Circulating Thrombospondin-4-Positive Fibroblasts Might be a Useful Marker for Diagnosis of Gastric Cancer

Cancer-associated fibroblasts (CAFs) have been reported to be tumor-specific cells. We have recently reported that thrombospondin-4 (THBS4) expression is exclusive to CAFs. This study aimed to clarify whether the identification of circulating CAFs (cir-CAFs) by THBS4 is detectable in the blood of gastric cancer (GC) patients, and whether cir-CAFs are useful for the screening test of GC.

CAFs and normal fibroblasts (NFs) were respectively established from 17 GC specimens. A total of 24 healthy volunteers and 77 GC patients were enrolled. Flow cytometric analysis was performed using anti-THBS4 antibody. The sensitivity and specificity of THBS4-positive cir-CAFs for detection of GC were calculated.

THBS4+ cells showed ovoid-like cells and expressed THBS4. THBS4⁺ expression was significantly (p = 0.014) higher on CAFs than NFs. GC patients had a significantly (p = 0.0323) higher average number of THBS4-positive cir-CAFs than healthy volunteers: 212 cells versus 6.4 cells. The ROC curve indicated that 27 THBS4-positive cells per 10,000 blood cells was an adequate cutoff for GC diagnosis. The sensitivity and specificity of cir-CAFs were 76.6% and 100%, respectively. In contrast, the sensitivities of CEA and CA19-9 were only 22.1% and 9.1%, respectively. The sensitivity of cir-CAFs was high even for Stage I GC, at 73.5%, while the sensitivity of CEA and CA19-9 was low at 14.7% and 0%, respectively.

THBS4-positive cir-CAFs are detectable in the blood of GC patients. The cir-CAFs might be a useful tumor marker in a GC screening test, especially for early-stage GC.