Induction and transport of Wnt 5a during macrophage-induced malignant invasion is mediated by two types of extracellular vesicles
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Kerstin Menck1,*, Florian Klemm1,*, Julia Christina Gross2, Tobias Pukrop1, Dirk Wenzel3, Claudia Binder1
1 Dept of Hematology/Oncology, University Medicine, Göttingen, Germany
2 Div. Signaling and Functional Genomics, German Cancer Research Center, Heidelberg, Germany
3 Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
* These authors contributed equally to this work.
Claudia Binder, email:
Keywords: Breast cancer, exosomes, Evi, microvesicles, macrophages, Wnt 5a
Received: August 27, 2013 Accepted: October 19, 2013 Published: October 21, 2013
Recently, we have shown that macrophage (MΦ)-induced invasion of breast cancer cells requires upregulation of Wnt 5a in MΦ leading to activation of β-Catenin-independent Wnt signaling in the tumor cells. However, it remained unclear, how malignant cells induce Wnt 5a in MΦ and how it is transferred back to the cancer cells. Here we identify two types of extracellular particles as essential for this intercellular interaction in both directions. Plasma membrane-derived microvesicles (MV) as well as exosomes from breast cancer cells, although biologically distinct populations, both induce Wnt 5a in MΦ. In contrast, the particle-free supernatant and vesicles from benign cells, such as platelets, have no such effect. Induction is antagonized by the Wnt inhibitor Dickkopf-1. Subsequently, Wnt 5a is shuttled via responding MΦ-MV and exosomes to the tumor cells enhancing their invasion. Wnt 5a export on both vesicle fractions depends at least partially on the cargo protein Evenness interrupted (Evi). Its knockdown leads to Wnt 5a depletion of both particle populations and reduced vesicle-mediated invasion. In conclusion, MV and exosomes are critical for MΦ-induced invasion of cancer cells since they are responsible for upregulation of MΦ-Wnt 5a as well as for its delivery to the recipient cells via a reciprocal loop. Although of different biogenesis, both populations share common features regarding function and Evi-dependent secretion of non-canonical Wnts.
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