TGF-β1, EGF and FGF4 synergistically induce differentiation of the seminoma cell line TCam-2 into a cell type resembling mixed non-seminoma

D Nettersheim, A J M Gillis, L H J Looijenga, H Schorle

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)e189-203
JournalInternational journal of andrology
Issue number4 Pt 2
Publication statusPublished - Aug 2011
Externally publishedYes


  • Adaptor Proteins, Signal Transducing/biosynthesis
  • Biomarkers/metabolism
  • Bone Morphogenetic Protein Receptors/metabolism
  • Cell Differentiation
  • Cell Line, Tumor
  • Choriocarcinoma/embryology
  • DNA-Binding Proteins/biosynthesis
  • Epidermal Growth Factor/metabolism
  • Fibroblast Growth Factor 4/metabolism
  • Giant Cells
  • Histones/metabolism
  • Humans
  • Male
  • Muscle Proteins/biosynthesis
  • Neoplasms, Germ Cell and Embryonal/pathology
  • Polymerase Chain Reaction
  • Positive Regulatory Domain I-Binding Factor 1
  • Repressor Proteins/biosynthesis
  • Seminoma/pathology
  • Signal Transduction
  • Smad Proteins/metabolism
  • TEA Domain Transcription Factors
  • Testicular Neoplasms
  • Transcription Factors/biosynthesis
  • Transforming Growth Factor beta1/metabolism
  • Tumor Microenvironment


Dive into the research topics of 'TGF-β1, EGF and FGF4 synergistically induce differentiation of the seminoma cell line TCam-2 into a cell type resembling mixed non-seminoma'. Together they form a unique fingerprint.

Cite this