Fibroblast Activation Protein Overexpression and Clinical Implications in Solid Tumors: A Meta-Analysis

Abstract

ObjectiveFibroblast activation protein (FAP) plays a vital role in tumor invasion and metastasis. Previous studies have reported its prognostic value in different tumors. However, the results of these reports remain controversial. In this study, a meta-analysis was performed to clarify this issue.MethodsA search of the PubMed, Embase and CNKI databases was conducted to analyze relevant articles. The outcomes included the relations between FAP expression and histological differentiation, tumor invasion, lymph node metastasis, distant metastasis and overall survival (OS). Sensitivity analysis by FAP expression in different cells and tumor types were further subjected to sensitivity analyses as subgroups. Pooled odds ratios (ORs) and hazard ratios (HRs) were evaluated using the random-effects model.ResultsThe global analysis included 15 studies concerning various solid tumors. For global analysis, FAP overexpression in tumor tissue displayed significant associations with poor OS and tumor progression (OS: HR = 2.18, P = 0.004; tumor invasion: OR = 4.48, P = 0.007; and lymph node metastasis: OR = 3.80, P = 0.004). The subgroup analyses yielded two notable results. First, the relation between FAP overexpression and poor OS and tumor lymph node metastasis was closer in the patients with FAP expression in tumor cells. Second, the pooled analyses of colorectal cancers or pancreatic cancers all indicated that FAP overexpression was associated with a detrimental OS (HR: 1.72, P = 0.009; HR: 3.18, P = 0.005, respectively). The magnitude of this effect was not statistically significant compared with that in patients with non-colorectal cancers or non-pancreatic cancers. These analyses did not display a statistically significant correlation between FAP expression and histological differentiation and distant metastasis in all of the groups.ConclusionsFAP expression is associated with worse prognosis in solid tumors, and this association is particularly pronounced if FAP overexpression is found in the tumor cells rather than the stroma.

The Expression of Fibroblast Activation Protein in Clear Cell Renal Cell Carcinomas Is Associated with Synchronous Lymph Node Metastases

“…As previously described in other cancers [11], most mCCRCCs metastasizing into the lymph nodes were FAP positive. These results suggest an early migration of cancer cells from FAP positive primary tumors to lymph nodes, and could explain, at least in part, both the shorter survival outcome of mCCRCC with lymph node metastases [19,26] and also the relationship between FAP expression and worse prognosis of mCCRCC patients.…”

“…FAP is a marker of activated fibroblasts and its expression is more abundant in tumors with invasive phenotype that are more likely to metastasize [9]. The relationship between FAP expression and poor clinical outcome has been reported [11]. However, these studies have been performed in primary tumors and information about FAP expression in metastatic lesions is scarce.…”

“…A hallmark of the activation of these CAFs is the cell surface expression of fibroblast activation protein-α (FAP), a serine peptidase with multifunctional properties [10]. The overexpression of FAP in CAFs and in tumor cells has been associated with higher risk of metastases and worse survival in several solid tumors [9,11]. …”

The application of the fibroblast activation protein α-targeted immunotherapy strategy

“…FAP α is a tumor-associated antigen which is a serine protease involved in extracellular matrix remodeling and highly expressed on reactive stromal fibroblasts in >90% of human epithelial carcinomas, but is not detectable in normal adult human tissues [83, 84]. Stromal cells expressing FAP α may suppress the immune response to tumors as a consequence of producing massive amounts of stromal cell-derived factor-1 (SDF-1/CXCL12).…”

Expression of CAF-Related Proteins Is Associated with Histologic Grade of Breast Phyllodes Tumor

“…The expression of FAP in CAFs is reported in various carcinomas and is used as an important marker of CAF [32, 33]. In a meta-analysis that analyzed the clinical implication of FAP overexpression in solid tumors of colorectal cancer, pancreatic adenocarcinoma, non-small cell lung cancer, breast cancer, medullary thyroid carcinoma, and oral squamous cell carcinoma, high FAP expression was related to the risk of distant metastasis (OR: 2.56) [34], showing similar results to our study. FAP regulates proteolysis of the extracellular cell matrix in tumor stroma, causing stromal cell proliferation and invasiveness.…”