Evaluation of Biologic Phenotype by Midkine Gene Expression in Gastric Cancer as a Target for Biotherapy

PURPOSE: We studied biological phenotypes of gastric cancer cell lines based on a novel heparin-binding growth/differentiation factor, midkine (MK) expression. MATERIALS AND METHODS: Nine gastric cancer cell lines and 25 gastric cancer tissues were tested for MK expression by Northern blot analysis. Soft agar assay for in vitro tumorigenesis, cross- feeding assay for paracrine angiogenic activity, ELISA for uPA and PAI-1 measurement were performed. RESULTS: MK expression was found in 67% (6/9) of the gastric cancer cell lines, and 56% (14/25) of the primary gastric cancer tissues. Gastric cancer cell lines with MK expression were more tumorigenic in soft agar assay and endothelial cell growth stimulatory in cross-feeding assay than cells which did not express MK. However, urokinase-type plasminogen activator (uPA) expression did not correlate with MK expression. Growth of MK expressing cells was inhibited by a heparin-binding blocking agent, pentosan polysulfate (PPS). In cancer tissues, MK expression correlated with tumor size, suggesting in vivo autocrine and paracrine activity. CONCLUSION: Gastric cancer cells with increased MK gene expression showed increased tumorigenic and angiogenic activity. Therefore, this proliferation promoting activity of MK can be targeted by an anti-heparin binding agent as a biotherapy model in gastric cancer treatment.ope