title: Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN.
abstract: Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that are known to support the establishment of a favorable tumor niche by influencing the surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also directly influence the tumor cells by enhancing their invasion in a both autologous and heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. Uptake of T-MV is essential for the proinvasive effect. We further identify the highly glycosylated form of the extracellular matrix metalloproteinase inducer (EMMPRIN) as a marker for proinvasive MV. EMMPRIN is also present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides, inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN.
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Menck
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medicine Greifswald, Walther-Rathenau-Str. 43-45, 17475 Greifswald, Germany Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487 Greifswald, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Scharf
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Dyck
authors.affiliation: Institute for Organic and Biomolecular Chemistry, University of Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Rost
authors.affiliation: Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487 Greifswald, Germany.
authors.forename: Vishnu M
authors.initials: VM
authors.lastname: Dhople
authors.affiliation: Department of Neurosurgery, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Laila
authors.initials: L
authors.lastname: Siam
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
authors.affiliation: Department of Hematology/Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany Present address: Sloan Kettering Institute, Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 417 E 68th St., Z-1306, New York, NY 10065, USA klemmf@mskcc.org.
authors.forename: Florian
authors.initials: F
authors.lastname: Klemm
mesh_terms: D000595:Amino Acid Sequence; D051926:Basigin / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D055252:Cell-Derived Microparticles / Q000502:physiology*; D004790:Enzyme Induction; D005260:Female; D006031:Glycosylation; D006801:Humans; D061986:MCF-7 Cells; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011499:Protein Processing, Post-Translational; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C497886:BSG protein, human; D051926:Basigin; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases
keywords: EMMPRIN; breast cancer; glycosylation; invasion; microvesicles