title: Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy.
abstract: Exosomes are endosome-derived nanovesicles actively released into the extracellular environment and biological fluids, both under physiological and pathological conditions, by different cell types. We characterized exosomes constitutively secreted by HER2-overexpressing breast carcinoma cell lines and analyzed in vitro and in vivo their potential role in interfering with the therapeutic activity of the humanized antibody Trastuzumab and the dual tyrosine kinase inhibitor (TKI) Lapatinib anti-HER2 biodrugs. We show that exosomes released by the HER2-overexpressing tumor cell lines SKBR3 and BT474 express a full-length HER2 molecule that is also activated, although to a lesser extent than in the originating cells. Release of these exosomes was significantly modulated by the growth factors EGF and heregulin, two of the known HER2 receptor-activating ligands and naturally present in the surrounding tumor microenvironment. Exosomes secreted either in HER2-positive tumor cell-conditioned supernatants or in breast cancer patients' serum bound to Trastuzumab. Functional assays revealed that both xenogeneic and autologous HER2-positive nanovesicles, but not HER2-negative ones, inhibited Trastuzumab activity on SKBR3 cell proliferation. By contrast, Lapatinib activity on SKBR3 cell proliferation was unaffected by the presence of autologous exosomes. Together, these findings point to the role of HER2-positive exosomes in modulating sensitivity to Trastuzumab, and, consequently, to HER2-driven tumor aggressiveness.
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciravolo
authors.forename: Veronica
authors.initials: V
authors.lastname: Huber
authors.forename: Gaia C
authors.initials: GC
authors.lastname: Ghedini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Venturelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.forename: Manuela
authors.initials: M
authors.lastname: Campiglio
authors.forename: Daniele
authors.initials: D
authors.lastname: Morelli
authors.forename: Antonello
authors.initials: A
authors.lastname: Villa
authors.forename: Pamela
authors.initials: P
authors.lastname: Della Mina
authors.forename: Sylvie
authors.initials: S
authors.lastname: Menard
authors.forename: Paola
authors.initials: P
authors.lastname: Filipazzi
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.forename: Serenella M
authors.initials: SM
authors.lastname: Pupa
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D055354:Exosomes / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009361:Neoplasm Invasiveness; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human