PDGFRβ and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells

Ilaria Plantamura, Patrizia Casalini, Erica Dugnani, Marianna Sasso, Elvira D'Ippolito, Monica Tortoreto, Matilde Cacciatore, Carla Guarnotta, Cristina Ghirelli, Isabella Barajon, Francesca Bianchi, Tiziana Triulzi, Roberto Agresti, Andrea Balsari, Manuela Campiglio, Claudio Tripodo, Marilena V. Iorio, Elda Tagliabue

Research output: Contribution to journalArticle

Abstract

Triple negative breast cancer (TNBC) is a very aggressive subgroup of breast carcinoma, still lacking specific markers for an effective targeted therapy and with a poorer prognosis compared to other breast cancer subtypes.In this study we investigated the possibility that TNBC cells contribute to the establishment of tumor vascular network by the process known as vasculogenic mimicry, through endothelial cell differentiation.Vascular-like functional properties of breast cancer cell lines were investigated in vitro by tube formation assay and in vivo by confocal microscopy, immunofluorescence or immunohistochemistry on frozen tumor sections. TNBCs express endothelial markers and acquire the ability to form vascular-like channels in vitro and in vivo, both in xenograft models and in human specimens, generating blood lacunae surrounded by tumor cells. Notably this feature is significantly associated with reduced disease free survival. The impairment of the main pathways involved in vessel formation, by treatment with inhibitors (i.e. Sunitinib and Bevacizumab) or by siRNA-mediating silencing, allowed the identification of PDGFRβ and FGFR2 as relevant players in this phenomenon. Inhibition of these tyrosine kinase receptors negatively affects vascular lacunae formation and significantly inhibits TNBC growth in vivo.In summary, we demonstrated that TNBCs have the ability to form vascular-like channels in vitro and to generate blood lacunae lined by tumor cells in vivo. Moreover, this feature is associated with poor outcome, probably contributing to the aggressiveness of this breast cancer subgroup. Finally, PDGFRβ and FGFR2-mediated pathways, identified as relevant in mediating this characteristic, potentially represent valid targets for a specific therapy of this breast cancer subgroup.

Original languageEnglish
Pages (from-to)968-981
Number of pages14
JournalMolecular Oncology
Volume8
Issue number5
DOIs
Publication statusPublished - 2014

Keywords

  • FGFR
  • PDGFR
  • TNBC
  • Vasculogenic mimicry

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine
  • Medicine(all)

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  • Cite this

    Plantamura, I., Casalini, P., Dugnani, E., Sasso, M., D'Ippolito, E., Tortoreto, M., Cacciatore, M., Guarnotta, C., Ghirelli, C., Barajon, I., Bianchi, F., Triulzi, T., Agresti, R., Balsari, A., Campiglio, M., Tripodo, C., Iorio, M. V., & Tagliabue, E. (2014). PDGFRβ and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells. Molecular Oncology, 8(5), 968-981. https://doi.org/10.1016/j.molonc.2014.03.015