Biomarkers in Tumor Microenvironment? Upregulation of Fibroblast Activation Protein-α Correlates with Gastric Cancer Progression and Poor Prognosis

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Recent evidence points to importance of cross talk between cancer cells and the surrounding stroma on gastric cancer progression. Tumor microenvironment biomarkers thus represent a new opportunity for diagnostics innovation. Reactive stromal fibroblasts selectively express the fibroblast activation protein alpha (FAP-alpha), a homodimeric integral membrane gelatinase that belongs to the serine protease family. We report here that FAP-alpha expression is significantly elevated in gastric cancer samples by more than fivefold (p < 0.05), using transcriptome data from The Cancer Genome Atlas. Notably, the greatest FAP-alpha upregulation was observed in the poorly differentiated group (p < 0.001). Moreover, elevated FAP-alpha expression levels correlated with adverse clinical-pathological characteristics, such as diffuse histological subtype (p < 0.001), advanced pathological stage (p < 0.01) and poor survival. Functional annotation analysis demonstrated that FAP-alpha upregulation was associated with activation of biological processes implicated in tumor progression, including cell migration and angiogenesis pathways. These observations underscore the possible prognostic significance of FAP-alpha in gastric cancer and its potential as a novel biomarker for personalized medicine. We caution, however, that further multiomics, biochemical, and animal studies are necessary to ascertain the role of FAP-alpha as a causative and mechanistic biomarker. Based on pathway analyses, we hypothesize that gastric cancer patients exhibiting FAP-alpha upregulation might presumably benefit from antiangiogenic drugs in addition to standard therapeutic regimens. We call for future research focusing on the tumor microenvironment biomarkers in clinical oncology.