Dual blockade of MET and VEGFR2 signaling pathways as a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer

• Published in: Biochemical and biophysical research communications Vol. 600; pp. 80 - 86
• Main Authors: Kasai, Suguru, Kuwayama, Naomi, Motoo, Yoshiharu, Kawashima, Atsuhiro, Matsumoto, Kunio, Yano, Seiji, Matsushima, Kouji, Yasumoto, Kazuo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.04.2022
• Subjects: Anilides - pharmacology; Animals; Ascites - drug therapy; Cell Line, Tumor; Gastric cancer; Hepatocyte growth factor; Humans; MET; Mice; Mice, Nude; Peritoneal carcinomatosis; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - pathology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Pyridines - pharmacology; Signal Transduction - drug effects; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR2; VEGFR2; Hepatocyte growth factor; Gastric cancer; MET; Peritoneal carcinomatosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.02.045

Scirrhous gastric cancer frequently develops into peritoneal carcinomatosis with malignant ascites, leading to an extremely poor prognosis. We had demonstrated that paracrine hepatocyte growth factor (HGF)-induced MET activation promotes peritoneal carcinomatosis with ascites formation. The vascular endothelial growth factor (VEGF) receptor (VEGFR)/VEGF axis facilitates tumor progression and formation of malignant ascites. This study investigated the role of MET and VEGFR2 in the development of peritoneal carcinomatosis with malignant ascites. Cabozantinib is a dual inhibitor of MET and VEGFR2. We examined the effects of cabozantinib on MET- and VEGFR2-mediated progression of peritoneal carcinomatosis in human scirrhous gastric cancer in vitro and in vivo. Cabozantinib inhibited HGF-stimulated proliferation of scirrhous cancer cell lines NUGC4 and GCIY, with a high potential to generate peritoneal carcinomatosis with ascites fluid, as well as the constitutive proliferation of MKN45 cells with MET amplification. Cabozantinib also inhibited the phosphorylation of both MET and VEGFR2 in scirrhous cancer cells and HGF- or VEGF-stimulated HUVECs. It effectively reduced ascitic fluid and prolonged the survival of NUGC4-inoculated nude mice. In clinical specimens, malignant ascites fluid from patients with peritoneal carcinomatosis contained high levels of HGF and VEGF. Our results strongly suggest that MET- and VEGFR2-mediated signaling pathways play pivotal roles in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer. Thus, the dual blockade of MET and VEGFR2 signaling may be a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer. •Scirrhous gastric cancer often develops into peritoneal carcinomatosis with ascites.•Hepatocyte growth factor (HGF) stimulates proliferation of scirrhous cancer cells.•Cabozantinib is a dual inhibitor of the MET and VEGFR2 signaling pathways.•Cabozantinib inhibits HGF- and VEGF-enhanced proliferation of HUVECs.•Cabozantinib inhibits ascites formation and prolongs NUGC4-injected mouse survival.