Abstract
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.
Highlights
Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, molecular mechanism of mesothelin has not been well-known
The expression of mesothelin in Panc-1 was detected, that was weak compared with those in Capan-2 and AsPC-1 (Fig. 1a). The result using another primary antibody for mesothelin showed that the mesothelin expression in Panc-1 was low level (Supplemental Figure 1), and the order of expression level was same in both results
We examined a panel of Cancer stem cell (CSC)-related molecules and found that the levels of p-MET were reduced in both AsPC-1 and Capan-2 cells treated with Amatuximab compared with controls
Summary
Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, 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. Pancreatic cancer shows rapid growth and metastasis and is one of the most fatal human cancers. Over half of patients are diagnosed at a stage where metastases have developed, and the overall 5-year survival rate for the pancreatic patients with metastases is only 10% [1, 2]. 15–20% of patients have resectable disease at the time of diagnosis [3]. The majority of patients have local and distant micrometastases at the time of surgery. Disease recurrence following operation is very high. Hattangadi et al reported that the peritoneum (55%) and the liver (53%) were the most common sites of recurrence [4]
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