Nuclear signalling by tumour-associated antigen EpCAM

Maetzel, Dorothea; Denzel, Sabine; Mack, Brigitte; Canis, Martin; Went, Philip; Benk, Michael; Kieu, C.; Papior, Peer; Baeuerle, Patrick A.; Münz, Markus; Gires, Olivier

doi:10.1038/ncb1824

Cited by 610 publications

(814 citation statements)

References 48 publications

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“…Epcam expression was predominantly nuclear in tumors (Fig. 2C), but membranous in the biliary epithelial cells present in normal liver, consistent with the proposed mitogenic role of the Epcam intracellular domain after its nuclear translocation (28). The tumor nodules had increased DNA synthesis compared with adjacent normal tissue based on their uptake of BrdU (Fig.…”

Section: Resultssupporting

confidence: 64%

Induction of hepatocellular carcinoma by in vivo gene targeting

Wang¹,

Xu²,

Toffanin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ∼1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300-kb chromosomal domain containing multiple mRNAs, snoRNAs, and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy.

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Section: Resultssupporting

confidence: 64%

Induction of hepatocellular carcinoma by in vivo gene targeting

Wang¹,

Xu²,

Toffanin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…13). EpCAM, also known as CD326, is a 40 kDa type I membrane glycoprotein frequently expressed in human carcinomas, and involved in cell proliferation by linking to components of the Wnt signaling pathway and regulators of the cell cycle (14,15). It initially attracted attention as a target for cancer-related immunotherapy due to its abundant expression in solid tumors, although expression in normal epithelia is low (14)(15)(16)(17), and recent studies further unveiled its association with cancer stem cells (15)(16)(17)(18)(19) and circulating tumor cells (16,18,19).…”

Section: Introductionmentioning

confidence: 99%

Increasing the Antitumor Effect of an EpCAM-Targeting Fusion Toxin by Facile Click PEGylation

Simon

Stefan

Borsig

et al. 2014

Molecular Cancer Therapeutics

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Fusion toxins used for cancer-related therapy have demonstrated short circulation half-lives, which impairs tumor localization and, hence, efficacy. Here, we demonstrate that the pharmacokinetics of a fusion toxin composed of a designed ankyrin repeat protein (DARPin) and domain I-truncated Pseudomonas Exotoxin A (PE40/ETA 00 ) can be significantly improved by facile bioorthogonal conjugation with a polyethylene glycol (PEG) polymer at a unique position. Fusion of the anti-EpCAM DARPin Ec1 to ETA 00 and expression in methionine-auxotrophic E. coli enabled introduction of the nonnatural amino acid azidohomoalanine (Aha) at position 1 for strain-promoted click PEGylation. PEGylated Ec1-ETA 00 was characterized by detailed biochemical analysis, and its potential for tumor targeting was assessed using carcinoma cell lines of various histotypes in vitro, and subcutaneous and orthotopic tumor xenografts in vivo. The mild click reaction resulted in a welldefined mono-PEGylated product, which could be readily purified to homogeneity. Despite an increased hydrodynamic radius resulting from the polymer, the fusion toxin demonstrated high EpCAM-binding activity and retained cytotoxicity in the femtomolar range. Pharmacologic analysis in mice unveiled an almost 6-fold increase in the elimination half-life (14 vs. 82 minutes) and a more than 7-fold increase in the area under the curve (AUC) compared with non-PEGylated Ec1-ETA 00 , which directly translated in increased and longer-lasting effects on established tumor xenografts. Our data underline the great potential of combining the inherent advantages of the DARPin format with bioorthogonal click chemistry to overcome the limitations of engineering fusion toxins with enhanced efficacy for cancer-related therapy. Mol Cancer Ther; 13(2); 375-85. Ó2013 AACR.

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“…In this study, tumor cell showed high expression level of PCNA, representing high proliferation stage of hepatic tumors, however, no expression in normal appearing hepatocytes. A recent report showed that regulated intramembrane proteolysis activates EpCAM as a mitogenic signal transducer, resulting elevated expression of c-myc and cyclin A and E (Maetzel et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Epithelial Cell Adhesion Molecule (EpCAM) in Rat Hepatic Tumors Induced by Diethylnitrosamine

Kang

2012

Asian Pacific Journal of Cancer Prevention

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The epithelial cell adhesion molecule (EpCAM) is a pan-epithelial differentiation antigen that is expressed on almost all carcinomas. However, a role in rat liver carcinogenesis has never been reported previously. Thus, its expression was investigated herein in rat liver tumors induced by diethylnitrosamine (DEN). Twenty male 5-week-old F344 rats were used in this experiment. Mini-osmotic pumps containing doses of 47.5 mg of DEN were inserted into the abdominal cavity of each animal to initiate liver carcinogenesis. All animals were sacrificed at 26 weeks after DEN treatment. At necropsy, hepatic masses were processed for histopathological examination, which revealed forty-four hepatocellular adenomas (HCAs) and twenty hepatocellular carcinomas (HCC). Tumors were immunohistochemically analyzed for EpCAM, proliferating cell nuclear antigen (PCNA) and co-localization of the two.

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Nuclear signalling by tumour-associated antigen EpCAM

Cited by 610 publications

References 48 publications

Induction of hepatocellular carcinoma by in vivo gene targeting

Induction of hepatocellular carcinoma by in vivo gene targeting

Increasing the Antitumor Effect of an EpCAM-Targeting Fusion Toxin by Facile Click PEGylation

Increased Expression of Epithelial Cell Adhesion Molecule (EpCAM) in Rat Hepatic Tumors Induced by Diethylnitrosamine

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