    Article  CAS  Google Scholar 

  • Lv B, Xie F, Zhao P, Ma X, Jiang WG, Yu J, Zhang X, Jia J (2016) Promotion of cellular growth and motility is independent of enzymatic activity of fibroblast activation protein-α. Cancer Genomics Proteomics 13:201–208

    CAS  Google Scholar 

  • Mathew S, Scanlan MJ, Mohan Raj BK, Murty VVVS, Garin-Chesa P, Old LJ, Rettig WJ, Chaganti RSK (1995) The gene for fibroblast activation protein α (FAP), a putative cell surface-bound serine protease expressed in cancer stroma and wound healing, maps to chromosome band 2q23. Genomics 25:335–337

    Article  CAS  Google Scholar 

  • Matrasova I, Busek P, Balaziova E, Sedo A (2017) Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 161:252–260

    Article  Google Scholar 

  • Meletta R, Müller Herde A, Chiotellis A, Isa M, Rancic Z, Borel N, Ametamey SM, Krämer SD, Schibli R (2015) Evaluation of the radiolabeled boronic acid-based FAP inhibitor MIP-1232 for atherosclerotic plaque imaging. Molecules 20:2081–2099

    Article  Google Scholar 

  • Mentlein R, Hattermann K, Hemion C, Jungbluth AA, Held-Feindt J (2011) Expression and role of the cell surface protease seprase/fibroblast activation protein-α (FAP-α) in astroglial tumors. Biol Chem 392(3):199–207

    Article  CAS  Google Scholar 

  • Mersmann M, Schmidt A, Rippmann JF, Wüest T, Brocks B, Rettig WJ, Garin-Chesa P, Pfizenmaier K, Moosmayer D (2001) Human antibody derivatives against the fibroblast activation protein for tumor stroma targeting of carcinomas. Int J Cancer 92:240–248

    Article  CAS  Google Scholar 

  • Mikheeva SA, Mikheev AM, Petit A, Beyer R, Oxford RG, Khorasani L, Maxwell J-P, Glackin CA, Wakimoto H, González-Herrero I (2010) TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Mol Cancer 9:1–18

    Article  Google Scholar 

  • Millul J, Bassi G, Mock J, Elsayed A, Pellegrino C, Zana A, Plaza SD, Nadal L, Gloger A, Schmidt E (2021) An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications. Proc Natl Acad Sci 118

    Google Scholar 

  • Monsky WL, Lin C-Y, Aoyama A, Kelly T, Akiyama SK, Mueller SC, Chen W-T (1994) A potential marker protease of invasiveness, separase, is localized on invadopodia of human malignant melanoma cells. Cancer Res 54:5702–5710

    CAS  Google Scholar 

  • Mori Y, Kono K, Matsumoto Y, Fujii H, Yamane T, Mitsumata M, Chen W-T (2004) The expression of a type II transmembrane serine protease (Seprase) in human gastric carcinoma. Oncology 67:411–419

    Article  CAS  Google Scholar 

  • Mueller SC, Ghersi G, Akiyama SK, Sang Q-XA, Howard L, Pineiro-Sanchez M, Nakahara H, Yeh Y, Chen W-T (1999) A novel protease-docking function of integrin at invadopodia*. J Biol Chem 274:24947–24952

    Article  CAS  Google Scholar 

  • Muliaditan T, Caron J, Okesola M, Opzoomer JW, Kosti P, Georgouli M, Gordon P, Lall S, Kuzeva DM, Pedro L, Shields JD, Gillett CE, Diebold SS, Sanz-Moreno V, Ng T, Hoste E, Arnold JN (2018) Macrophages are exploited from an innate wound healing response to facilitate cancer metastasis. Nat Commun 9:2951

    Article  Google Scholar 

  • Narra K, Mullins SR, Lee H-O, Strzemkowski-Brun B, Magalong K, Christiansen VJ, McKee PA, Egleston B, Cohen SJ, Weiner LM (2007) Phase II trial of single agent Val-boroPro (Talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer. Cancer Biol Ther 6:1691–1699

    Article  CAS  Google Scholar 

  • Niedermeyer J, Enenkel B, Park JE, Lenter M, Rettig WJ, Damm K, Schnapp A (1998) Mouse fibroblast-activation protein. Eur J Biochem 254:650–654

    Article  CAS  Google Scholar 

  • Niedermeyer J, Kriz M, Hilberg F, Garin-Chesa P, Bamberger U, Lenter MC, Park J, Viertel B, Puschner H, Mauz M, Rettig WJ, Schnapp A (2000) Targeted disruption of mouse fibroblast activation protein. Mol Cell Biol 20:1089–1094

    Article  CAS  Google Scholar 

  • O’Brien P, O’Connor BF (2008) Seprase: an overview of an important matrix serine protease. Biochim Biophys Acta 1784:1130–1145

    Article  Google Scholar 

  • Okada K, Chen W-T, Iwasa S, Jin X, Yamane T, Ooi A, Mitsumata M (2003) Seprase, a membrane-type serine protease, has different expression patterns in intestinal-and diffuse-type gastric cancer. Oncology 65:363–370

    Article  CAS  Google Scholar 

  • Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ (1999) Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 274:36505–36512

    Article  CAS  Google Scholar 

  • Park SY, Kim HM, Koo JS (2015) Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer. Breast Cancer Res Treat 149:727–741

    Article  CAS  Google Scholar 

  • Park CK, Jung WH, Koo JS (2016) Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma. Breast Cancer Res Treat 159:55–69

    Article  CAS  Google Scholar 

  • Park H, Lee Y, Lee H, Kim J-W, Hwang J-H, Kim J, Yoon Y-S, Han H-S, Kim H (2017) The prognostic significance of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Tumor Biol 39:1010428317718403

    Article  Google Scholar 

  • Pennisi A, Li X, Ling W, Khan S, Gaddy D, Suva LJ, Barlogie B, Shaughnessy JD, Aziz N, Yaccoby S (2009) Inhibitor of DASH proteases affects expression of adhesion molecules in osteoclasts and reduces myeloma growth and bone disease. Br J Haematol 145:775–787

    Article  CAS  Google Scholar 

  • Piñeiro-Sánchez ML, Goldstein LA, Dodt J, Howard L, Yeh Y, Chen W-T (1997) Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease. J Biol Chem 272:7595–7601

    Article  Google Scholar 

  • Qin C, Shao F, Gai Y, Liu Q, Ruan W, Liu F, Hu F, Lan X (2022) 68Ga-DOTA-FAPI-04 PET/MR in the evaluation of gastric carcinomas: comparison with 18F-FDG PET/CT. J Nucl Med 63:81–88

    Article  CAS  Google Scholar 

  • Ramirez-Montagut T, Blachere NE, Sviderskaya EV, Bennett DC, Rettig WJ, Garin-Chesa P, Houghton AN (2004) FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor. Oncogene 23:5435–5446

    Article  CAS  Google Scholar 

  • Rettig WJ, Chesa PG, Beresford HR, Feickert H-J, Jennings MT, Cohen J, Oettgen HF, Old LJ (1986) Differential expression of cell surface antigens and glial fibrillary acidic protein in human astrocytoma subsets. Cancer Res 46:6406–6412

    CAS  Google Scholar 

  • Rettig WJ, Garin-Chesa P, Beresford HR, Oettgen HF, Melamed MR, Old LJ (1988) Cell-surface glycoproteins of human sarcomas: differential expression in normal and malignant tissues and cultured cells. Proc Natl Acad Sci USA 85:3110–3114

    Article  CAS  Google Scholar 

  • Rettig WJ, Su SL, Fortunato SR, Scanlan MJ, Raj BK, Garin-Chesa P, Healey JH, Old LJ (1994) Fibroblast activation protein: purification, epitope mapping and induction by growth factors. Int J Cancer 58:385–392

    Article  CAS  Google Scholar 

  • Riet T, Abken H (2015) Chimeric antigen receptor T cells: power tools to wipe out leukemia and lymphoma, vol 8. Taylor & Francis, pp 383–385

    Google Scholar 

  • Röhrich M, Loktev A, Wefers AK, Altmann A, Paech D, Adeberg S, Windisch P, Hielscher T, Flechsig P, Floca R (2019) IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein–specific PET/CT. Eur J Nucl Med Mol Imaging 46:2569–2580

    Article  Google Scholar 

  • Rosenblum JS, Kozarich JW (2003) Prolyl peptidases: a serine protease subfamily with high potential for drug discovery. Curr Opin Chem Biol 7:496–504

    Article  CAS  Google Scholar 

  • Rüger R, Tansi FL, Rabenhold M, Steiniger F, Kontermann RE, Fahr A, Hilger I (2014) In vivo near-infrared fluorescence imaging of FAP-expressing tumors with activatable FAP-targeted, single-chain Fv-immunoliposomes. J Control Release 186:1–10

    Article  Google Scholar 

  • Santos AM, Jung J, Aziz N, Kissil JL, Puré E (2009) Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest 119:3613–3625

    Article  CAS  Google Scholar 

  • Schmidt A, Müller D, Mersmann M, Wüest T, Gerlach E, Garin-Chesa P, Rettig WJ, Pfizenmaier K, Moosmayer D (2001) Generation of human high-affinity antibodies specific for the fibroblast activation protein by guided selection. Eur J Biochem 268:1730–1738

    Article  CAS  Google Scholar 

  • Schuberth PC, Hagedorn C, Jensen SM, Gulati P, van den Broek M, Mischo A, Soltermann A, Jüngel A, Belaunzaran OM, Stahel R (2013) Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J Transl Med 11:1–11

    Article  Google Scholar 

  • Segerer SE, Bartmann C, Schwab M, Kammerer U (2020) Expression of the peptidase “fibroblast activation protein” on decidual stromal cells facilitating tissue Remodeling. Gynecol Obstet Investig 85:428–436

    Article  CAS  Google Scholar 

  • Shi M, Yu D-H, Chen Y, Zhao C-Y, Zhang J, Liu Q-H, Ni C-R, Zhu M-H (2012) Expression of fibroblast activation protein in human pancreatic adenocarcinoma and its clinicopathological significance. World J Gastroenterol: WJG 18:840

    Article  CAS  Google Scholar 

  • Stremenova J, Krepela E, Mares V, Trim J, Dbaly V, Marek J, Vanickova Z, Lisa V, Yea C, Sedo A (2007) Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade. Int J Oncol 31:785–792

    CAS  Google Scholar 

  • Sun S, Albright CF, Fish BH, George HJ, Selling BH, Hollis GF, Wynn R (2002) Expression, purification, and kinetic characterization of full-length human fibroblast activation protein. Protein Expr Purif 24:274–281

    Article  CAS  Google Scholar 

  • Tanswell P, Garin-Chesa P, Rettig WJ, Welt S, Divgi CR, Casper ES, Finn RD, Larson SM, Old LJ, Scott AM (2001) Population pharmacokinetics of antifibroblast activation protein monoclonal antibody F19 in cancer patients. Br J Clin Pharmacol 51:177–180

    Article  CAS  Google Scholar 

  • Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee C-CR, Restifo NP, Rosenberg SA (2013) Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med 210:1125–1135

    Article  CAS  Google Scholar 

  • Uitte de Willige S, Malfliet JJ, Janssen HL, Leebeek FW, Rijken DC (2013) Increased N-terminal cleavage of alpha-2-antiplasmin in patients with liver cirrhosis. J Thromb Haemost 11:2029–2036

    Article  CAS  Google Scholar 

  • Walsh MP, Duncan B, Larabee S, Krauss A, Davis JP, Cui Y, Kim SY, Guimond M, Bachovchin W, Fry TJ (2013) Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors. PLoS One 8:e58860

    Article  CAS  Google Scholar 

  • 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 (2014) Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. Cell Death Dis 5:e1155–e1155

    Article  CAS  Google Scholar 

  • Watabe T, Liu Y, Kaneda-Nakashima K, Shirakami Y, Lindner T, Ooe K, Toyoshima A, Nagata K, Shimosegawa E, Haberkorn U (2020) Theranostics targeting fibroblast activation protein in the tumor stroma: 64Cu-and 225Ac-labeled FAPI-04 in pancreatic cancer xenograft mouse models. J Nucl Med 61:563–569

    Article  CAS  Google Scholar 

  • Welt S, Divgi CR, Scott AM, Garin-Chesa P, Finn RD, Graham M, Carswell EA, Cohen A, Larson SM, Old LJ (1994) Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts. J Clin Oncol 12:1193–1203

    Article  CAS  Google Scholar 

  • Wen Y, Wang CT, Ma TT, Li ZY, Zhou LN, Mu B, Leng F, Shi HS, Li YO, Wei YQ (2010) Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci 101:2325–2332

    Article  CAS  Google Scholar 

  • Wen X, He X, Jiao F, Wang C, Sun Y, Ren X, Li Q (2017) Fibroblast activation protein-α-positive fibroblasts promote gastric cancer progression and resistance to immune checkpoint blockade. Oncol Res 25:629

    Article  Google Scholar 

  • Wikberg ML, Edin S, Lundberg IV, Van Guelpen B, Dahlin AM, Rutegård J, Stenling R, Öberg Å, Palmqvist R (2013) High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis. Tumor Biol 34:1013–1020

    Article  CAS  Google Scholar 

  • Xin L, Gao J, Zheng Z, Chen Y, Lv S, Zhao Z, Yu C, Yang X, Zhang R (2021) Fibroblast activation protein-α as a target in the bench-to-bedside diagnosis and treatment of tumors: a narrative review. Frontiers. Oncology 11

    Google Scholar 

  • Yang W, Han W, Ye S, Liu D, Wu J, Liu H, Li C, Chen H (2013a) Fibroblast activation protein-α promotes ovarian cancer cell proliferation and invasion via extracellular and intracellular signaling mechanisms. Exp Mol Pathol 95:105–110

    Article  CAS  Google Scholar 

  • Yang L, Ma L, Lai D (2013b) Over-expression of fibroblast activation protein alpha increases tumor growth in xenografts of ovarian cancer cells. Acta Biochim Biophys Sin 45:928–937

    Article  Google Scholar 

  • Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, Dang Y, Chu Y, Fan J, He R (2016) FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res 76:4124–4135

    Article  CAS  Google Scholar 

  • Yu H, Yang J, Li Y, Jiao S (2015) The expression of fibroblast activation protein-α in primary breast cancer is associated with poor prognosis. Xi bao yu fen zi mian yi xue za zhi=. Chin J Cell Mol Immunol 31:370–374

    CAS  Google Scholar 

  • Yue D, Li H, Che J, Zhang Y, Tseng HH, Jin JQ, Luh TM, Giroux-Leprieur E, Mo M, Zheng Q, Shi H, Zhang H, Hao X, Wang C, Jablons DM, He B (2014) Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J Exp Clin Cancer Res 33:34

    Article  Google Scholar 

  • Zhang M-Z, Qiao Y-H, Nesland JM, Suo Z-H (2007) Expression of seprase in effusions from patients with epithelial ovarian carcinoma. Chin Med J 120:663–668

    Article  CAS  Google Scholar 

  • Zhang Y, Tang H, Cai J, Zhang T, Guo J, Feng D, Wang Z (2011) Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett 303:47–55

    Article  CAS  Google Scholar 

  • Zhang J, Valianou M, Simmons H, Robinson MK, Lee HO, Mullins SR, Marasco WA, Adams GP, Weiner LM, Cheng JD (2013) Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. FASEB J 27:581–589

    Article  CAS  Google Scholar 

  • Zhang M, Xu L, Wang X, Sun B, Ding J (2015) Expression levels of seprase/FAPα and DPPIV/CD26 in epithelial ovarian carcinoma. Oncol Lett 10:34–42

    Article  CAS  Google Scholar 

  • Zhen EY, Jin Z, Ackermann BL, Thomas MK, Gutierrez JA (2016) Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem J 473:605–614

    Article  CAS  Google Scholar 

  • Zhen Z, Tang W, Wang M, Zhou S, Wang H, Wu Z, Hao Z, Li Z, Liu L, Xie J (2017) Protein nanocage mediated fibroblast-activation protein targeted photoimmunotherapy to enhance cytotoxic T cell infiltration and tumor control. Nano Lett 17:862–869

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Allied Medicine, Department of Hematology, Bushehr University of Medical Sciences, Bushehr, Iran

    Mohammad Javad Mousavi

  2. Department of Laboratory Sciences, Khomein University of Medical Sciences, Khomein, Iran

    Jafar Karami

  3. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Masoumeh Alimohammadi & Nima Rezaei

  4. Department of Biological Sciences, North Dakota State University, Fargo, ND, USA

    Farid Solaymani-Mohammadi

  5. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  6. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden

    Nima Rezaei

Authors
  1. Mohammad Javad Mousavi
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  2. Jafar Karami
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  3. Masoumeh Alimohammadi
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  4. Farid Solaymani-Mohammadi
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  5. Nima Rezaei
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Corresponding author

Correspondence to Nima Rezaei .

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Editors and Affiliations

  1. Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Sweden

    Nima Rezaei

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Mousavi, M.J., Karami, J., Alimohammadi, M., Solaymani-Mohammadi, F., Rezaei, N. (2023). Fibroblast Activation Protein (FAP): A Key Modulator of the Cancer Microenvironment. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_357-1

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  • DOI: https://doi.org/10.1007/978-3-030-80962-1_357-1

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  • Print ISBN: 978-3-030-80962-1

  • Online ISBN: 978-3-030-80962-1

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