Journal of Pharmaceutical and Biomedical Sciences

Meta-analysis and Clinical Evaluation of the Relationship Between FAPalpha Expression and Malignant Degree of Solid Tumors

Enpan Mo, Qiutong Tan, Shaohui Cai, Mingjie Shi, Jun Xu

Abstract


Background Aim This study aimed to identify the prognostic significance of Fibroblast activation protein alpha (FAPalpha) in solid tumor.

Method A literature search was performed by using Pubmed, EMbase and CNKI for relevant articles published with the following key words “fibroblast activation protein” or “seprase”, “clinical” and “cancer” or “carcinoma”. Pooled effects with 95% confidence interval (CI) for outcomes (age, gender, positive ratio, histological differentiation, depth of tumor invasion, lymph node metastasis, clinical stage and overall survival) were calculated. Besides, immunohistochemical analysis was performed to evaluate FAPalpha positive ratio in normal, benign and malignant tumor tissues as well as in different degrees of differentiation, clinical stages and lymph node metastasis tissues.

Results Finally, 28 articles with different types of solid tumors were included in the meta-analysis. Results revealed that solid tumors had a higher positive ratio of FAPalpha expression (OR: 39.51, P < 0.001), and FAPalpha overexpression also indicated higher degree of tumor depth invasion (OR: 2.82, P = 0.010), lymph node metastasis (OR: 2.52, P = 0.003), clinical stage (OR: 3.36, P = 0.003) and worse overall survival (HR: 2.03, P < 0.001). Results from immunohistochemistry demonstrated that FAPalpha expressed higher in malignant solid tumors than that in benign solid tumors (P = 0.022), and it significantly overexpress in lymph node metastasis tissues (P = 0.04).

Conclusion Our findings indicate that FAP? expression is associated with worse prognosis in solid tumors and may be a promising prognosis predictor.


Keywords


Fibroblast activation protein ?, Solid tumor, Meta-analysis, Immunohistochemistry.

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References


Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010 Jun 15;18(6):884-901. doi: 10.1016/j.devcel.2010.05.012.

Sung SY, Hsieh CL, Wu D, Chung LW, Johnstone PA. Tumor microenvironment promotes cancer progression, metastasis, and therapeutic resistance. Curr Probl Cancer. 2007 Mar-Apr;31(2):36-100. doi: 10.1016/j.currproblcancer.2006.12.002.

Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004 Nov;4(11):839-49. doi: 10.1038/nrc1477.

Schreiber H, Rowley DA. Cancer. Awakening immunity. Science. 2010 Nov 5;330(6005):761-2. doi: 10.1126/science.1198345.

Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005 Feb 11;120(3):303-13. doi: 10.1016/j.cell.2004.12.018.

Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, Albino AP, Old LJ. Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 1993 Jul 15;53(14):3327-35.

Zhang J, Valianou M, Simmons H, Robinson MK, Lee HO, Mullins SR, Marasco WA, Adams GP, Weiner LM, Cheng JD. Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. FASEB J. 2013 Feb;27(2):581-9. doi: 10.1096/fj.12-210377.

Wang ZH, Ding KF, Yu JK, Zhai XH, Ruan SQ, Wang SW, Zhu YL, Zheng S, Zhang SZ. Proteomic analysis of primary colon cancer-associated fibroblasts using the SELDI-ProteinChip platform. J Zhejiang Univ Sci B. 2012 Mar;13(3):159-67. doi: 10.1631/jzus.B1100266.

Lee HO, Mullins SR, Franco-Barraza J, Valianou M, Cukierman E, Cheng JD. FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer. 2011 Jun 13;11:245. doi: 10.1186/1471-2407-11-245.

Huang Y, Simms AE, Mazur A, Wang S, Leon NR, Jones B, Aziz N, Kelly T. Fibroblast activation protein-alpha promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clinical & Experimental Metastasis. 2011; 28: 567-579.

LeBeau AM, Brennen WN, Aggarwal S, Denmeade SR. Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol Cancer Ther. 2009 May;8(5):1378-86. doi: 10.1158/1535-7163.MCT-08-1170.

Canady J, Arndt S, Karrer S, Bosserhoff AK. Increased KGF expression promotes fibroblast activation in a double paracrine manner resulting in cutaneous fibrosis. J Invest Dermatol. 2013 Mar;133(3):647-657. doi: 10.1038/jid.2012.389.

Cohen SJ, Alpaugh RK, Palazzo I, Meropol NJ, Rogatko A, Xu Z, Hoffman JP, Weiner LM, Cheng JD. Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas. 2008 Aug;37(2):154-8. doi: 10.1097/MPA.0b013e31816618ce.

Yuan D, Liu B, Liu K, Zhu G, Dai Z, Xie Y. Overexpression of fibroblast activation protein and its clinical implications in patients with osteosarcoma. J Surg Oncol. 2013 Sep;108(3):157-62. doi: 10.1002/jso.23368.

Shi M, Yu DH, Chen Y, Zhao CY, Zhang J, Liu QH, Ni CR, Zhu MH. Expression of fibroblast activation protein in human pancreatic adenocarcinoma and its clinicopathological significance. World J Gastroenterol. 2012 Feb 28;18(8):840-6. doi: 10.3748/wjg.v18.i8.840.

Thirunavukkarasu M, Penumathsa SV, Koneru S, Juhasz B, Zhan L, Otani H, Bagchi D, Das DK, Maulik N. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med. 2007 Sep 1;43(5):720-9. doi: 10.1016/j.freeradbiomed.2007.05.004.

Guyot P, Ades AE, Ouwens MJ, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012 Feb 1;12:9. doi: 10.1186/1471-2288-12-9.

Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007 Jun 7;8:16. doi: 10.1186/1745-6215-8-16.

Wikberg ML, Edin S, Lundberg IV, Van Guelpen B, Dahlin AM, Rutegård J, Stenling R, Oberg A, Palmqvist R. High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis. Tumour Biol. 2013 Apr;34(2):1013-20. doi: 10.1007/s13277-012-0638-2.

Iwasa S, Jin X, Okada K, Mitsumata M, Ooi A. Increased expression of seprase, a membrane-type serine protease, is associated with lymph node metastasis in human colorectal cancer. Cancer Lett. 2003 Sep 10;199(1):91-8. doi: 10.1016/s0304-3835(03)00315-x. Erratum in: Cancer Lett. 2005 Sep 28;227(2):227. Corrected and republished in: Cancer Lett. 2005 Sep 28;227(2):229-36.

Zhang XF, Jin X, Guo-Qiang WU, Wang XZ, Jin LI. Relationship Between Expression of Seprase and Clinicopathologic Characteristics in Colorectal Cancer. Chinese Journal of Bases & Clinics in General Surgery. 2006; 13: 89-93.

Henry LR, Lee HO, Lee JS, Klein-Szanto A, Watts P, Ross EA, Chen WT, Cheng JD. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res. 2007 Mar 15;13(6):1736-41. doi: 10.1158/1078-0432.CCR-06-1746.

Herrera M, Herrera A, Domínguez G, Silva J, García V, García JM, Gómez I, Soldevilla B, Muñoz C, Provencio M, Campos-Martin Y, García de Herreros A, Casal I, Bonilla F, Peña C. Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients. Cancer Sci. 2013 Apr;104(4):437-44. doi: 10.1111/cas.12096.

Liao Y, Ni Y, He R, Liu W, Du J. Clinical implications of fibroblast activation protein-? in non-small cell lung cancer after curative resection: a new predictor for prognosis. J Cancer Res Clin Oncol. 2013 Sep;139(9):1523-8. doi: 10.1007/s00432-013-1471-8.

Wang H, Dong W, Yang Z, Zhu H. Expression of fibroblast activation protein and its clinical significance in esophageal cancer. Chinese Journal of Gastroenterology & Hepatology. 2009; 18: 1102-1104.

Zhou HY, Ai-Ping WU, Liu Y. Effect of tumor-associated fibroblasts on the infiltration and metastasis of adenocarcinoma of esophagogastric junction. Chongqing Medicine. 2010; 39: 257-258.

Jin-Bo WU, Jin ZF. Relationship of FAP Expression with Malignant Biological Behaviors in Gastric Carcinoma. Heilongjiang Medical Journal. 2008; 32: 21-23

Yuan XH, Xu ZQ, Xie ZP, Gao HC, Zhang RF, Song JR, Zheng LS, Li DD, Jin M, Cheng WX, Jin Y, Duan ZJ, Hou YD. [WU polyomavirus and KI polyomavirus detected in specimens from children with acute respiratory tract infection in China]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2008 Feb;22(1):21-3. Chinese.

Miao ZF, Zhao TT, Wang ZN, Miao F, Xu YY, Mao XY, Gao J, Xu HM. Tumor-associated mesothelial cells are negative prognostic factors in gastric cancer and promote peritoneal dissemination of adherent gastric cancer cells by chemotaxis. Tumour Biol. 2014 Jun;35(6):6105-11. doi: 10.1007/s13277-014-1808-1.

Wang RF, Zhang LH, Shan LH, Sun WG, Chai CC, Wu HM, Ibla JC, Wang LF, Liu JR. Effects of the fibroblast activation protein on the invasion and migration of gastric cancer. Exp Mol Pathol. 2013 Dec;95(3):350-56. PMID: 24422232.

Yang X, Huang C, Peng C, Cheng F, Xiong B, Li Y. Clinical significance of fibroblast activation protein in gastric cancer. 2016; 37: 757-760.

López JI, Errarte P, Erramuzpe A, Guarch R, Cortés JM, Angulo JC, Pulido R, Irazusta J, Llarena R, Larrinaga G. Fibroblast activation protein predicts prognosis in clear cell renal cell carcinoma. Hum Pathol. 2016 Aug;54:100-5. doi: 10.1016/j.humpath.2016.03.009.

Song J, Yue L I, Wang Q Y. Expression and correlation of fibroblast activation protein and TGF?1 in endometrial carcinoma. Journal of Harbin Medical University. 2011; 45: 153-156.

Mhawech-Fauceglia P, Wang D, Samrao D, Kim G, Lawrenson K, Meneses T, Liu S, Yessaian A, Pejovic T. Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy. Cancer Microenviron. 2014 Aug;7(1-2):33-9. doi: 10.1007/s12307-013-0140-4.

Ariga N, Sato E, Ohuchi N, Nagura H, Ohtani H. 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 Jan 20;95(1):67-72. doi: 10.1002/1097-0215(20010120)95:1<67::aid-ijc1012>3.0.co;2-u.

Koperek O, Scheuba C, Puri C, Birner P, Haslinger C, Rettig W, Niederle B, Kaserer K, Garin Chesa P. Molecular characterization of the desmoplastic tumor stroma in medullary thyroid carcinoma. Int J Oncol. 2007 Jul;31(1):59-67.

PP Tan?LI Jing?JM Zhong. Clinical pathological significance of fibroblast activation protein expression in breast cancer. Acta Medicinae Sinica. 2014; 27: 1-3

Kim GJ, Rhee H, Yoo JE, Ko JE, Lee JS, Kim H, Choi JS, Park YN. Increased expression of CCN2, epithelial membrane antigen, and fibroblast activation protein in hepatocellular carcinoma with fibrous stroma showing aggressive behavior. PLoS One. 2014 Aug 15;9(8):e105094. doi: 10.1371/journal.pone.0105094.

Strom RG, Kalhorn SP, Russell SM, Huang PP. Pleural effusion accumulating in the epidural space: recurrent cord compression in a patient with progressive lung adenocarcinoma. Clin Neurol Neurosurg. 2013 Jan;115(1):91-4. doi: 10.1016/j.clineuro.2012.03.043.

Liu, M., Zhang, G., Wei, L., Min, Z. Expression and significance of fibroblast activation protein in papillary thyroid carcinoma and its significance. Acta Academiae Medicinae Wannan. 2014; 386-388.

Zhang LP, Yang P, Li FH, Yan Y, Wen M, Zhang YR, Jiang YZ. [Hepatitis viruses infection situation in Mianyang of the Sichuan province]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2008 Dec;22(6):449-51. Chinese.

Wang Q, Zhao H D, Yin J K., Dong, R.. Expressions of fap-1 and rac-1 in primary pancreatic cancer and their clinical significances. Journal of Regional Anatomy & Operative Surgery. 2012; 21: 527-528

Cohen SJ, Alpaugh RK, Palazzo I, Meropol NJ, Rogatko A, Xu Z, Hoffman JP, Weiner LM, Cheng JD. Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas. 2008 Aug;37(2):154-8. doi: 10.1097/MPA.0b013e31816618ce.

Wang Y, Jin M, Wei P, Jiang L, Liu M. Expression of fibroblast activation protein ? in lung adenocarcinoma and its clinical significance. Journal of Modern Oncology. 2014; 22: 2590-2593.

Sounni NE, Noel A. Targeting the tumor microenvironment for cancer therapy. Clin Chem. 2013 Jan;59(1):85-93. doi: 10.1373/clinchem.2012.185363.

Zhang J, Liu J. Tumor stroma as targets for cancer therapy. Pharmacol Ther. 2013 Feb;137(2):200-15. doi: 10.1016/j.pharmthera.2012.10.003.

Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, Shultz L, Bhatia R. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-?-catenin signaling. Blood. 2013 Mar 7;121(10):1824-38. doi: 10.1182/blood-2012-02-412890.

Konopleva MY, Jordan CT. Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol. 2011 Feb 10;29(5):591-9. doi: 10.1200/JCO.2010.31.0904.

Goscinski MA, Suo Z, Flørenes VA, Vlatkovic L, Nesland JM, Giercksky KE. FAP-alpha and uPA show different expression patterns in premalignant and malignant esophageal lesions. Ultrastruct Pathol. 2008 May-Jun;32(3):89-96. doi: 10.1080/01913120802034934.

Christiansen VJ, Jackson KW, Lee KN, Downs TD, McKee PA. Targeting inhibition of fibroblast activation protein-alpha and prolyl oligopeptidase activities on cells common to metastatic tumor microenvironments. Neoplasia. 2013 Apr;15(4):348-58. doi: 10.1593/neo.121850.

Lakhani, R S, O EI, Schnitt, J S, Tan, H P, van de Vijver, J M. WHO Classification of Tumours of the Breast, Fourth Edition: International Agency for Research on Cancer. 2012.


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