Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
Department of Surgery, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan.
BMC Cancer. 2021 Feb 26;21(1):200. doi: 10.1186/s12885-020-07722-3.
Mesothelin 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.
We 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.
Mesothelin 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.
Our 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.
间皮素是一种 40kDa 的糖蛋白，在多种类型的癌症中高度过表达，但间皮素的分子机制尚未被很好地了解。Amatuximab 是一种针对间皮素的嵌合单克隆 IgG1/k 抗体。我们最近证明，Amatuximab 联合吉西他滨治疗胰腺癌腹膜炎在小鼠模型中是有效的。
我们在体外实验和胰腺癌腹膜炎小鼠模型中发现了 Amatuximab 阻断间皮素在高或低表达间皮素的人胰腺细胞中的作用和潜在机制。
Amatuximab 阻断间皮素导致 AsPC-1 和 Capan-2（高间皮素表达）侵袭和迁移能力的抑制，并降低 pMET 表达水平。Amatuximab 和吉西他滨的联合使用比单独使用吉西他滨更能抑制 AsPC-1 和 Capan-2 的增殖。这些现象在 Panc-1 和 MIA Paca-2（间皮素低表达）中没有观察到。我们之前证明，Amatuximab 减少了小鼠 AsPC-1 腹膜炎模型中的腹膜肿块，并诱导了雪葩状癌细胞聚集，这些聚集被吉西他滨消除。在这项研究中，我们表明，癌症干细胞相关分子，如 ALDH1、CD44、c-MET 以及增殖相关分子，在雪葩状聚集物中被抑制，但一旦雪葩状聚集物附着在腹膜上，它们就会强烈表达这些分子，而没有形态变化。
我们的工作表明，Amatuximab 抑制癌细胞与腹膜的黏附，并抑制这些细胞的干性和活力，从而增强对吉西他滨的敏感性。
