Abstract A55: Role of EpCAM in maintenance of stemness of cancer cells.
Authors: Yoshida Go J. , Nagano Osamu , Saya Hideyuki 
Published: June 2012

EpCAM (Epithelial cell adhesion molecule: CD326) is a type I transmembrane glycoprotein that functions as an epithelial-specific cell-adhesion molecule. This molecule has long been recognized as one of the cancer stem cell markers, but the detailed function of EpCAM is still elusive. EpCAM is expressed in tumor cells in the vast majority of patients with epithelial cancers, such as ovarian, gastric, colorectal, pancreatic, breast, lung, and endometrial tumors. EpCAM-positive carcinomas maintain EpCAM expression even in the metastatic conditions, including dissemination into the peritoneal cavity. In some carcinomas, highly expressed EpCAM is reportedly associated with a poor prognosis due to the repeated relapse and latent metastasis. In the clinical perspective, catumaxomab has two different antigen-binding specificities: one for EpCAM on tumor cells and one for the CD3 antigen on T-cells. Since this drug is effective for advanced ovarian cancers with malignant ascites, the molecular mechanism underlying the significantlly clinical development should be further investigated.

Recent study using the proteomics technology has strongly suggested that EpCAM expression promotes the active transport of amino acids into tumor cells by forming the complex with CD147, CD98hc (heavy chain) and other amino acid transporters such as LAT1, LAT2, and xCT. Besides, a novel MCT (monocarboxylate transporter)-CD147-CD98hc-LAT1 (L-type amino acid transporter 1) complex has previously been reported to promote the proliferation and metabolism of epithelial cells via the activation of AMPK. Therefore, we firstly performed the immunocytochemical and immunoblot analyzes to identify what kinds of amino acid transporters co-localize to EpCAM in HCT-116 and SKOV-III cells. Secondly, we investigated the relationship between EpCAM expression and the cell proliferation and ATP synthesis. While EpCAM-positive cancer cells have the robust potential for proliferation, EpCAM-negative cancer cells have the robust potential for ATP production. The treatment with rapamycin, one of the immune-suppressing drugs, reduced the activity of mTOR(mammalian target of rapamycin)/Akt pathway in cancer cells. The phenotypes of EpCAM-positive cells, such as the dependency to glycolysis and the proliferative ability, were attenuated by the treatment with rapamycin. These results strongly suggest that mTOR/Akt signal is the downstream pathway of EpCAM expression. Taken together, EpCAM is thought of as not only a cancer stem cell marker but also a functional molecule to maintain stemness for the following reasons.EpCAM-positive cancer cells tend to more depend on glycolysis than EpCAM-negative cancer cells.EpCAM expression activates mTOR/Akt signal.EpCAM molecule functions as a sensor to the nutrient in the tumor microenvironment, thereby adapting to starvation by acquiring dormancy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A55.