Although erythropoietin-producing human hepatocellular receptor A2 (EphA2) signaling serves an important role in the tumor microenvironment, its contribution to vasculogenic mimicry (VM) formation in gastric cancer cells remains unclear. The aim of the present study was to investigate the role of EphA2 in VM formation induced by cancer-associated fibroblasts (CAFs). The conditioned medium of CAFs (CAF-CM) was prepared from 12 patients with gastric adenocarcinoma. VM was evaluated by the number of tubules and intersections in gastric cancer cells following CAF-CM treatment. The role of EphA2-phosphoinositide 3-kinase (PI3K) in VM was investigated using EphA2-targeted small interfering (si)RNAs (siEphA2), EphA2 inhibitors and PI3K-inhibitors. CAF-CM-induced VM formation was significantly associated with high protein expression levels of EphA2. EphA2 inhibitor and siEphA2 manipulation significantly decreased VM formation by CAF-CM. In siEphA2 cells, decreased expression levels of VM-associated proteins were observed. CAF-CM-induced VM formation was blocked by the PI3K-inhibitor. In conclusion, CAFs facilitate VM formation via EphA2-PI3K signaling in gastric cancer cells. Thus, EphA2-PI3K signaling may be required for CAF-promoted VM formation during gastric tumorigenesis.
Keywords: cancer-associated fibroblasts; erythropoietin-producing human hepatocellular receptor tyrosine kinase; gastric cancer; tumor microenvironment; vasculogenic mimicry.