Current status and perspective in research of fibroblast activation protein_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

TANG Sumin , ZHANG Bo ,  CHEN Zhixin

Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

CHEN Zhixin, Email: chenzhixin@medmail.com.cn

Keywords：

fibroblast activation protein; tumor; targeted therapy

DOI：

10.7507/1007-9424.201701006

Video：

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Objective To summarize functions and mechanisms of fibroblast activation protein (FAP) and its application in targeted therapy. Method Literatures about FAP in recent years were collected to make a review. Results Thereis an important relationship between the FAP and the dipeptidyl peptidase-Ⅳ. FAP has a serine protease activity and is an important immunosuppressive component in the tumor microenvironment. FAP participate in the pathological process of the neoplastic and the non-neoplastic diseases. In the targeted therapy, the enzyme inhibitors, antibodies, vaccines, and prodrugs of FAP had been extensively studied. Conclusion FAP have various functions and participates in pathological process of many diseases, and it is of great significance to research of tumor targeted therapy.

Citation： TANG Sumin, ZHANG Bo, CHEN Zhixin. Current status and perspective in research of fibroblast activation protein. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(10): 1284-1288. doi: 10.7507/1007-9424.201701006 Copy

1.	Collins PJ, McMahon G, O’Brien P, et al. Purification, identification and characterisation of seprase from bovine serum. Int J Biochem Cell Biol, 2004, 36(11): 2320-2333.
2.	Lee KN, Jackson KW, Christiansen VJ, et al. Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein. Blood, 2006, 107(4): 1397-1404.
3.	Tillmanns J, Fraccarollo D, Galuppo P, et al. Changes in concentrations of circulating fibroblast activation protein alpha are associated with myocardial damage in patients with acute ST-elevation MI. Int J Cardiol, 2017, 232: 155-159.
4.	Wild N, Andres H, Rollinger W, et al. A combination of serum markers for the early detection of colorectal cancer. Clin Cancer Res, 2010, 16(24): 6111-6121.
5.	Hamson EJ, Keane FM, Tholen S, et al. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl, 2014, 8(5-6): 454-463.
6.	Yamaguchi U, Honda K, Yamada T. Gene expression profiling of gastrointestinal stromal tumor: implications for clinical management. European J Clin Med Oncol, 2010, 2(2): 1-4.
7.	Baerts L, Brouns R, Kehoe K, et al. Acute ischemic stroke severity, progression, and outcome relate to changes in dipeptidyl peptidase Ⅳ and fibroblast activation protein activity. Transl Stroke Res, 2017, 8(2): 157-164.
8.	Busek P, Hrabal P, Fric P, et al. Co-expression of the homologous proteases fibroblast activation protein and dipeptidyl peptidase-Ⅳ in the adult human Langerhans islets. Histochem Cell Biol, 2015, 143(5): 497-504.
9.	Keane FM, Nadvi NA, Yao TW, et al. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α. FEBS J, 2011, 278(8): 1316-1332.
10.	Christiansen VJ, Jackson KW, Lee KN, et al. Effect of fibroblast activation protein and alpha2-antiplasmin cleaving enzyme on collagen types Ⅰ, Ⅲ, and Ⅳ. Arch Biochem Biophys, 2007, 457(2): 177-186.
11.	Sánchez-Garrido MA, Habegger KM, Clemmensen C, et al. Fibroblast activation protein (FAP) as a novel metabolic target. Mol Metab, 2016, 5(10): 1015-1024.
12.	Jiang GM, Xu W, Du J, et al. The application of the fibroblast activation protein α-targeted immunotherapy strategy. Oncotarget, 2016, 7(22): 33472-33482.
13.	Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science, 2010, 330(6005): 827-830.
14.	Jiang GM, Xie WY, Wang HS, 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(28): 25932-25942.
15.	Wikberg ML, Edin S, Lundberg IV, et al. High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis. Tumour Biol, 2013, 34(2): 1013-1020.
16.	Iwasa S, Jin X, Okada K, et al. Increased expression of seprase, a membrane-type serine protease, is associated with lymph node metastasis in human colorectal cancer. Cancer Lett, 2003, 199(1): 91-98.
17.	Kawase T, Yasui Y, Nishina S, et al. Fibroblast activation protein-alpha-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. BMC Gastroenterol, 2015, 15: 109.
18.	Wang H, Wu Q, Liu Z, 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.
19.	Ariga N, Sato E, Ohuchi N, et al. 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, 2001, 95(1): 67-72.
20.	Ramirez-Montagut T, Blachere NE, Sviderskaya EV, et al. FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor. Oncogene, 2004, 23(32): 5435-5446.
21.	Williams KH, Viera de Ribeiro AJ, Prakoso E, et al. Lower serum fibroblast activation protein shows promise in the exclusion of clinically significant liver fibrosis due to non-alcoholic fatty liver disease in diabetes and obesity. Diabetes Res Clin Pract, 2015, 108(3): 466-472.
22.	Rovedatti L, Di Sabatino A, Knowles CH, et al. Fibroblast activation protein expression in Crohn’s disease strictures. Inflamm Bowel Dis, 2011, 17(5): 1251-1253.
23.	Wäldele S, Koers-Wunrau C, Beckmann D, et al. Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis. Arthritis Res Ther, 2015, 17: 12.
24.	Brokopp CE, Schoenauer R, Richards P, et al. Fibroblast activation protein is induced by inflammation and degrades type Ⅰ collagen in thin-cap fibroatheromata. Eur Heart J, 2011, 32(21): 2713-2722.
25.	Narra K, Mullins SR, Lee HO, 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(11): 1691-1699.
26.	Eager RM, Cunningham CC, Senzer N, et al. Phase Ⅱ trial of talabostat and docetaxel in advanced non-small cell lung cancer. Clin Oncol (R Coll Radiol), 2009, 21(6): 464-472.
27.	Eager RM, Cunningham CC, Senzer NN, et al. Phase Ⅱ assessment of talabostat and cisplatin in second-line stage Ⅳ melanoma. BMC Cancer, 2009, 9: 263.
28.	Hofheinz RD, al-Batran SE, Hartmann F, et al. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie, 2003, 26(1): 44-48.
29.	Kloft C, Graefe EU, Tanswell P, et al. Population pharmacokinetics of sibrotuzumab, a novel therapeutic monoclonal antibody, in cancer patients. Invest New Drugs, 2004, 22(1): 39-52.
30.	Ostermann E, Garin-Chesa P, Heider KH, et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res, 2008, 14(14): 4584-4592.
31.	Fischer E, Chaitanya K, Wüest T, et al. Radioimmunotherapy of fibroblast activation protein positive tumors by rapidly internalizing antibodies. Clin Cancer Res, 2012, 18(22): 6208-6218.
32.	van der Geest T, Laverman P, Gerrits D, et al. Liposomal treatment of experimental arthritis can be monitored noninvasively with a radiolabeled anti-fibroblast activation protein antibody. J Nucl Med, 2017, 58(1): 151-155.
33.	Xia Q, Zhang FF, Geng F, 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, 65(5): 613-624.
34.	Xia Q, Geng F, Zhang FF, 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(1): 37-44.
35.	Wen Y, Wang CT, Ma TT, et al. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci, 2010, 101(11): 2325-2332.
36.	张莉, 陈扬扬, 祝先潮, 等. 一种靶向 FAP 的蛋白疫苗设计及其抗肿瘤保护研究. 安徽师范大学学报(自然科学版), 2014, 37(4): 366-370.0.
37.	Gottschalk S, Yu F, Ji M, et al. A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. PLoS One, 2013, 8(12): e82658.
38.	Brennen WN, Rosen DM, Wang H, et al. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst, 2012, 104(17): 1320-1334.
39.	马伟峰, 杨飞华, 赵海山, 等. FAPα 酶激活式靶向抗肿瘤前药: Z-GP-Dox 对斑马鱼的毒性评价. 中国生物工程杂志, 2012, 32(7): 37-42.0.
40.	Brennen WN, Rosen DM, Chaux A, et al. Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer. Prostate, 2014, 74(13): 1308-1319.

1. Collins PJ, McMahon G, O’Brien P, et al. Purification, identification and characterisation of seprase from bovine serum. Int J Biochem Cell Biol, 2004, 36(11): 2320-2333.
2. Lee KN, Jackson KW, Christiansen VJ, et al. Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein. Blood, 2006, 107(4): 1397-1404.
3. Tillmanns J, Fraccarollo D, Galuppo P, et al. Changes in concentrations of circulating fibroblast activation protein alpha are associated with myocardial damage in patients with acute ST-elevation MI. Int J Cardiol, 2017, 232: 155-159.
4. Wild N, Andres H, Rollinger W, et al. A combination of serum markers for the early detection of colorectal cancer. Clin Cancer Res, 2010, 16(24): 6111-6121.
5. Hamson EJ, Keane FM, Tholen S, et al. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl, 2014, 8(5-6): 454-463.
6. Yamaguchi U, Honda K, Yamada T. Gene expression profiling of gastrointestinal stromal tumor: implications for clinical management. European J Clin Med Oncol, 2010, 2(2): 1-4.
7. Baerts L, Brouns R, Kehoe K, et al. Acute ischemic stroke severity, progression, and outcome relate to changes in dipeptidyl peptidase Ⅳ and fibroblast activation protein activity. Transl Stroke Res, 2017, 8(2): 157-164.
8. Busek P, Hrabal P, Fric P, et al. Co-expression of the homologous proteases fibroblast activation protein and dipeptidyl peptidase-Ⅳ in the adult human Langerhans islets. Histochem Cell Biol, 2015, 143(5): 497-504.
9. Keane FM, Nadvi NA, Yao TW, et al. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α. FEBS J, 2011, 278(8): 1316-1332.
10. Christiansen VJ, Jackson KW, Lee KN, et al. Effect of fibroblast activation protein and alpha2-antiplasmin cleaving enzyme on collagen types Ⅰ, Ⅲ, and Ⅳ. Arch Biochem Biophys, 2007, 457(2): 177-186.
11. Sánchez-Garrido MA, Habegger KM, Clemmensen C, et al. Fibroblast activation protein (FAP) as a novel metabolic target. Mol Metab, 2016, 5(10): 1015-1024.
12. Jiang GM, Xu W, Du J, et al. The application of the fibroblast activation protein α-targeted immunotherapy strategy. Oncotarget, 2016, 7(22): 33472-33482.
13. Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science, 2010, 330(6005): 827-830.
14. Jiang GM, Xie WY, Wang HS, 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(28): 25932-25942.
15. Wikberg ML, Edin S, Lundberg IV, et al. High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis. Tumour Biol, 2013, 34(2): 1013-1020.
16. Iwasa S, Jin X, Okada K, et al. Increased expression of seprase, a membrane-type serine protease, is associated with lymph node metastasis in human colorectal cancer. Cancer Lett, 2003, 199(1): 91-98.
17. Kawase T, Yasui Y, Nishina S, et al. Fibroblast activation protein-alpha-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. BMC Gastroenterol, 2015, 15: 109.
18. Wang H, Wu Q, Liu Z, 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.
19. Ariga N, Sato E, Ohuchi N, et al. 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, 2001, 95(1): 67-72.
20. Ramirez-Montagut T, Blachere NE, Sviderskaya EV, et al. FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor. Oncogene, 2004, 23(32): 5435-5446.
21. Williams KH, Viera de Ribeiro AJ, Prakoso E, et al. Lower serum fibroblast activation protein shows promise in the exclusion of clinically significant liver fibrosis due to non-alcoholic fatty liver disease in diabetes and obesity. Diabetes Res Clin Pract, 2015, 108(3): 466-472.
22. Rovedatti L, Di Sabatino A, Knowles CH, et al. Fibroblast activation protein expression in Crohn’s disease strictures. Inflamm Bowel Dis, 2011, 17(5): 1251-1253.
23. Wäldele S, Koers-Wunrau C, Beckmann D, et al. Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis. Arthritis Res Ther, 2015, 17: 12.
24. Brokopp CE, Schoenauer R, Richards P, et al. Fibroblast activation protein is induced by inflammation and degrades type Ⅰ collagen in thin-cap fibroatheromata. Eur Heart J, 2011, 32(21): 2713-2722.
25. Narra K, Mullins SR, Lee HO, 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(11): 1691-1699.
26. Eager RM, Cunningham CC, Senzer N, et al. Phase Ⅱ trial of talabostat and docetaxel in advanced non-small cell lung cancer. Clin Oncol (R Coll Radiol), 2009, 21(6): 464-472.
27. Eager RM, Cunningham CC, Senzer NN, et al. Phase Ⅱ assessment of talabostat and cisplatin in second-line stage Ⅳ melanoma. BMC Cancer, 2009, 9: 263.
28. Hofheinz RD, al-Batran SE, Hartmann F, et al. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie, 2003, 26(1): 44-48.
29. Kloft C, Graefe EU, Tanswell P, et al. Population pharmacokinetics of sibrotuzumab, a novel therapeutic monoclonal antibody, in cancer patients. Invest New Drugs, 2004, 22(1): 39-52.
30. Ostermann E, Garin-Chesa P, Heider KH, et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res, 2008, 14(14): 4584-4592.
31. Fischer E, Chaitanya K, Wüest T, et al. Radioimmunotherapy of fibroblast activation protein positive tumors by rapidly internalizing antibodies. Clin Cancer Res, 2012, 18(22): 6208-6218.
32. van der Geest T, Laverman P, Gerrits D, et al. Liposomal treatment of experimental arthritis can be monitored noninvasively with a radiolabeled anti-fibroblast activation protein antibody. J Nucl Med, 2017, 58(1): 151-155.
33. Xia Q, Zhang FF, Geng F, 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, 65(5): 613-624.
34. Xia Q, Geng F, Zhang FF, 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(1): 37-44.
35. Wen Y, Wang CT, Ma TT, et al. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci, 2010, 101(11): 2325-2332.
36. 张莉, 陈扬扬, 祝先潮, 等. 一种靶向 FAP 的蛋白疫苗设计及其抗肿瘤保护研究. 安徽师范大学学报(自然科学版), 2014, 37(4): 366-370.0.
37. Gottschalk S, Yu F, Ji M, et al. A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. PLoS One, 2013, 8(12): e82658.
38. Brennen WN, Rosen DM, Wang H, et al. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst, 2012, 104(17): 1320-1334.
39. 马伟峰, 杨飞华, 赵海山, 等. FAPα 酶激活式靶向抗肿瘤前药: Z-GP-Dox 对斑马鱼的毒性评价. 中国生物工程杂志, 2012, 32(7): 37-42.0.
40. Brennen WN, Rosen DM, Chaux A, et al. Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer. Prostate, 2014, 74(13): 1308-1319.

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Current status and perspective in research of fibroblast activation protein

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