The Emerging Role of EpCAM in Cancer and Stem Cell Signaling

Münz, Markus; Baeuerle, Patrick A.; Gires, Olivier

doi:10.1158/0008-5472.can-09-0654

Cited by 474 publications

(431 citation statements)

References 21 publications

(27 reference statements)

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“…The identity of cancer cells was ascertained by staining for EpCAM and confirmation of absence of CD45. Because loss of surface EpCAM is common (35), proportions of NKG2D + cancer cells may be underestimated. At this point, there is no hint at mechanisms of gene regulation that may underlie cancer-cell expression of NKG2D and DAP10, which might be induced by cytokines or growth factors in permissive cancer-cell subsets.…”

Section: Discussionmentioning

confidence: 99%

Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells

Benitez

Dai

Mann

et al. 2011

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

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The stimulatory natural killer group 2 member D (NKG2D) lymphocyte receptor and its tumor-associated ligands are important mediators in the immune surveillance of cancer. With advanced human tumors, however, persistent NKG2D ligand expression may favor tumor progression. We have found that cancer cells themselves express NKG2D in complex with the DNAX-activating protein 10 (DAP10) signaling adaptor. Triggering of NKG2D on ex vivo cancer cells or on tumor lines which express only few receptor complexes activates the oncogenic PI3K-protein kinase B (PKB/ AKT)-mammalian target of rapamycin (mTOR) signaling axis and downstream effectors, the ribosomal protein S6 kinase 1 (S6K1) and the translation initiation factor 4E-binding protein 1 (4E-BP1). In addition, as in lymphocytes, NKG2D ligand engagement stimulates phosphorylation of JNK and ERK in MAP kinase cascades. Consistent with these signaling activities, above-threshold expression of NKG2D-DAP10 in a ligand-bearing tumor line increases its bioenergetic metabolism and proliferation, thus suggesting functional similarity between this immunoreceptor and tumor growth factor receptors. This relationship is supported by significant correlations between percentages of cancer cells that are positive for surface NKG2D and criteria of tumor progression. Hence, in a conceptual twist, these results suggest that tumor co-option of NKG2D immunoreceptor expression may complement the presence of its ligands for stimulation of tumor growth.growth stimulation | signal transduction

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Section: Discussionmentioning

confidence: 99%

Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells

Benitez

Dai

Mann

et al. 2011

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

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“…Survivin and c-myc are key regulators of cell growth in most human cancers and unfavorable prognostic markers, inhibiting cell death induced by several anticancer agents (Mita et al, 2008;Albihn et al, 2010). The epithelial cell adhesion molecule EpCAM is involved in a positive regulatory loop of Wnt signaling (Munz et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

et al. 2010

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Constitutive activation of Wnt/b-catenin signaling in cancer results from mutations in pathway components, which frequently coexist with autocrine Wnt signaling or epigenetic silencing of extracellular Wnt antagonists. Among the extracellular Wnt inhibitors, the secreted frizzled-related proteins (SFRPs) are decoy receptors that contain soluble Wnt-binding frizzled domains. In addition to SFRPs, other endogenous molecules harboring frizzled motifs bind to and inhibit Wnt signaling. One of such molecules is V3Nter, a soluble SFRP-like frizzled polypeptide that binds to Wnt3a and inhibits Wnt signaling and expression of the b-catenin target genes cyclin D1 and c-myc. V3Nter is derived from the cell surface extracellular matrix component collagen XVIII. Here, we used HCT116 human colon cancer cells carrying the DS45 activating mutation in one of the alleles of b-catenin to show that V3Nter and SFRP-1 decrease baseline and Wnt3a-induced b-catenin stabilization. Consequently, V3Nter reduces the growth of human colorectal cancer xenografts by specifically controlling cell proliferation and cell cycle progression, without affecting angiogenesis or apoptosis, as shown by decreased

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“…EpCAM is ubiquitously expressed in bronchial epithelium but its high expression has been linked to stem cell properties in number of epithelial tissues. 38,39 Furthermore, downregulation of EpCAM is frequently observed in EMT. 40 top panel).…”

Section: Phenotypic Plasticity Of Bronchial-derived Basal Epithelial mentioning

confidence: 99%

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture

Jónsdóttir

Arason

Pálsson

et al. 2015

Laboratory Investigation

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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high morbidity and mortality. The cellular source of the fibrotic process is currently under debate with one suggested mechanism being epithelial-to-mesenchymal transition (EMT) in the alveolar region. In this study, we show that airway epithelium overlying fibroblastic foci in IPF contains a layer of p63-positive basal cells while lacking ciliated and goblet cells. This basal epithelium shows increased expression of CK14, Vimentin and N-cadherin while retaining E-cadherin. The underlying fibroblastic foci shows both E-and N-cadherin-positive cells. To determine if p63-positive basal cells were able to undergo EMT in culture, we treated VA10, a p63-positive basal cell line, with the serum replacement UltroserG. A sub-population of treated cells acquired a mesenchymal phenotype, including an E-to N-cadherin switch. After isolation, these cells portrayed a phenotype presenting major hallmarks of EMT (loss of epithelial markers, gain of mesenchymal markers, increased migration and anchorage-independent growth). This phenotypic switch was prevented in p63 knockdown (KD) cells. In conclusion, we show that airway epithelium overlying fibroblastic foci in IPF lacks its characteristic functional identity, shows increased reactivity of basal cells and acquisition of a partial EMT phenotype. This study suggests that some p63-positive basal cells are prone to phenotypic changes and could act as EMT progenitors in IPF.

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The Emerging Role of EpCAM in Cancer and Stem Cell Signaling

Cited by 474 publications

References 21 publications

Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells

Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture

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