Surgical insult is associated with transient increases in circulating glypican-3 independent of tumor expression in gastrointestinal carcinomas

Glypican-3 (GPC3) is a cell-surface proteoglycan and therapeutic target in hepatocellular carcinoma. Serum GPC3 (sGPC3) has been proposed as a biomarker for GPC3-targeted therapy. However, during tumor resection, its specificity may be compromised if surgical tissue injury releases GPC3 from non-tumor tissues. We investigated whether perioperative sGPC3 reflects tumor GPC3 expression or surgical insult. N-terminal and C-terminal epitope-containing sGPC3 species were measured perioperatively in 54 patients with gastrointestinal carcinomas and compared with tumor GPC3 immunohistochemistry. Surgical effects were evaluated after partial gastrectomy or sham surgery in tumor-free human GPC3 knock-in mice, and stimulus-dependent release was examined in epithelial cells. In patients, signals rose transiently after surgery, including in those with GPC3-negative tumors, and showed no consistent association with tumor GPC3 expression. Postoperative sGPC3 correlated with inflammatory markers, without establishing causality. In tumor-free mice, gastrectomy and sham surgery altered circulating GPC3 without early increases in tissue GPC3 messenger RNA. In vitro, phorbol 12-myristate 13-acetate induced protease-sensitive release of N-terminal GPC3 species and retention of a C-terminal codrituzumab epitope-containing fragment in the cellular fraction. Thus, surgical manipulation can alter circulating GPC3 independently of tumor expression and may confound perioperative biomarker interpretation. The tissue source and mechanism of postoperative GPC3 release remain unresolved.