Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy

Valentina Ciravolo, Veronica Huber, Gaia C. Ghedini, Elisabetta Venturelli, Francesca Bianchi, Manuela Campiglio, Daniele Morelli, Antonello Villa, Pamela Della Mina, Sylvie Menard, Paola Filipazzi, Licia Rivoltini, Elda Tagliabue, Serenella M. Pupa

Research output: Contribution to journalArticle

198 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)658-667
Number of pages10
JournalJournal of Cellular Physiology
Volume227
Issue number2
DOIs
Publication statusPublished - Jan 2012

Fingerprint

Exosomes
Tumors
Cells
Cell proliferation
Neuregulin-1
Antibodies, Monoclonal, Humanized
Therapeutics
Epidermal Growth Factor
Protein-Tyrosine Kinases
Assays
Cell Proliferation
Intercellular Signaling Peptides and Proteins
Breast Neoplasms
Ligands
Tumor Microenvironment
Endosomes
Molecules
Fluids
Trastuzumab
Tumor Cell Line

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. / Ciravolo, Valentina; Huber, Veronica; Ghedini, Gaia C.; Venturelli, Elisabetta; Bianchi, Francesca; Campiglio, Manuela; Morelli, Daniele; Villa, Antonello; Mina, Pamela Della; Menard, Sylvie; Filipazzi, Paola; Rivoltini, Licia; Tagliabue, Elda; Pupa, Serenella M.

In: Journal of Cellular Physiology, Vol. 227, No. 2, 01.2012, p. 658-667.

Research output: Contribution to journalArticle

Ciravolo, V, Huber, V, Ghedini, GC, Venturelli, E, Bianchi, F, Campiglio, M, Morelli, D, Villa, A, Mina, PD, Menard, S, Filipazzi, P, Rivoltini, L, Tagliabue, E & Pupa, SM 2012, 'Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy', Journal of Cellular Physiology, vol. 227, no. 2, pp. 658-667. https://doi.org/10.1002/jcp.22773
Ciravolo, Valentina ; Huber, Veronica ; Ghedini, Gaia C. ; Venturelli, Elisabetta ; Bianchi, Francesca ; Campiglio, Manuela ; Morelli, Daniele ; Villa, Antonello ; Mina, Pamela Della ; Menard, Sylvie ; Filipazzi, Paola ; Rivoltini, Licia ; Tagliabue, Elda ; Pupa, Serenella M. / Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. In: Journal of Cellular Physiology. 2012 ; Vol. 227, No. 2. pp. 658-667.
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