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Cell Oncol (Dordr). 2017 Oct;40(5):483-496. doi: 10.1007/s13402-017-0338-4. Epub 2017 Jul 18.

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

Author information

1
Laboratory of Pre-clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), via Padre Pio, 1, 85028, Rionero in Vulture, Italy. francesco.larocca@crob.it.
2
Laboratorio di Oncologia, IRCCS - G. Gaslini Institute, Genoa, Italy.
3
Ce.S.I.-MeT, Aging Research Center, Pathological Anatomy and Immuno-Oncology Unit, and Department of Medicine and Sciences of Aging, "G. D'Annunzio" University, Chieti, Italy.
4
Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
5
Department of Biology, University of Naples "Federico II", Naples, Italy.
6
Laboratory of Pre-clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), via Padre Pio, 1, 85028, Rionero in Vulture, Italy.
7
Department of Onco-Hematology, IRCCS-CROB, Rionero in Vulture, Italy.
8
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.
9
Laboratory of Clinical Research and Advanced Diagnostics, IRCCS-CROB, Rionero in Vulture, Italy.
10
Laboratorio Cellule Staminali post-natali e Terapie Cellulari, IRCCS - G. Gaslini Institute, Genoa, Italy.
11
Department of Clinical Sciences and Community Health, University of Milan and Hematology, Fondazione CĂ  Granda, Ospedale Maggiore Policlinico, Milan, Italy.
12
Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.
13
CEINGE-Biotecnologie Avanzate scarl, Naples, Italy.
14
Scientific Direction, IRCCS-CROB, Rionero in Vulture, Italy.
15
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
16
Laboratory of Pre-clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), via Padre Pio, 1, 85028, Rionero in Vulture, Italy. caivanoa@libero.it.

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.

KEYWORDS:

Anti EphA3 monoclonal antibody; Cell movement; EphA3; Multiple myeloma; Plasma cells

PMID:
28721629
DOI:
10.1007/s13402-017-0338-4
[Indexed for MEDLINE]
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