The biology of the 17-1A antigen (Ep-CAM).
ABSTRACT The glycoprotein recognized by the monoclonal antibody (mAb) 17-1A is present on most carcinomas, which makes it an attractive target for immunotherapy. Indeed, adjuvant treatment with mAb 17-1A did successfully reduce the 5 years mortality among colorectal cancer patients with minimal residual disease. Currently the antibody is approved for clinical use in Germany, and is on its way to approval in a number of other countries. New immunotherapeutic strategies targeting the 17-1A antigen are in development or even in early-phase clinical trials. Therefore, a better understanding of the biology of the 17-1A antigen may result in improved strategies for the treatment and diagnosis of human carcinomas. In this review the properties of the 17-1A antigen are discussed concerning tumor biology and the function of the molecule. This 40-kDa glycoprotein functions as an Epithelial Cell Adhesion Molecule, therefore the name Ep-CAM was suggested. Ep-CAM mediates Ca2+-independent homotypic cell-cell adhesions. Formation of Ep-CAM-mediated adhesions has a negative regulatory effect on adhesions mediated by classic cadherins, which may have strong effects on the differentiation and growth of epithelial cells. Indeed, in vivo expression of Ep-CAM is related to increased epithelial proliferation and negatively correlates with cell differentiation. A regulatory function of Ep-CAM in the morphogenesis of epithelial tissue has been demonstrated for a number of tissues, in particular pancreas and mammary gland. The function of Ep-CAM should be taken into consideration when developing new therapeutic approaches targeting this molecule.
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ABSTRACT: Appropriate use of multiple reliable molecular biomarkers in the right context will play a role in tailor-made medicine of clear cell renal cell carcinoma (RCC) patients in the future. A total of 11,056 patients from 53 studies were included in this review. The article numbers of the each evidence levels, using the grading system defined by the Oxford Centre for Evidence-based Medicine, in 1b, 2a, 2b, and 3b were 5 (9 %), 18 (34 %), 29 (55 %), and 1 (2 %), respectively. The main goal of using biomarkers is to refine predictions of tumor progression, pharmacotherapy responsiveness, and cancer-specific and/or overall survival. Currently, carbonic anhydrase (CA9) and vascular endothelial growth factor (VEGF) in peripheral blood and p53 in tumor tissues are measured to predict metastasis, while VEGF-related proteins in peripheral blood are used to assess pharmacotherapy responsiveness with sunitinib. Furthermore, interleukin 8, osteopontin, hepatocyte growth factor, and tissue inhibitors of metalloproteinases-1 in peripheral blood enable assessment of responsiveness to pazopanib treatment. Other reliable molecular biomarkers include von Hippel-Lindau gene alteration, hypoxia-inducible factor-1α, CA9, and survivin in tumor tissues and VEGF in peripheral blood for predicting cancer-specific survival. In the future, studies should undergo external validation for developing tailored management of clear cell RCC with molecular biomarkers, since individual institutional studies lack the generalization and consistency required to maintain accuracy among different patient series.Clinical and Experimental Metastasis 08/2013; · 3.46 Impact Factor
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ABSTRACT: INTRODUCTION: The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. However, effects of EpCAM overexpression on normal breast epithelial cells have never been studied before. Therefore, we analyzed effects of transient adenoviral overexpression of EpCAM on proliferation, migration and differentiation of primary human mammary epithelial cells (HMECs). METHODS: HMECs were transfected by an adenoviral system for transient overexpression of EpCAM. Thereafter, changes in cell proliferation and migration were studied using a real time measurement system. Target gene expression was evaluated by transcriptome analysis in proliferating and polarized HMEC cultures. A Chicken Chorioallantoic Membrane (CAM) xenograft model was used to study effects on in vivo growth of HMECs. RESULTS: EpCAM overexpression in HMECs did not significantly alter gene expression profile of proliferating or growth arrested cells. Proliferating HMECs displayed predominantly glycosylated EpCAM isoforms and were inhibited in cell proliferation and migration by upregulation of p27KIP1 and p53. HMECs with overexpression of EpCAM showed a down regulation of E-cadherin. Moreover, cells were more resistant to TGF-beta1 induced growth arrest and maintained longer capacities to proliferate in vitro. EpCAM overexpressing HMECs xenografts in chicken embryos showed hyperplastic growth, lack of lumen formation and increased infiltrates of the chicken leukocytes. CONCLUSIONS: EpCAM revealed oncogenic features in normal human breast cells by, inducing resistance to TGF-beta1-mediated growth arrest and supporting a cell phenotype with longer proliferative capacities in vitro. EpCAM overexpression resulted in hyperplastic growth in vivo. Thus, we suggest that EpCAM acts as a prosurvival factor counteracting terminal differentiation processes in normal mammary glands.Molecular Cancer 06/2013; 12(1):56. · 5.13 Impact Factor
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ABSTRACT: The association of EpCAM expression with the progression of gastric cancer remains unclear. Here, we investigated the expression of EpCAM in gastric cancer subtypes and correlated the data to tumor cell proliferation and clinicopathologic factors. The intratumoral expression of EpCAM was assessed in 163 primary gastric cancers (61 diffuse-, 62 intestinal-, 32 mixed-type and 8 unclassified tumors) by immunohistochemistry, using the monoclonal antibody Ber-EP4. Intensity of staining was classified according the HercepTest-score using a standardized scoring system. Ki-67 was used to examine the proliferation in tumor tissue. Strong EpCAM expression was observed in 77% of the tumors and in 85% of the corresponding lymph nodes. Of the primary tumors, 58% (n=74) presented a homogeneous intratumoral EpCAM expression while 42% were characterised by a heterogenous expression pattern. Tumors with high EpCAM expression at the invasive front were associated with significantly (p=0.03) higher proportion of lymph node metastases and lower median overall survival (p=0.001). Diffuse type tumors presented a significantly higher EpCAM expression at the invasion front compared with the tumor centre (p=0.036). Multivariate survival analysis identified high EpCAM expression at the invasive front as an independent prognostic factor.We observed a significant (p=0.001) correlation between high EpCAM expression and higher tumor cell proliferation. High EpCAM expression associates with proliferation and progression of gastric cancer, especially in the diffuse type. Considering the discontenting results of the current adjuvant concepts for gastric cancer patients, EpCAM might be target in the adjuvant therapy of this malignant disease.BMC Research Notes 07/2013; 6(1):253.