Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells

BMC Cancer

Tatsuzo Mizukami¹  Yuki Fujii¹  Fumihiko Matsuzawa¹  Futoshi Kawamata¹  Akinobu Taketomi¹  Moto Fukai¹  Hirofumi Kamachi¹  Nozomi Kobayashi¹  Takahiro Einama²  Yutaka Hatanaka³ 

[1] Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, 060-8638, Sapporo, Hokkaido, Japan;Department of Surgery, National Defense Medical College, Namiki 3-2, Tokorozawa, 359-8513, Saitama, Japan;Research Division of Companion Diagnostics, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, 060-8638, Sapporo, Hokkaido, Japan;

关键词: Amatuximab;    Mesothelin;    Peritoneal metastasis;    Cancer stem cell;    Pancreatic cancer;    pMET;    C-MET;   

DOI  :  10.1186/s12885-020-07722-3

来源: Springer

【 摘 要 】

BackgroundMesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model.MethodsWe discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer.ResultsMesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes.ConclusionsOur work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

【 授权许可】

CC BY