成纤维细胞活化蛋白在上皮癌中表达的意义及研究进展_West China Medical Journal

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蔡凡 , 彭枫

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Keywords：

成纤维细胞活化蛋白; 上皮癌; 肿瘤间质; 分子靶向治疗; 免疫治疗

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【摘要】　成纤维细胞活化蛋白（fibroblast activation protein，FAP）广泛存在于上皮癌组织中，在肿瘤间质成纤维细胞选择性表达而在正常的成熟组织中几乎不表达，是上皮癌的特异性靶标。FAP具有蛋白酶活性，并且可与其他细胞表面蛋白分子形成复合物，可能作用于细胞信号传导，参与肿瘤间质重塑和血管网的形成，调节肿瘤细胞的生长、分化、黏附和转移。目前，有许多临床前期实验及临床研究报导，靶向FAP能有效抑制上皮癌的生长和转移。FAP将可能成为治疗上皮癌的新靶点。现综述总结了FAP的生物学特性，其表达对上皮癌发生发展的影响，以及靶向FAP的抗肿瘤研究进展。

Citation： 蔡凡,彭枫. 成纤维细胞活化蛋白在上皮癌中表达的意义及研究进展. West China Medical Journal, 2011, 26(8): 1268-1271. doi: Copy

1.	Roskelley CD, Bissell MJ. The dominance of microenvironment in breast and ovarian cancer[J]. Cancer Biol, 2002, 12(2):97-104.
2.	Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development[J]. Annu Rev Pathol, 2006, 1: 119-150.
3.	Koyama H, Kobayashi N, Harada M, et al. Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis: pivotal role of a hyaluronan-rich tumor microenvironment[J]. Am J Pathol, 2008, 172(1): 179-193.
4.	Scanlan MJ, Raj BK, Calvo B, et al. Molecular cloning of fibroblast activation protein, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers[J]. Proc Natl Acad Sci USA, 1994, 91(12): 5657-5661.
5.	Pineiro-Sanchez ML, Goldstein LA, Dodt J, et al. Identification of the 170 kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease[J]. J Biol Chem, 1997, 272(12): 7595-7601.
6.	O’Brien P, O’Connor BF. Seprase:an overview of an important matrix serine protease[J].Biochim Biophys Acta, 2008, 1784(9): 1130-1145.
7.	Goldstein LA,Ghersi G,Pieiro-Sánchez ML, et al. Molecular cloning of seprase:a serine integral membrane protease from human melanoma[J]. Biochim Biophys Acta, 1997, 1361(1): 11-19.
8.	Cheng JD, Dunbrack RL Jr, Valianou M, et al. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model[J]. Cancer Res, 2002, 62(16): 4767-4772.
9.	Aertgeerts K, Levin I, Shi L, et al. Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha[J]. J Biol Chem, 2005, 280(20): 19441-19444.
10.	Aggarwal S, Brennen WN, Kole TP, et al. Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites[J]. Biochemistry, 2008, 47(3): 1076-1086.
11.	Kelly T. Fibroblast activation protein-alpha and dipeptidyl peptidase IV (CD26):cell-surface proteases that activate cell signaling and are potential targets for cancer therapy[J]. Drug Resist Updat, 2005, 8(1-2): 51-58.
12.	Cheng JD, Valianou M, Canutescu AA, et al. Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth[J]. Mol Cancer Ther, 2005, 4(3): 351-360.
13.	Kelly T, Kechelava S, Rozypal TL, et al. Seprase, a membrane-bound protease, is overexpressed by invasiveand microinvasive ductal carcinoma cells of human breast cancers[J]. Mod Pathol, 1998, 11(9): 855-863.
14.	Levy MT, McCaughan GW, Abbott CA, et al. Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis[J]. Hepatology, 1999, 29(6):1768-1778.
15.	Tahtis K, Lee FT, Wheatley JM, et al. Expression and targeting of human fibroblast activation protein in a human skin/severe combined immunodeficient mouse breast cancer xenograft model[J]. Mol Cancer Ther, 2003, 2(8): 729-737.
16.	Henry LR, Lee HO, Lee JS, et al. Clinical implications of fibroblast activation protein in patients with colon cancer[J]. Clin Cancer Res, 2007, 13(6): 1736-1741.
17.	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[J]. Int J Cancer, 2001, 95(1): 67-72.
18.	Huang Y, Wang S, Kelly T. Seprase promotes rapid tumor growth and increased microvessel density in a mouse model of human breast cancer[J]. Cancer Res, 2004, 64(8): 2712-2716.
19.	Santos AM, Jung J, Aziz N, et al. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice[J]. J Clin Invest, 2009, 119(12): 3613-3625.
20.	Hayward SW. Preclinical assessment of fibroblast activation protein as a target for antitumor therapy[J]. Future Oncol, 2010, 6(3): 347-349.
21.	Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-α[J]. Science, 2010, 330(6005): 827-830.
22.	Huber MA, Kraut N, Park JE, et al. Fibroblast activation protein: dirential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors[J]. J Invest Dermal, 2003, 120(2): 182-188.
23.	Ramirez-Montagut T, Blachere NE, Sviderskaya EV, et al. FAPalpha, a surface peptidase expressed during wound healing, is a tumor suppressor[J]. Oncogene, 2004, 23(32): 5435-5446.
24.	Wuest T, Moosmayer D, Pfizenmaier K. Construction of a bispecific single chain antibody for recruitment of cytotoxic T cells to the tumour stroma associated antigen fibroblast activation protein[J]. J Biotechnol, 2001, 92(2): 159-168.
25.	Hofheinz RD, al-Batran SE, Hartmann F, et al. Stromal antigen targeting by a humanized monoclonal antibody: an early phase Ⅱ trial of sibrotuzumab in patients with metastatic colorectal cancer[J]. Onkologie. 2003, 26(1): 44-48.
26.	Kloft C, Graefe EU, Tanswell P, et al. Population pharmacokinetics of sibrotuzumab, a novel therapeutic monoclonal antibody, in cancer patients[J]. Invest New Drugs, 2004, 22(1): 39-52.
27.	Liao D, Luo Y, Markowitz D, et al. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model[J]. PLoS One, 2009, 4(11): e7965.
28.	Loeffler M, Krüger JA, Niethammer AG, et al. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake[J]. J Clin Invest, 2006, 116(7): 1955-1962.
29.	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[J]. Cancer Sci, 2010, 101(11): 2325-2332.
30.	LeBeau AM, Brennen WN, Aggarwal S, et al. Targeting cancer stroma with a fibroblast activation protein-activated promelittin protoxin[J]. Mol Cancer Ther, 2009, 8(5): 1378-1386.
31.	Lo PC, Chen J, Stefflova K, et al. Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers[J]. J Med Chem, 2009, 52(2): 358-368.
32.	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[J]. Cancer Biol Ther, 2007, 6(11): 1691-1699.
33.	Eager RM, Cunningham CC, Senzer NN, et al. Phase Ⅱ assessment of talabostat and cisplatin in second-line stage Ⅳ melanoma[J]. BMC Cancer, 2009, 9: 263.
34.	Eager RM, Cunningham CC, Senzer NN, et al. Phase Ⅱ Trial of talabostat and docetaxel in advanced non-small cell lung cancer[J]. Clin Oncol, 2009, 21(6): 464-472.
35.	Tsai TY, Yeh TK, Chen X, et al. Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein[J]. J Med Chem, 2010, 53(18): 6572-6583.

1. 　Roskelley CD, Bissell MJ. The dominance of microenvironment in breast and ovarian cancer[J]. Cancer Biol, 2002, 12(2):97-104.
2. 　Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development[J]. Annu Rev Pathol, 2006, 1: 119-150.
3. 　Koyama H, Kobayashi N, Harada M, et al. Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis: pivotal role of a hyaluronan-rich tumor microenvironment[J]. Am J Pathol, 2008, 172(1): 179-193.
4. 　Scanlan MJ, Raj BK, Calvo B, et al. Molecular cloning of fibroblast activation protein, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers[J]. Proc Natl Acad Sci USA, 1994, 91(12): 5657-5661.
5. 　Pineiro-Sanchez ML, Goldstein LA, Dodt J, et al. Identification of the 170 kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease[J]. J Biol Chem, 1997, 272(12): 7595-7601.
6. 　O’Brien P, O’Connor BF. Seprase:an overview of an important matrix serine protease[J].Biochim Biophys Acta, 2008, 1784(9): 1130-1145.
7. 　Goldstein LA,Ghersi G,Pieiro-Sánchez ML, et al. Molecular cloning of seprase:a serine integral membrane protease from human melanoma[J]. Biochim Biophys Acta, 1997, 1361(1): 11-19.
8. 　Cheng JD, Dunbrack RL Jr, Valianou M, et al. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model[J]. Cancer Res, 2002, 62(16): 4767-4772.
9. 　Aertgeerts K, Levin I, Shi L, et al. Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha[J]. J Biol Chem, 2005, 280(20): 19441-19444.
10. 　Aggarwal S, Brennen WN, Kole TP, et al. Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites[J]. Biochemistry, 2008, 47(3): 1076-1086.
11. 　Kelly T. Fibroblast activation protein-alpha and dipeptidyl peptidase IV (CD26):cell-surface proteases that activate cell signaling and are potential targets for cancer therapy[J]. Drug Resist Updat, 2005, 8(1-2): 51-58.
12. 　Cheng JD, Valianou M, Canutescu AA, et al. Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth[J]. Mol Cancer Ther, 2005, 4(3): 351-360.
13. 　Kelly T, Kechelava S, Rozypal TL, et al. Seprase, a membrane-bound protease, is overexpressed by invasiveand microinvasive ductal carcinoma cells of human breast cancers[J]. Mod Pathol, 1998, 11(9): 855-863.
14. 　Levy MT, McCaughan GW, Abbott CA, et al. Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis[J]. Hepatology, 1999, 29(6):1768-1778.
15. 　Tahtis K, Lee FT, Wheatley JM, et al. Expression and targeting of human fibroblast activation protein in a human skin/severe combined immunodeficient mouse breast cancer xenograft model[J]. Mol Cancer Ther, 2003, 2(8): 729-737.
16. 　Henry LR, Lee HO, Lee JS, et al. Clinical implications of fibroblast activation protein in patients with colon cancer[J]. Clin Cancer Res, 2007, 13(6): 1736-1741.
17. 　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[J]. Int J Cancer, 2001, 95(1): 67-72.
18. 　Huang Y, Wang S, Kelly T. Seprase promotes rapid tumor growth and increased microvessel density in a mouse model of human breast cancer[J]. Cancer Res, 2004, 64(8): 2712-2716.
19. 　Santos AM, Jung J, Aziz N, et al. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice[J]. J Clin Invest, 2009, 119(12): 3613-3625.
20. 　Hayward SW. Preclinical assessment of fibroblast activation protein as a target for antitumor therapy[J]. Future Oncol, 2010, 6(3): 347-349.
21. 　Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-α[J]. Science, 2010, 330(6005): 827-830.
22. 　Huber MA, Kraut N, Park JE, et al. Fibroblast activation protein: dirential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors[J]. J Invest Dermal, 2003, 120(2): 182-188.
23. 　Ramirez-Montagut T, Blachere NE, Sviderskaya EV, et al. FAPalpha, a surface peptidase expressed during wound healing, is a tumor suppressor[J]. Oncogene, 2004, 23(32): 5435-5446.
24. 　Wuest T, Moosmayer D, Pfizenmaier K. Construction of a bispecific single chain antibody for recruitment of cytotoxic T cells to the tumour stroma associated antigen fibroblast activation protein[J]. J Biotechnol, 2001, 92(2): 159-168.
25. 　Hofheinz RD, al-Batran SE, Hartmann F, et al. Stromal antigen targeting by a humanized monoclonal antibody: an early phase Ⅱ trial of sibrotuzumab in patients with metastatic colorectal cancer[J]. Onkologie. 2003, 26(1): 44-48.
26. 　Kloft C, Graefe EU, Tanswell P, et al. Population pharmacokinetics of sibrotuzumab, a novel therapeutic monoclonal antibody, in cancer patients[J]. Invest New Drugs, 2004, 22(1): 39-52.
27. 　Liao D, Luo Y, Markowitz D, et al. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model[J]. PLoS One, 2009, 4(11): e7965.
28. 　Loeffler M, Krüger JA, Niethammer AG, et al. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake[J]. J Clin Invest, 2006, 116(7): 1955-1962.
29. 　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[J]. Cancer Sci, 2010, 101(11): 2325-2332.
30. 　LeBeau AM, Brennen WN, Aggarwal S, et al. Targeting cancer stroma with a fibroblast activation protein-activated promelittin protoxin[J]. Mol Cancer Ther, 2009, 8(5): 1378-1386.
31. 　Lo PC, Chen J, Stefflova K, et al. Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers[J]. J Med Chem, 2009, 52(2): 358-368.
32. 　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[J]. Cancer Biol Ther, 2007, 6(11): 1691-1699.
33. 　Eager RM, Cunningham CC, Senzer NN, et al. Phase Ⅱ assessment of talabostat and cisplatin in second-line stage Ⅳ melanoma[J]. BMC Cancer, 2009, 9: 263.
34. 　Eager RM, Cunningham CC, Senzer NN, et al. Phase Ⅱ Trial of talabostat and docetaxel in advanced non-small cell lung cancer[J]. Clin Oncol, 2009, 21(6): 464-472.
35. 　Tsai TY, Yeh TK, Chen X, et al. Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein[J]. J Med Chem, 2010, 53(18): 6572-6583.

West China Medical Journal

成纤维细胞活化蛋白在上皮癌中表达的意义及研究进展

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