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Mol Oncol. 2014 Jul;8(5):968-81. doi: 10.1016/j.molonc.2014.03.015. Epub 2014 Mar 27.

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

Author information

  • 1Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: ilaria.plantamura@istitutotumori.mi.it.
  • 2Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: patrizia.casalini@istitutotumori.mi.it.
  • 3Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: erica.dugnani@istitutotumori.mi.it.
  • 4Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: marianna.sasso@istitutotumori.mi.it.
  • 5Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: elvira.dippolito@istitutotumori.mi.it.
  • 6Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: monica.tortoreto@istitutotumori.mi.it.
  • 7Department of Human Pathology, University of Palermo, Palermo, Italy. Electronic address: matilde.cacciatore@unipa.it.
  • 8Department of Human Pathology, University of Palermo, Palermo, Italy. Electronic address: carla.guarnotta@unipa.it.
  • 9Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: cristina.ghirelli@istitutotumori.mi.it.
  • 10Institute of Human Morphology and Biomedical Sciences "Città Studi", University of Milan, 20133 Milan, Italy. Electronic address: isabella.barajon@unimi.it.
  • 11Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: francesca.bianchi@istitutotumori.mi.it.
  • 12Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: tiziana.triulzi@istitutotumori.mi.it.
  • 13Division of Surgical Oncology, Breast Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: roberto.agresti@istitutotumori.mi.it.
  • 14Institute of Human Morphology and Biomedical Sciences "Città Studi", University of Milan, 20133 Milan, Italy. Electronic address: andrea.balsari@unimi.it.
  • 15Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: manuela.campiglio@istitutotumori.mi.it.
  • 16Department of Human Pathology, University of Palermo, Palermo, Italy. Electronic address: claudio.tripodo@unipa.it.
  • 17Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: marilena.iorio@istitutotumori.mi.it.
  • 18Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy. Electronic address: elda.tagliabue@istitutotumori.mi.it.

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.

Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

FGFR; PDGFR; TNBC; Vasculogenic mimicry

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