Reducing tumor invasiveness by ramucirumab and TGF‐β receptor kinase inhibitor in a diffuse‐type gastric cancer patient‐derived cell model

BACKGROUND: Diffuse‐type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse‐type GC. METHODS: Using a panel of 10 GC cell lines and 3 GC patient‐derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse‐type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF‐β receptor kinase inhibitor (TEW‐7197) alone, or in combination to investigate the drug's effects on invasiveness, spheroid formation, EMT marker expression, and tumor‐induced angiogenesis using a spheroid‐on‐a‐chip model. RESULTS: Both TEW‐7197 and ramucirumab treatments profoundly decreased invasiveness of EMT‐high cell lines and PDCs. With a 3D tumor spheroid‐on‐a‐chip, we identified versatile influence of co‐treatment on cancer cell‐induced blood vessel formation as well as on EMT progression in tumor spheroids. The 3D tumor spheroid‐on‐a‐chip demonstrated that TEW‐7197 + ramucirumab combination significantly decreased PDC‐induced vessel formation. CONCLUSIONS: In this study, we showed TEW‐7197 and ramucirumab considerably decreased invasiveness, thus EMTness in a panel of diffuse‐type GC cell lines including GC PDCs. Taken together, we confirmed that combination of TEW‐7197 and ramucirumab reduced tumor spheroid and GC PDC‐induced blood vessel formation concomitantly in the spheroid‐on‐a‐chip model.