Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

Abstract

Fibroblast activation protein (FAP) is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and, especially in recent years, a great deal of research has gone into design and testing of diverse FAP-targeted treatments. Yet despite this growing field of research, our knowledge of FAP’s basic biology and functional roles in various cancers has lagged behind its use as a tumor-stromal marker. In this review, we summarize and analyze recent advances in understanding the functions of FAP in cancer, most notably its prognostic value in various tumor types, cellular effects on various cell types, and potential as a therapeutic target. We highlight outstanding questions in the field, the answers to which could shape preclinical and clinical studies of FAP.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rettig WJ, Chesa PG, Beresford HR, Feickert H-J, Jennings MT, Cohen J, et al. Differential expression of cell surface antigens and glial fibrillary acidic protein in human astrocytoma subsets. Cancer Res. 1986;46. http://cancerres.aacrjournals.org/content/46/12_Part_1/6406.full-text.pdf. Accessed 28 Aug 2017.

  2. Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, et al. Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin1. Cancer Res. 1993;53:3327–35.

    PubMed  CAS  Google Scholar 

  3. Aoyama A, Chen WT. A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells. Proc Natl Acad Sci USA. 1990;87:8296–300.

    Article  PubMed  CAS  Google Scholar 

  4. Monsky WL, Lin CY, Aoyama A, Kelly T, Akiyama SK, Mueller SC, et al. A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells. Cancer Res. 1994;54:5702–10.

    PubMed  CAS  Google Scholar 

  5. Goldstein LA, Ghersi G, Piñeiro-Sánchez ML, Salamone M, Yeh Y, Flessate D, et al. Molecular cloning of seprase: a serine integral membrane protease from human melanoma. Biochim Biophys Acta. 1997;1361:11–9.

    Article  PubMed  Google Scholar 

  6. Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA. 1994;91:5657–61.

    Article  PubMed  CAS  Google Scholar 

  7. Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem. 1999;274:36505–12. https://doi.org/10.1074/jbc.274.51.36505.

    Article  PubMed  CAS  Google Scholar 

  8. Aertgeerts K, Levin I, Shi L, Snell GP, Jennings A, Prasad GS, et al. Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha. J Biol Chem. 2005;280:19441–4.

    Article  PubMed  CAS  Google Scholar 

  9. Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S, Chen W-T. 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. 2006;66:4652–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lee KN, Jackson KW, Christiansen VJ, Lee CS, Chun J-G, McKee PA. Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein. Blood. 2006;107:1397–404.

    Article  PubMed  CAS  Google Scholar 

  11. Niedermeyer J, Garin-Chesa P, Kriz M, Hilberg F, Mueller E, Bamberger U, et al. Expression of the fibroblast activation protein during mouse embryo development. Int J Dev Biol. 2001;45:445–7.

    PubMed  CAS  Google Scholar 

  12. Jacob M, Chang L, Puré E. Fibroblast activation protein in remodeling tissues. Curr Mol Med. 2012;12:1–24.

    Article  Google Scholar 

  13. Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteom Appl. 2014;8:454–63.

    Article  CAS  Google Scholar 

  14. Zi F, He J, He D, Li Y, Yang L, Cai Z. Fibroblast activation protein?? In tumor microenvironment: recent progression and implications (review). Mol Med Rep. 2015;11:3203–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Verdelli C, Avagliano L, Creo P, Guarnieri V, Scillitani A, Vicentini L, et al. Tumour-associated fibroblasts contribute to neoangiogenesis in human parathyroid neoplasia. Endocr Relat Cancer. 2015;22:87–98.

    Article  PubMed  CAS  Google Scholar 

  16. Gong C, Nie Y, Qu S, Liao J-Y, Cui X, Yao H, et al. miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors. Cancer Res. 2014;74:4341–52.

  17. Krepela E, Busek P, Hilser M, Vanickova Z, Sedo A. Species-specific real-time RT-PCR analysis of expression of stromal cell genes in a tumor xenotransplantation model in mice. Biochem Biophys Res Commun. 2017;491:126–33.

  18. Tyulkina DV, Pleshkan VV, Alekseenko IV, Kopantseva MR, Sverdlov ED. Expression of the FAP gene in non-fibroblast human cell lines. Development of cancer-associated fibroblast models. Dokl Biochem Biophys. 2016;470:319–21.

    Article  PubMed  CAS  Google Scholar 

  19. Augoff K, Hryniewicz-Jankowska A, Tabola R, Czapla L, Szelachowski P, Wierzbicki J, et al. Upregulated expression and activation of membrane-associated proteases in esophageal squamous cell carcinoma. Oncol Rep. 2014;31:2820–6.

    Article  PubMed  CAS  Google Scholar 

  20. Busek P, Vanickova Z, Hrabal P, Brabec M, Fric P, Zavoral M, et al. Increased tissue and circulating levels of dipeptidyl peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma. Pancreatology. 2016;16:829–38.

    Article  PubMed  CAS  Google Scholar 

  21. Patsouras D, Papaxoinis K, Kostakis A, Safioleas MC, Lazaris AC, Nicolopoulou-Stamati P. Fibroblast activation protein and its prognostic significance in correlation with vascular endothelial growth factor in pancreatic adenocarcinoma. Mol Med Rep. 2015;11:4585–90.

  22. Busek P, Balaziova E, Matrasova I, Hilser M, Tomas R, Syrucek M, et al. Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma. Tumor Biol. 2016;37:13961–71. https://doi.org/10.1007/s13277-016-5274-9.

    Article  CAS  Google Scholar 

  23. Roberts EW, Deonarine A, Jones JO, Denton AE, Feig C, Lyons SK, et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med. 2013;210:1137–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Ackermann AM, Wang Z, Schug J, Naji A, Kaestner KH. Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes. Mol Metab. 2016;5:233–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Liao Y, Xing S, Xu B, Liu W, Zhang G. Evaluation of the circulating level of fibroblast activation protein α for diagnosis of esophageal squamous cell carcinoma. Oncotarget. 2017;8:30050–62.

    PubMed  PubMed Central  Google Scholar 

  26. Lessard J, Pelletier M, Biertho L, Biron S, Marceau S, Hould F-S, et al. Characterization of dedifferentiating human mature adipocytes from the visceral and subcutaneous fat compartments: fibroblast-activation protein alpha and dipeptidyl peptidase 4 as major components of matrix remodeling. PLoS ONE. 2015;10:e0122065.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Busek P, Hrabal P, Fric P, Sedo A. Co-expression of the homologous proteases fibroblast activation protein and dipeptidyl peptidase-IV in the adult human Langerhans islets. Histochem Cell Biol. 2015;143:497–504.

    Article  PubMed  CAS  Google Scholar 

  28. Arnold JN, Magiera L, Kraman M, Fearon DT. Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1. Cancer Immunol Res. 2014;2:121–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Tchou J, Zhang PJ, Bi Y, Satija C, Marjumdar R, Stephen TL, et al. Fibroblast activation protein expression by stromal cells and tumor-associated macrophages in human breast cancer. Hum Pathol. 2013;44:2549–57. https://doi.org/10.1016/j.humpath.2013.06.016.

    Article  PubMed  CAS  Google Scholar 

  30. Wäster P, Orfanidis K, Eriksson I, Rosdahl I, Seifert O, Öllinger K. UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins–TGF-β1–FAP-α. Br J Cancer. 2017;117:535–44. https://doi.org/10.1038/bjc.2017.182.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Du H, Chen D, Zhou Y, Han Z, Che G. Fibroblast phenotypes in different lung diseases. J Cardiothorac Surg. 2014;9:147.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ivanov VN, Lopez Bergami P, Maulit G, Sato T-A, Sassoon D, Ronai Z. FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface. Mol Cell Biol. 2003;23:3623–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827–30.

    Article  PubMed  CAS  Google Scholar 

  34. Park SY, Kim HM, Koo JS. Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer. Breast Cancer Res Treat. 2015;149:727–41.

    Article  PubMed  CAS  Google Scholar 

  35. Park CK, Jung WH, Koo JS. Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma. Breast Cancer Res Treat. 2016;159:55–69. https://doi.org/10.1007/s10549-016-3929-2.

    Article  PubMed  CAS  Google Scholar 

  36. Yang Jung Y, Kyung Lee Y, Seung Koo J. Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer. Tumor Biol. 2016;36:8685–95.

  37. Kawase T, Yasui Y, Nishina S, Hara Y, Yanatori I, Tomiyama Y, et al. Fibroblast activation protein-α-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. BMC Gastroenterol. 2015;15:109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Lo A, Li C-P, Buza EL, Blomberg R, Govindaraju P, Avery D, et al. Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma. JCI Insight. 2017. https://insight.jci.org/articles/view/92232#sd. Accessed 30 Oct 2017.

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

  40. Miao Z-F, Zhao T-T, Wang Z-N, Miao F, Xu Y-Y, Mao X-Y, et al. Tumor-associated mesothelial cells are negative prognostic factors in gastric cancer and promote peritoneal dissemination of adherent gastric cancer cells by chemotaxis. Tumor Biol. 2014;35:6105–11. https://doi.org/10.1007/s13277-014-1808-1.

    Article  CAS  Google Scholar 

  41. Kahounová Z, Kurfürstová D, Bouchal J, Kharaishvili G, Navrátil J, Remšík J, et al. The fibroblast surface markers FAP, anti-fibroblast, and FSP are expressed by cells of epithelial origin and may be altered during epithelial-to-mesenchymal transition. Cytom Part A. 2017. https://doi.org/10.1002/cyto.a.23101.

  42. Wolczyk D, Zaremba-Czogalla M, Hryniewicz-Jankowska A, Tabola R, Grabowski K, Sikorski AF, et al. TNF-α promotes breast cancer cell migration and enhances the concentration of membrane-associated proteases in lipid rafts. Cell Oncol. 2016;39:353–63.

    Article  CAS  Google Scholar 

  43. Pearl ML, Dong H, Tulley S, Zhao Q, Golightly M, Zucker S, et al. Treatment monitoring of patients with epithelial ovarian cancer using invasive circulating tumor cells (iCTCs). Gynecol Oncol. 2015;137:229–38.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Liu F, Qi L, Liu B, Liu J, Zhang H, Che D, et al. Fibroblast activation protein overexpression and clinical implications in solid tumors: a meta-analysis. PLoS ONE. 2015;10:e0116683.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. López JI, Errarte P, Erramuzpe A, Guarch R, Cortés JM, Angulo JC, et al. Fibroblast activation protein predicts prognosis in clear cell renal cell carcinoma. Hum Pathol. 2016;54:100–5.

    Article  PubMed  CAS  Google Scholar 

  46. Errarte P, Guarch R, Pulido R, Blanco L, Nunes-Xavier CE, Beitia M, et al. The expression of fibroblast activation protein in clear cell renal cell carcinomas is associated with synchronous lymph node metastases. PLoS ONE. 2016;11:e0169105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Chen L, Qiu X, Wang X, He J. FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression. Biochem Biophys Res Commun. 2017;487:8–14.

    Article  PubMed  CAS  Google Scholar 

  48. Wen X, He X, Jiao F, Wang C, Sun Y, Ren X, et al. Fibroblast activation protein-α-positive fibroblasts promote gastric cancer progression and resistance to immune checkpoint blockade. Oncol Res Featur Preclin Clin Cancer Ther. 2017;25:629–40. https://doi.org/10.3727/096504016X14768383625385.

    Article  Google Scholar 

  49. Hu M, Qian C, Hu Z, Fei B, Zhou H. Biomarkers in tumor microenvironment? Upregulation of fibroblast activation protein-α correlates with gastric cancer progression and poor prognosis. Omi AJ Integr Biol. 2017;2:38–44.

    Article  CAS  Google Scholar 

  50. Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3–CCL2 signaling. Cancer Res. 2016;76:4124–35.

  51. Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y, et al. Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. Cell Death Dis. 2014;5:e1155.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Mhawech-Fauceglia P, Yan L, Sharifian M, Ren X, Liu S, Kim G, et al. Stromal expression of fibroblast activation protein alpha (FAP) predicts platinum resistance and shorter recurrence in patients with epithelial ovarian cancer. Cancer Microenviron. 2015;8:23–31.

    Article  PubMed  CAS  Google Scholar 

  53. Kim GJ, Rhee H, Yoo JE, Ko JE, Lee JS, Kim H, et al. Increased expression of CCN2, epithelial membrane antigen, and fibroblast activation protein in hepatocellular carcinoma with fibrous stroma showing aggressive behavior. PLoS ONE. 2014;9:e105094.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Ha SY, Yeo S-Y, Xuan Y, Kim S-H. The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma. PLoS ONE. 2014;9:e99955.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Werner S, Krause F, Rolny V, Strobl M, Morgenstern D, Datz C, et al. Evaluation of a 5-marker blood test for colorectal cancer early detection in a colorectal cancer screening setting. Clin Cancer Res. 2016;22:1725–33.

  56. Park J-I, Lee J, Kwon J-L, Park H-B, Lee S-Y, Kim J-Y, et al. Scaffold-free coculture spheroids of human colonic adenocarcinoma cells and normal colonic fibroblasts promote tumorigenicity in nude mice. Transl Oncol. 2016;9:79–88.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Zi F-M, He J-S, Li Y, Wu C, Wu W-J, Yang Y, et al. Fibroblast activation protein protects bortezomib-induced apoptosis in multiple myeloma cells through β-catenin signaling pathway. Cancer Biol Ther. 2014;15:1413–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Wu X, Wang Y, Xu J, Luo T, Deng J, Hu Y, et al. MM-BMSCs induce naïve CD4+ T lymphocytes dysfunction through fibroblast activation protein α. Oncotarget. 2017;8:52614–28.

  59. Yang J, Miao Y, Chang Y, Zhang F, Wang Y, Zheng S. Condition medium of HepG-2 cells induces the transdifferentiation of human umbilical cord mesenchymal stem cells into cancerous mesenchymal stem cells. Am J Transl Res. 2016;8:3429–38.

    PubMed  PubMed Central  CAS  Google Scholar 

  60. Cui Y, Sun S, Ren K, Quan M, Song Z, Zou H, et al. Reversal of liver cancer-associated stellate cell-induced stem-like characteristics in SMMC-7721 cells by 8-bromo-7-methoxychrysin via inhibiting STAT3 activation. Oncol Rep. 2016;35:2952–62.

    Article  PubMed  CAS  Google Scholar 

  61. Chung K-M, Hsu S-C, Chu Y-R, Lin M-Y, Jiaang W-T, Chen R-H, et al. Fibroblast activation protein (FAP) is essential for the migration of bone marrow mesenchymal stem cells through RhoA activation. PLoS ONE. 2014;9:e88772.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Sorrentino C, Miele L, Porta A, Pinto A, Morello S. Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression. Oncotarget. 2016;7:64274–88.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Wang L, Yang D, Tian J, Gao A, Shen Y, Ren X, et al. Tumor necrosis factor receptor 2/AKT and ERK signaling pathways contribute to the switch from fibroblasts to CAFs by progranulin in microenvironment of colorectal cancer. Oncotarget. 2017;8:26323–33.

    PubMed  PubMed Central  Google Scholar 

  64. Luo N, Guan Q, Zheng L, Qu X, Dai H, Cheng Z. Estrogen-mediated activation of fibroblasts and its effects on the fibroid cell proliferation. Transl Res. 2014;16:232–41.

    Article  CAS  Google Scholar 

  65. Jia B, Gao Y, Li M, Shi J, Peng Y, Du X, et al. GPR30 promotes prostate stromal cell activation via suppression of ERα expression and its downstream signaling pathway. Endocrinology. 2016;157:3023–35. https://doi.org/10.1210/en.2016-1035.

    Article  PubMed  CAS  Google Scholar 

  66. Wei M, Yang T, Chen X, Wu Y, Deng X, He W, et al. Malignant ascites-derived exosomes promote proliferation and induce carcinoma-associated fibroblasts transition in peritoneal mesothelial cells. Oncotarget. 2017;8:42262–71.

    PubMed  PubMed Central  Google Scholar 

  67. Guo J, Zheng L, Chen L, Luo N, Yang W, Qu X, et al. Lipopolysaccharide activated TLR4/NF-κB signaling pathway of fibroblasts from uterine fibroids. Int J Clin Exp Pathol. 2015;8:10014–25.

    PubMed  PubMed Central  CAS  Google Scholar 

  68. Park Y-J, Kim EK, Bae JY, Moon S, Kim J. Human telomerase reverse transcriptase (hTERT) promotes cancer invasion by modulating cathepsin D via early growth response (EGR)-1. Cancer Lett. 2016;370:222–31.

    Article  PubMed  CAS  Google Scholar 

  69. Zhang J, Valianou M, Cheng JD. Identification and characterization of the promoter of fibroblast activation protein. Front Biosci. 2010;2:1154–63.

    Google Scholar 

  70. Tulley S, Chen W-T. Transcriptional regulation of seprase in invasive melanoma cells by transforming growth factor-β signaling. J Biol Chem. 2014;289:15280–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Gong Q, Shi W, Li L, Wu X, Ma H. Ultrasensitive fluorescent probes reveal an adverse action of dipeptide peptidase IV and fibroblast activation protein during proliferation of cancer cells. Anal Chem. 2016;88:8309–14. https://doi.org/10.1021/acs.analchem.6b02231.

    Article  PubMed  CAS  Google Scholar 

  72. Kuiper GGJM, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology. 1998;139:4252–63.

    Article  PubMed  CAS  Google Scholar 

  73. Prossnitz ER, Barton M. Estrogen biology: new insights into GPER function and clinical opportunities. Mol Cell Endocrinol. 2014;389:71–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Ruan P, Tan A, Tao Z. Low expression of miR-30a-5p induced the proliferation and invasion of oral cancer via promoting the expression of FAP. Biosci Rep. 2017;38. http://www.ncbi.nlm.nih.gov/pubmed/29026005. Accessed 16 Oct 2017.

  75. Ha Q, Yang G, Ao Z, Han D, Niu F, Wang S, et al. Rapid fibroblast activation in mammalian cells induced by silicon nanowire arrays. Nanoscale. 2014;6:8318.

    Article  PubMed  CAS  Google Scholar 

  76. Qi S, Yi C, Ji S, Fong C-C, Yang M. Cell adhesion and spreading behavior on vertically aligned silicon nanowire arrays. ACS Appl Mater Interfaces. 2009;1(1):30–4.

  77. Kuo S-W, Lin H-I, Hui J, Ho -Chun, Shih Y-RV, Chen H-F, et al. Regulation of the fate of human mesenchymal stem cells by mechanical and stereo-topographical cues provided by silicon nanowires. Biomaterials. 2012;33:5013–22.

    Article  PubMed  CAS  Google Scholar 

  78. Avery D, Govindaraju P, Jacob M, Todd L, Monslow J, Puré E. Extracellular matrix directs phenotypic heterogeneity of activatedfibroblasts. Matrix Biol [Internet]. 2018 Apr [cited 2018 Apr 20];67:90–106. http://www.ncbi.nlm.nih.gov/pubmed/29248556..

  79. Wonganu B, Berger BW. A specific, transmembrane interface regulates fibroblast activation protein (FAP) homodimerization, trafficking and exopeptidase activity. Biochim Biophys Acta. 2016;185:1876–82.

    Article  CAS  Google Scholar 

  80. Osborne B, Yao T-W, Wang XM, Chen Y, Kotan LD, Nadvi NA, et al. A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation. Biochim Biophys Acta Proteom. 2014;1844:1248–59.

    Article  CAS  Google Scholar 

  81. Mueller SC, Ghersi G, Akiyama SK, Sang QX, Howard L, Pineiro-Sanchez M, et al. A novel protease-docking function of integrin at invadopodia. J Biol Chem. 1999;274:24947–52.

    Article  PubMed  CAS  Google Scholar 

  82. Knopf JD, Tholen S, Koczorowska MM, De Wever O, Biniossek ML, Schilling O. The stromal cell-surface protease fibroblast activation protein-α localizes to lipid rafts and is recruited to invadopodia. Biochim Biophys Acta. 2015;1853:2515–25.

  83. Keane FM, Nadvi NA, Yao T-W, Gorrell MD. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α. FEBS J. 2011;27:1316–32. https://doi.org/10.1111/j.1742-4658.2011.08051.x.

    Article  CAS  Google Scholar 

  84. Wong PF, Gall MG, Bachovchin WW, McCaughan GW, Keane FM, Gorrell MD Neuropeptide Y is a physiological substrate of fibroblast activation protein: Enzyme kinetics in blood plasma and expression of Y2R and Y5R in human liver cirrhosis and hepatocellular carcinoma. Peptides. 2016;75:80–95.

  85. Grindel BJ, Martinez JR, Pennington CL, Muldoon M, Stave J, Chung LW, et al. Matrilysin/matrix metalloproteinase-7(MMP7) cleavage of perlecan/HSPG2 creates a molecular switch to alter prostate cancer cell behavior. Matrix Biol. 2014;36:64–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Fan M-H, Zhu Q, Li H-H, Ra H-J, Majumdar S, Gulick DL, et al. Fibroblast activation protein (FAP) accelerates collagen degradation and clearance from lung in mice. J Biol Chem. 2015;291:8070–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Christiansen VJ, Jackson KW, Lee KN, McKee PA. Effect of fibroblast activation protein and α2-antiplasmin cleaving enzyme on collagen types I, III, and IV. Arch Biochem Biophys. 2007;457:177–86.

    Article  PubMed  CAS  Google Scholar 

  88. Mazur A, Holthoff E, Vadali S, Kelly T, Post SR. Cleavage of type I collagen by fibroblast activation protein-α enhances class a scavenger receptor mediated macrophage adhesion. PLoS ONE. 2016;11:e0150287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Koczorowska MM, Tholen S, Bucher F, Lutz L, Kizhakkedathu JN, De Wever O, et al. Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations. Mol Oncol. 2016;10:40–58.

    Article  PubMed  CAS  Google Scholar 

  90. Luo Y, Ye S, Chen X, Gong F, Lu W, Li X. Rush to the fire: FGF21 extinguishes metabolic stress, metaflammation and tissue damage. Cytokine Growth Factor Rev. 2017. http://www.ncbi.nlm.nih.gov/pubmed/28887067. Accessed 30 Oct 2017.

  91. Coppage AL, Heard KR, DiMare MT, Liu Y, Wu W, Lai JH, et al. Human FGF-21 is a substrate of fibroblast activation protein. PLoS One. 2016;11:e0151269.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Dunshee DR, Bainbridge TW, Kljavin NM, Zavala-Solorio J, Schroeder AC, Chan R, et al. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J Biol Chem. 2016;291:5986–96. https://doi.org/10.1074/jbc.M115.710582.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Zhen EY, Jin Z, Ackermann BL, Thomas MK, Gutierrez JA. Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem J. 2016;473:605–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Santos A, Jung J, Aziz N, Kissil J. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin. 2009;119:3613–25.

    CAS  Google Scholar 

  95. Baird SK, Allan L, Renner C, Scott FE, Scott AM. Fibroblast activation protein increases metastatic potential of fibrosarcoma line HT1080 through upregulation of integrin-mediated signaling pathways. Clin Exp Metastas. 2015;32:507–16. https://doi.org/10.1007/s10585-015-9723-4.

    Article  CAS  Google Scholar 

  96. Tansi FL, Rüger R, Böhm C, Kontermann RE, Teichgraeber UK, Fahr A, et al. Dataset on FAP-induced emergence of spontaneous metastases and on the preparation of activatable FAP-targeting immunoliposomes to detect the metastases. Data Br. 2016;9:143–8.

    Article  Google Scholar 

  97. Baird SK, Rigopoulos A, Cao D, Allan L, Renner C, Scott FE, et al. Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms. Apoptosis. 2015;20:1483–98. https://doi.org/10.1007/s10495-015-1166-5.

    Article  PubMed  CAS  Google Scholar 

  98. Tulley S, Chen W-T. Transcriptional regulation of seprase in invasive melanoma cells by transforming growth factor-β signaling. J Biol Chem. 2014;289:15280–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Ding L, Ye L, Xu J, Jiang WG. Impact of fibroblast activation protein on osteosarcoma cell lines in vitro. Oncol Lett. 2014;7:699–704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Jia J, Martin TA, Ye L, Jiang WG. 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. 2014;15:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Teichgräber V, Monasterio C, Chaitanya K, Boger R, Gordon K, Dieterle T, et al. Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumor progression in vitro. Adv Med Sci. 2015;60:264–72.

    Article  PubMed  Google Scholar 

  102. Lv B, Xie F, Zhao P, Ma X, Jiang WG, Yu J, et al. Promotion of cellular growth and motility is independent of enzymatic activity of fibroblast activation protein-α. Cancer Genom Proteom. 2016;1:201–8.

    Google Scholar 

  103. Lee J, Fassnacht M, Nair S, Boczkowski D, Gilboa E. Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res. 2005;65:11156–63.

    Article  PubMed  CAS  Google Scholar 

  104. Loeffler M, Krüger JA, Niethammer AG, Reisfeld RA. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest. 2006;116:1955–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Ostermann E, Garin-Chesa P, Heider KH, Kalat M, Lamche H, Puri C, et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res. 2008;14:4584–92.

    Article  PubMed  CAS  Google Scholar 

  106. Xia Q, Zhang F-F, Geng F, Liu C-L, Xu P, Lu Z-Z, et al. Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model. Cancer Immunol Immunother. 2016;6:613–24. https://doi.org/10.1007/s00262-016-1827-4.

    Article  CAS  Google Scholar 

  107. Xia Q, Geng F, Zhang FF, Liu CL, Xu P, Lu ZZ, et al. Enhancement of fibroblast activation protein α-based vaccines and adenovirus boost immunity by cyclophosphamide through inhibiting IL-10 expression in 4T1 tumor bearing mice. Vaccine. 2016;34:4526–35.

    Article  PubMed  CAS  Google Scholar 

  108. Xia Q, Zhang FF, Geng F, Liu CL, Wang YQ, Xu P, et al. Improvement of anti-tumor immunity of fibroblast activation protein α based vaccines by combination with cyclophosphamide in a murine model of breast cancer. Cell Immunol. 2016;310:89–98.

    Article  PubMed  CAS  Google Scholar 

  109. Xia Q, Geng F, Zhang F-F, Liu C-L, Xu P, Lu Z-Z, et al. Cyclophosphamide enhances anti-tumor effects of a fibroblast activation protein α-based DNA vaccine in tumor-bearing mice with murine breast carcinoma. Immunopharmacol Immunotoxicol. 2017;39:37–44. https://doi.org/10.1080/08923973.2016.1269337.

    Article  PubMed  CAS  Google Scholar 

  110. Zhang Y, Ertl HCJ. Depletion of FAP+cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors. Oncotarget. 2016;7:23282–99.

    PubMed  PubMed Central  Google Scholar 

  111. Jiang G-M, Xie W-Y, Wang H-S, Du J, Wu B-P, Xu W, et al. Curcumin combined with FAPαc vaccine elicits effective antitumor response by targeting indolamine-2,3-dioxygenase and inhibiting EMT induced by TNF-α in melanoma. Oncotarget. 2015;6:25932–42.

    PubMed  PubMed Central  Google Scholar 

  112. Meng M, Wang W, Yan J, Tan J, Liao L, Shi J, et al. Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model. Tumor Biol. 2016;37:10317–27. https://doi.org/10.1007/s13277-016-4825-4.

    Article  CAS  Google Scholar 

  113. Chen M, Xiang R, Wen Y, Xu G, Wang C, Luo S, et al. A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts. Sci Rep. 2015;5:14421.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Zhen Z, Tang W, Wang M, Zhou S, Wang H, Wu Z, et al. Protein nanocage mediated fibroblast-activation protein targeted photoimmunotherapy to enhance cytotoxic T cell infiltration and tumor control. Nano Lett. 2017;17:862–9. https://doi.org/10.1021/acs.nanolett.6b04150.

    Article  PubMed  CAS  Google Scholar 

  115. Fang J, Xiao L, Joo K-I, Liu Y, Zhang C, Liu S, et al. A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int J Cancer. 2016;138:1013–23.

    Article  PubMed  CAS  Google Scholar 

  116. Fang J, Hu B, Li S, Zhang C, Liu Y, Wang P. A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma. Mol Ther Oncolytics. 2016;3:16007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Huang T, Wang H, Chen NG, Frentzen A, Minev B, Szalay AA. Expression of anti-VEGF antibody together with anti-EGFR or anti-FAP enhances tumor regression as a result of vaccinia virotherapy. Mol Ther Oncolytics. 2015;2:15003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Brünker P, Wartha K, Friess T, Grau-Richards S, Waldhauer I, Koller CF, et al. RG7386, a novel tetravalent FAP-DR5 antibody, effectively triggers FAP-dependent, avidity-driven DR5 hyperclustering and tumor cell apoptosis. Mol Cancer Ther. 2016;1:946–57.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  120. Rabenhold M, Steiniger F, Fahr A, Kontermann RE, Rüger R. Bispecific single-chain diabody-immunoliposomes targeting endoglin (CD105) and fibroblast activation protein (FAP) simultaneously. J Control Release. 2015;201:56–67.

    Article  PubMed  CAS  Google Scholar 

  121. Tansi FL, Rüger R, Ohm CB, Kontermann RE, Teichgraeber UK, Fahr A, et al. Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases. Biomaterials. 2016;88:70–82.

  122. Tansi FL, Rüger R, Böhm C, Steiniger F, Kontermann RE, Teichgraeber UK, et al. Activatable bispecific liposomes bearing fibroblast activation protein directed single chain fragment/Trastuzumab deliver encapsulated cargo into the nuclei of tumor cells and the tumor microenvironment simultaneously. Acta Biomater. 2017;54:281–93. https://doi.org/10.1016/j.actbio.2017.03.033.

    Article  PubMed  CAS  Google Scholar 

  123. Kakarla S, Chow KKH, Mata M, Shaffer DR, Song X-T, Wu M-F, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther. 2013;21:1611–20. https://doi.org/10.1038/mt.2013.110.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2:154–66.

    Article  PubMed  CAS  Google Scholar 

  125. Lo A, Wang L-CS, Scholler J, Monslow J, Avery D, Newick K, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015;75:2800–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Hofheinz R-D, al-Batran S-E, Hartmann F, Hartung G, Jäger D, Renner C, et al. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Oncol Res Treat. 2003;26:44–8.

    Article  CAS  Google Scholar 

  127. Deng L-J, Wang L-H, Peng C-K, Li Y-B, Huang M-H, Chen M-F, et al. Fibroblast activation protein α activated tripeptide bufadienolide antitumor prodrug with reduced cardiotoxicity. J Med Chem. 2017;60:5320–33. https://doi.org/10.1021/acs.jmedchem.6b01755.

    Article  PubMed  CAS  Google Scholar 

  128. Brennen WN, Rosen DM, Chaux A, Netto GJ, Isaacs JT, Denmeade SR. Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer. Prostate. 2014;74:1308–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Akinboye ES, Brennen WN, Rosen DM, Bakare O, Denmeade SR. Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy. Prostate. 2016;76:703–14.

    Article  PubMed  CAS  Google Scholar 

  130. Ke MR, Chen SF, Peng XH, Zheng QF, Zheng BY, Yeh CK, et al. A tumor-targeted activatable phthalocyanine-tetrapeptide-doxorubicin conjugate for synergistic chemo-photodynamic therapy. Eur J Med Chem. 2017;127:200–9.

    Article  PubMed  CAS  Google Scholar 

  131. Zhang Y, Zhang X, Liu H, Cai S, Wu B. Mixed nanomicelles as potential carriers for systemic delivery of Z-GP-Dox, an FAPα-based doxorubicin prodrug: formulation and pharmacokinetic evaluation. Int J Nanomed. 2015;10:1625–36.

    CAS  Google Scholar 

  132. Ji T, Zhao Y, Ding Y, Wang J, Zhao R, Lang J, et al. Transformable peptide nanocarriers for expeditious drug release and effective cancer therapy via cancer-associated fibroblast activation. Angew Chem Int Ed Engl. 2016;55:1050–5.

    Article  PubMed  CAS  Google Scholar 

  133. Kim M-G, Shon Y, Kim J, Oh Y-K. Selective activation of anticancer chemotherapy by cancer-associated fibroblasts in the tumor microenvironment. J Natl Cancer Inst. 2017;109:djw186 https://doi.org/10.1093/jnci/djw186.

    Article  PubMed  Google Scholar 

  134. Feng X, Wang Q, Liao Y, Zhou X, Wang Y, Liu W, et al. A synthetic urinary probe-coated nanoparticles sensitive to fibroblast activation protein α for solid tumor diagnosis. Int J Nanomed. 2017;12:5359–72.

    Article  Google Scholar 

  135. Bainbridge TW, Dunshee DR, Kljavin NM, Skelton NJ, Sonoda J, Ernst JA. Selective homogeneous assay for circulating endopeptidase fibroblast activation protein (FAP). Sci Rep. 2017;7:12524.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Narra K, Mullins SR, Lee H-O, Strzemkowski-Brun B, Magalong K, Christiansen VJ, et al. Phase II trial of single agent Val-boroPro (talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer. Cancer Biol Ther. 2007;6:1691–9.

    Article  PubMed  CAS  Google Scholar 

  137. Eager RM, Cunningham CC, Senzer N, Richards DA, Raju RN, Jones B, et al. Phase II trial of talabostat and docetaxel in advanced non-small cell lung cancer. Clin Oncol. 2009;21:464–72.

    Article  CAS  Google Scholar 

  138. Eager RM, Cunningham CC, Senzer NN, Stephenson J, Anthony SP, O’Day SJ, et al. Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma. BMC Cancer. 2009;9:263.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Li M, Li M, Yin T, Shi H, Wen Y, Zhang B, et al. Targeting of cancer‑associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment. Mol Med Rep. 2016;1:2476–84.

    Article  CAS  Google Scholar 

  140. Jackson KW, Christiansen VJ, Yadav VR, Silasi-Mansat R, Lupu F, Awasthi V, et al. Suppression of tumor growth in mice by rationally designed pseudopeptide inhibitors of fibroblast activation protein and prolyl oligopeptidase. Neoplasia. 2015;17:43–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Jansen K, Heirbaut L, Verkerk R, Cheng JD, Joossens J, Cos P, et al. Extended structure–activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J Med Chem. 2014;5:3053–74. https://doi.org/10.1021/jm500031w.

    Article  CAS  Google Scholar 

  142. Dvořáková P, Bušek P, Knedlík T, Schimer J, Etrych T, Kostka L, et al. Inhibitor-decorated polymer conjugates targeting fibroblast activation protein. J Med Chem. 2017;60:8385–93.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ellen Puré.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Puré, E., Blomberg, R. Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. Oncogene 37, 4343–4357 (2018). https://doi.org/10.1038/s41388-018-0275-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0275-3

This article is cited by

Search

Quick links