Effects of the fibroblast activation protein on the invasion and migration of gastric cancer

Objective: Cancer-associated fibroblasts (CAFs) are one of the most important components of tumor microenvironment. CAFs are believed to play an important role in tumor invasion and metastasis. Recently, fibroblast activation protein (FAP), a type II integral membrane glycoprotein belonging to the serine protease family, has emerged as a specific marker of CAFs. FAP was overexpressed in stromal fibroblasts of solid malignancies, however, the role of PAP on the process of invasion and metastasis of gastric carcinomas is still unknown. Methods: Expression of PAP level was detected by immunohistochemistry in 60 gastric cancer surgical specimens (28 with omentum metastasis and 32 without), 20 normal human gastric tissues and omentum of 10 nonneoplastic gastric diseases. Fibroblasts were isolated from patient's tissues in the distal normal zones and tumor zones respectively, which were correspondingly designated as normal zone fibroblasts (NFs) and cancer-associated fibroblasts (CAFs). To explore the effects of PAP on NFs or CAFs, fibroblasts were co-cultured with human gastric cancer cell line MGC-803 cells. The ability of invasion and migration of MGC-803 cells was evaluated after transfecting FAP siRNA into CAFs of gastric carcinomas. Results: We investigated the level of expression of PAP in surgical specimens, and found overexpressed in CAFs and non-expressed in NPs. Expression of FAP level in CAFs is significantly associated with Lauren classification, the degree of differentiation, depth of tumor invasion and TNM stage, but it is not correlated to age and gender in gastric carcinoma patients. There was positive correlation between the FAP level with metastasis to the omentum (p < 0.05, R-2 = 02736, p < 0.05, R-2 = 0.1479). In addition, the invasion and migration abilities of MGC-803 cells were significantly increased when cells were co-cultured with CAFs. On the other hand, invasion and migration abilities were significantly decreased by 46.9 and 50.3%, respectively, after knocking down PAP in CAFs. Further, NFs did not have appreciable effect on the invasion and migration of MGC-803 cells. Conclusions: Our findings showed that FAP was overexpressed in CAFs of gastric carcinomas, and siRNA-mediated knock down of FAP significantly suppressed invasion and migration of MGC-803 cells. PAP may be an important regulator in the invasion and migration of gastric cancer and may provide a novel therapeutic target in gastric carcinomas. (C) 2013 Elsevier Inc. All rights reserved.