| RRC ID |
70272
|
| 著者 |
Kasai S, Kuwayama N, Motoo Y, Kawashima A, Matsumoto K, Yano S, Matsushima K, Yasumoto K.
|
| タイトル |
Dual blockade of MET and VEGFR2 signaling pathways as a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
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.
|
| 巻・号 |
600
|
| ページ |
80-86
|
| 公開日 |
2022-4-16
|
| DOI |
10.1016/j.bbrc.2022.02.045
|
| PII |
S0006-291X(22)00234-0
|
| PMID |
35196631
|
| MeSH |
Anilides* / pharmacology
Animals
Ascites / drug therapy
Cell Line, Tumor
Humans
Mice
Mice, Nude
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
|
| IF |
2.985
|
| リソース情報 |
| ヒト・動物細胞 |
GCIY(RCB0555) |
