title: TGF-β1, EGF and FGF4 synergistically induce differentiation of the seminoma cell line TCam-2 into a cell type resembling mixed non-seminoma.
abstract: Malignant germ-cell tumours arise from a neoplastic precursor, the carcinoma in situ, and develop into seminomas and/or non-seminomas (embryonal carcinomas, teratomas, yolk-sac tumours and choriocarcinomas). Based on histological and clinical findings, it has been postulated that seminomas can eventually transform into non-seminomas. Here, we used the cell line TCam-2 as model for seminomas and interrogated their differentiation potential. We demonstrate that TCam-2 cells are able to differentiate into mixed non-seminomatous lineages after supplementing the media with TGF-β1, EGF and FGF4. On a molecular level, the differentiation is initiated by repression of BMP/SMAD signalling. As a consequence, BLIMP1, a molecule known to inhibit the differentiation of murine primordial germ cells, is down-regulated and differentiation-inhibiting histone modifications are lost. The appearance of multinucleated giant cells and the expression of marker genes indicate that cells differentiate predominantly into extra-embryonic choriocarcinoma-like cells. This is most likely due to the presence of components of the Hippo pathway, TEAD4 and YAP1. These molecules have been described to trigger extra-embryonic fate determination in the murine system. This study supports the model that seminomas indeed have an intrinsic ability to transform into a non-seminoma. In addition, the data suggest that the transformation does not require an additional mutation, but can be triggered by changes in the tumour microenvironment.
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Nettersheim
authors.forename: A J M
authors.initials: AJ
authors.lastname: Gillis
authors.forename: L H J
authors.initials: LH
authors.lastname: Looijenga
authors.forename: H
authors.initials: H
authors.lastname: Schorle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D015415:Biomarkers / Q000378:metabolism; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000196:embryology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism / Q000494:pharmacology*; D015726:Giant Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009373:Neoplasms, Germ Cell and Embryonal / Q000473:pathology*; D016133:Polymerase Chain Reaction; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D018239:Seminoma / Q000473:pathology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D013736:Testicular Neoplasms; D014157:Transcription Factors / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D059016:Tumor Microenvironment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D004268:DNA-Binding Proteins; C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D006657:Histones; D009124:Muscle Proteins; D012097:Repressor Proteins; D051785:Smad Proteins; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C087042:PRDM1 protein, human; D004815:Epidermal Growth Factor; D000074462:Positive Regulatory Domain I-Binding Factor 1; D052004:Bone Morphogenetic Protein Receptors