Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas

Pauli, Christof; Münz, Markus; Kieu, C.; Mack, Brigitte; Breinl, Peter; Wollenberg, Barbara; Lang, Stephan; Zeidler, Reinhard; Gires, Olivier

doi:10.1016/s0304-3835(03)00003-x

Cited by 79 publications

(62 citation statements)

References 12 publications

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“…Point mutation analysis of potential Nglycosylation sites verified that all three sites in EpCAM are modified in human epithelial cells (see Figure 1A) in contrast to data claiming the lack of glycosylation at Asp 198 (Chong and Speicher, 2001). Studies with tumour samples from head and neck cancer patients indicate that EpCAM can be aberrantly glycosylated on tumour cells (Pauli et al, 2003). The nature and functional implications of these carbohydrate modifications awaits further analysis.…”

Section: Epcam Structure and Functionmentioning

confidence: 82%

EpCAM (CD326) finding its role in cancer

Baeuerle¹,

2007

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Although epithelial cell adhesion/activating molecule (EpCAM/CD326) is one of the first tumour-associated antigens identified, it has never received the same level of attention as other target proteins for therapy of cancer. It is also striking that ever since its discovery in the late 1970s the actual contribution of EpCAM to carcinogenesis remained unexplored until very recently. With a First International Symposium on EpCAM Biology and Clinical Application this is now changing. Key topics discussed at the meeting were the frequency and level of EpCAM expression on various cancers and its prognostic potential, the role of EpCAM as an oncogenic signalling molecule for cancer cells, recent progress on EpCAM-directed immunotherapeutic approaches in clinical development and the interaction of EpCAM with other proteins, which may provide a basis for a therapeutic window and repression of its growthpromoting signalling in carcinoma. Future research on EpCAM may benefit from a unified nomenclature and more frequent exchange among those who have been working on this cancer target during the past 30 years and will do so in the future.

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Section: Epcam Structure and Functionmentioning

confidence: 82%

EpCAM (CD326) finding its role in cancer

Baeuerle¹,

2007

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“…Secondly, the extracellular domain of EpCAM is assumably responsible for the aggregation of EpCAM upon binding of an extracellular ligand and/or homophilic aggregation due to overexpression. Additional experiments from our laboratory demonstrated a tissue-specific glycosylation of EpCAM in tumours, raising the question of different functions of these variants (Pauli et al, 2003). Elucidating the impact of such a modification may help to explain the potentially different roles of EpCAM in healthy and diseased tissues with respect to ligand binding and/or self-aggregation.…”

Section: Discussionmentioning

confidence: 96%

The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation

Münz¹,

et al. 2004

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Epithelial cell adhesion molecule (EpCAM) is a membrane glycoprotein expressed on adenomatous and simple epithelia, where it is involved in homophilic adhesion at the basolateral membrane. Carcinomas strongly overexpress EpCAM through an, as yet, unknown mechanism. Interestingly, otherwise EpCAM-negative squamous epithelia are seen to express EpCAM concomitant with their transformation and de-differentiation. The amount of EpCAM and the number of expressing cells both increase with the grade of dysplasia. Despite an important amount of data correlating the expression of EpCAM with cellular proliferation and de-differentiation, such as the coexpression with Ki-67, a marker for proliferation, it is unknown whether EpCAM may directly contribute to carcinogenesis. Here, we show that EpCAM has a direct impact on cell cycle and proliferation, and the ability to rapidly upregulate the proto-oncogene c-myc and cyclin A/E. Human epithelial 293 cells as well as murine NIH3T3 fibroblasts expressing EpCAM had a decreased requirement for growth factors, enhanced metabolic activity and colony formation capacity. Importantly, the inhibition of EpCAM expression with antisense mRNA led to a strong decrease in proliferation and metabolism in human carcinoma cells. Moreover, domain swapping experiments demonstrated that the intracellular part of EpCAM is necessary and sufficient to transduce the effects described. Thus, the data presented here highlight the role of EpCAM, demonstrating for the first time a direct link to cell cycle and proliferation.

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“…Thus, HO-3, just like the great majority of EpCAM-specific antibodies, targets EpCAM mainly within the EGF like domains, which represent the most immunogenic components of this protein (Balzar et al, 1999). Driven by the knowledge of differential glycosylation of EpCAM in normal vs carcinoma tissue (Pauli et al, 2003), we assessed the dependence of HO-3 binding on the glycosylation status of the molecule. A potential impact of post-translational modification of EpCAM on the binding of therapeutic antibodies available so far remained entirely unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…Differential usage of these N-glycosylation sequences results in the generation of EpCAM variants of different sizes ranging from 37 to 42 kDa. Notably, a hyperglycosylation pattern was observed in head and neck carcinoma when compared with healthy EpCAMpositive epithelium (Pauli et al, 2003). EpCAM was strongly glycosylated in 77% of cases of head and neck carcinomas studied (n ¼ 44).…”

Section: Recognition Of Epcam By Ho-3 Is Independent Of Epcam's Glycomentioning

confidence: 90%

Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer

Rosenberger¹,

Gires²,

Jäger³

et al. 2007

Br J Cancer

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Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein that is frequently overexpressed in a variety of carcinomas. This pan-carcinoma antigen has served as the target for a plethora of immunotherapies. Innovative therapeutic approaches include the use of trifunctional antibodies (trAbs) that recruit and activate different types of immune effector cells at the tumour site. The trAb catumaxomab has dual specificity for EpCAM and CD3. In patients with malignant ascites, catumaxomab significantly increased the paracentesis-free interval, corroborating the high efficacy of this therapeutic antibody. Here, we characterised the monoclonal antibody (mAb) HO-3, that is, the EpCAM-binding arm of catumaxomab. Peptide mapping indicated that HO-3 recognises a discontinuous epitope, having three binding sites in the extracellular region of EpCAM. Studies with glycosylation-deficient mutants showed that mAb HO-3 recognised EpCAM independently of its glycosylation status. High-affinity binding was not only detected for mAb HO-3, but also for the monovalent EpCAM-binding arm of catumaxomab with an excellent K D of 5.6 Â 10 À10 M. Furthermore, trAb catumaxomab was at least a 1000-fold more effective in eliciting the eradication of tumour cells by effector peripheral blood mononuclear cells compared with mAb HO-3. These findings suggest the great therapeutic potential of trAbs and clearly speak in favour of EpCAM-directed cancer immunotherapies.

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Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas

Cited by 79 publications

References 12 publications

EpCAM (CD326) finding its role in cancer

EpCAM (CD326) finding its role in cancer

The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation

Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer

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