title: Small cell lung cancer: Circulating tumor cells of extended stage patients express a mesenchymal-epithelial transition phenotype.
abstract: Small cell lung cancer (SCLC) is distinguished by aggressive growth, early dissemination and a poor prognosis at advanced stage. The remarkably high count of circulating tumor cells (CTCs) of SCLC allowed for the establishment of permanent CTC cultures at our institution for the first time. CTCs are assumed to have characteristics of cancer stem cells (CSCs) and an epithelial-mesenchymal transition (EMT) phenotype, but extravasation of tumors at distal sites is marked by epithelial features. Two SCLC CTC cell lines, namely BHGc7 and BHGc10, as well as SCLC cell lines derived from primary tumors and metastases were analyzed for the expression of pluripotent stem cell markers and growth factors. Expression of E-cadherin and β-Catenin were determined by flow cytometry. Stem cell-associated markers SOX17, α-fetoprotein, OCT-3/4, KDR, Otx2, GATA-4, Nanog, HCG, TP63 and Goosecoid were not expressed in the 2 CTC lines. In contrast, high expression was found for HNF-3β/FOXA2, SOX2, PDX-1/IPF1 and E-cadherin. E-cadherin expression was restricted to the 2 CTCs and 2 cell lines derived from pleural effusion (SCLC26A) and bone metastases (NCI-H526), respectively. Thus, these SCLC CTCs established from extended disease SCLC patients lack expression of stem cell markers which suppress the epithelial phenotype. Instead they express high levels of E-cadherin consistent with a mesenchymal-epithelial transition (MET or EMrT) and form large tumorospheres possibly in response to the selection pressure of first-line chemotherapy. HNF-3β/FOXA2 and PDX-1/IPF1 expression seem to be related to growth factor dependence on insulin/IGF-1 receptors and IGF-binding proteins.
authors.affiliation: a Department of Surgery , Medical University of Vienna , Vienna , Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hamilton
authors.affiliation: b Respiratory Oncology Unit, Otto Wagner Hospital , Vienna , Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Hochmair
authors.affiliation: c Ludwig Boltzmann Cluster of Translational Oncology , Vienna , Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rath
authors.affiliation: c Ludwig Boltzmann Cluster of Translational Oncology , Vienna , Austria.|d Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna , Vienna , Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Klameth
authors.affiliation: e Molecular Oncology Group , Department of Obstetrics and Gynecology , Medical University of Vienna , Vienna , Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
mesh_terms: D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000378:metabolism / Q000473:pathology*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D007328:Insulin; D051176:beta Catenin; D007334:Insulin-Like Growth Factor I
keywords: E-cadherin; SOX2; stem cell markers; circulating tumor cells; dissemination; mesenchymal-epithelial transition; small cell lung cancer