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01-10-2017 | Original Paper

EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells

Authors: Francesco La Rocca, Irma Airoldi, Emma Di Carlo, Pina Marotta, Geppino Falco, Vittorio Simeon, Ilaria Laurenzana, Stefania Trino, Luciana De Luca, Katia Todoerti, Oreste Villani, Martin Lackmann, Fiorella D’Auria, Francesco Frassoni, Antonino Neri, Luigi Del Vecchio, Pellegrino Musto, Daniela Cilloni, Antonella Caivano

Published in: Cellular Oncology | Issue 5/2017

Abstract

Purpose

Multiple myeloma (MM) is a hematologic malignancy characterized by a clonal expansion of plasma cells (PCs) in the bone marrow (BM). Since MM has so far remained incurable, further insights into its pathogenesis and the concomitant identification of new therapeutic targets are urgently needed. The tyrosine kinase receptor EphA3 is known to be involved in various cellular processes including cell viability, cell movement and cell-cell interactions. Recently, EphA3 has emerged as a potential therapeutic target in several hematologic and solid tumors. Here, we aimed to uncover the role of EphA3 in MM.

Methods

EphA3 mRNA and protein expression in primary MM bone marrow plasma cells (BMPCs), in MM-derived cell lines and in healthy controls (HCs) was assessed using qRT-PCR, Western blotting and flow cytometry. The effects of siRNA-mediated EphA3 silencing and anti EphA3 antibody (EphA3mAb) treatment on MM PC trafficking and viability were evaluated using in vitro assays. The effects of EphA3mAb treatment were also assessed in two MM-derived mouse xenograft models.

Results

We found that EphA3 was overexpressed in primary MM BMPCs and MM-derived cell lines compared to HCs. We also found that siRNA-mediated EphA3 silencing and EphA3mAb treatment significantly inhibited the ability of MM PCs to adhere to fibronectin and stromal cells and to invade in vitro, without affecting cell proliferation and viability. Gene expression profiling showed that EphA3 silencing resulted in expression modulation of several molecules that regulate adhesion, migration and invasion processes. Importantly, we found that EphA3mAb treatment significantly inhibited in vivo tumor growth and angiogenesis in two MM-derived mouse xenograft models.

Conclusions

Our findings suggest that EphA3 plays an important role in the pathogenesis of MM and provide support for the notion that its targeting may represent a novel therapeutic opportunity for MM.

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Title: EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells
Authors: Francesco La Rocca
Irma Airoldi
Emma Di Carlo
Pina Marotta
Geppino Falco
Vittorio Simeon
Ilaria Laurenzana
Stefania Trino
Luciana De Luca
Katia Todoerti
Oreste Villani
Martin Lackmann
Fiorella D’Auria
Francesco Frassoni
Antonino Neri
Luigi Del Vecchio
Pellegrino Musto
Daniela Cilloni
Antonella Caivano
Publication date: 01-10-2017
Publisher: Springer Netherlands
Published in: Cellular Oncology / Issue 5/2017
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-017-0338-4

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