J Cancer 2010; 1:141-149. doi:10.7150/jca.1.141
Mesothelin as a Potential Therapeutic Target in Human Cholangiocarcinoma
1. Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
2. College of Life Sciences, East China Normal University, Shanghai, China
3. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
4. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
5. Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland USA
*These authors contributed equally to this paper.
Yu L, Feng M, Kim H, Phung Y, Kleiner DE, Gores GJ, Qian M, Wang XW, Ho M. Mesothelin as a Potential Therapeutic Target in Human Cholangiocarcinoma. J Cancer 2010; 1:141-149. doi:10.7150/jca.1.141. Available from http://www.jcancer.org/v01p0141.htm
Background: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common primary liver cancers, yet there have been no significant advances in effective therapeutics. Mesothelin has been reported as a new therapeutic target in various types of cancer. Here, we investigated the expression of mesothelin in liver cancer and its potential role as a novel therapeutic target for immunotherapy.
Methods: HCC and CCA specimens were examined by immunohistochemistry for mesothelin expression. Protein expression was assessed by immunoblotting and flow cytometry. The SS1P immunotoxin targeting mesothelin was evaluated in the well-established CCA cell lines HuCCT1, HuH-28, KMBC, KMCH, Mz-ChA-1 and OZ.
Results: We showed strong immunochemical mesothelin staining in 33% of the surgically resected CCA specimens and 3 of 6 CCA cell lines (OZ, KMBC and KMCH). No mesothelin staining was found in HCC or normal liver tissue. Mesothelin was primarily localized to the cellular plasma membrane and the mature form (molecular weight, ~40 kDa) was expressed at a high level in CCA tissues. Moreover, 22% of CCA specimens had a high mesothelin expression level which was comparable to the CCA cell line models. Interestingly, SS1P showed very high and specific growth inhibition when added to mesothelin-expressing CCA cells with IC50 values ranging from 0.5 to 11 ng/mL.
Conclusions: Mesothelin is overexpressed in one-third of CCA tissues. SS1P targeting mesothelin reveals a remarkable single agent activity against CCA in vitro. These findings indicate a potential for SS1P in the immunotherapeutic treatment of CCA.
Keywords: cholangiocarcinoma, hepatocellular carcinoma, bile duct carcinoma, immunotoxin, mesothelin, SS1P