title: PDGFRβ and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells.
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.
authors.affiliation: Molecular 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.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Plantamura
authors.affiliation: Molecular 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.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casalini
authors.affiliation: Molecular 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.
authors.forename: Erica
authors.initials: E
authors.lastname: Dugnani
authors.affiliation: Molecular 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.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sasso
authors.affiliation: Start 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.
authors.forename: Elvira
authors.initials: E
authors.lastname: D'Ippolito
authors.affiliation: Molecular 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.
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.affiliation: Department of Human Pathology, University of Palermo, Palermo, Italy. Electronic address: matilde.cacciatore@unipa.it.
authors.forename: Matilde
authors.initials: M
authors.lastname: Cacciatore
authors.affiliation: Department of Human Pathology, University of Palermo, Palermo, Italy. Electronic address: carla.guarnotta@unipa.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarnotta
authors.affiliation: Molecular 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghirelli
authors.affiliation: Institute of Human Morphology and Biomedical Sciences "Città Studi", University of Milan, 20133 Milan, Italy. Electronic address: isabella.barajon@unimi.it.
authors.forename: Isabella
authors.initials: I
authors.lastname: Barajon
authors.affiliation: Molecular 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.affiliation: Molecular 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.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Triulzi
authors.affiliation: Division of Surgical Oncology, Breast Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: roberto.agresti@istitutotumori.mi.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Agresti
authors.affiliation: Institute of Human Morphology and Biomedical Sciences "Città Studi", University of Milan, 20133 Milan, Italy. Electronic address: andrea.balsari@unimi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balsari
authors.affiliation: Molecular 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.
authors.forename: Manuela
authors.initials: M
authors.lastname: Campiglio
authors.affiliation: Department of Human Pathology, University of Palermo, Palermo, Italy. Electronic address: claudio.tripodo@unipa.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Start 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.
authors.forename: Marilena V
authors.initials: MV
authors.lastname: Iorio
authors.affiliation: Molecular 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.
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
mesh_terms: D000818:Animals; D001940:Breast / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D034741:RNA, Small Interfering; D051497:Receptor, Fibroblast Growth Factor, Type 2; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: FGFR; PDGFR; TNBC; Vasculogenic mimicry
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