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

Int J Androl. 2011 Aug;34(4 Pt 2):e189-203. doi: 10.1111/j.1365-2605.2011.01172.x. Epub 2011 Jun 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Epidermal Growth Factor / pharmacology*
  • Fibroblast Growth Factor 4 / metabolism
  • Fibroblast Growth Factor 4 / pharmacology*
  • 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
  • Repressor Proteins / genetics
  • Seminoma / pathology*
  • Signal Transduction
  • Smad Proteins / metabolism
  • Testicular Neoplasms
  • Transcription Factors / biosynthesis
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / pharmacology*
  • Tumor Microenvironment

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • DNA-Binding Proteins
  • FGF4 protein, human
  • Fibroblast Growth Factor 4
  • Histones
  • Muscle Proteins
  • Repressor Proteins
  • Smad Proteins
  • TEAD4 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta1
  • PRDM1 protein, human
  • Epidermal Growth Factor
  • Positive Regulatory Domain I-Binding Factor 1
  • Bone Morphogenetic Protein Receptors

Supplementary concepts

  • Nonseminomatous germ cell tumor