Potential role of HER2‐overexpressing exosomes in countering trastuzumab‐based therapy
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- 23 November 2011
- journal article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 227 (2), 658-667
- https://doi.org/10.1002/jcp.22773
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. J. Cell. Physiol. 227: 658–667, 2012.Keywords
This publication has 36 references indexed in Scilit:
- Shed HER2 extracellular domain in HER2‐mediated tumor growth and in trastuzumab susceptibilityJournal of Cellular Physiology, 2010
- Breast cancer-specific mutations in CK1ε inhibit Wnt/β-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migrationBreast Cancer Research, 2010
- Management of breast cancer with targeted agents: importance of heterogenicityNature Reviews Clinical Oncology, 2010
- Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cellsJCI Insight, 2010
- HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironmentBreast Cancer Research and Treatment, 2009
- Membrane vesicles as conveyors of immune responsesNature Reviews Immunology, 2009
- A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and MetastasisMolecular and Cellular Biology, 2009
- High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma PatientsPLOS ONE, 2009
- Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot studyBlood, 2009
- Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast CancerJNCI Journal of the National Cancer Institute, 2007