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

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)483-496
Number of pages14
JournalCellular Oncology
Volume40
Issue number5
DOIs
Publication statusPublished - 2017

Fingerprint

Multiple Myeloma
Growth
Plasma Cells
Cell Survival
In Vitro Techniques
EphA3 Receptor
Heterografts
Bone Marrow Cells
Small Interfering RNA
Cell Line
Receptor Protein-Tyrosine Kinases
Gene Expression Profiling
Hematologic Neoplasms
Stromal Cells
Fibronectins
Cell Communication
Cell Movement
Anti-Idiotypic Antibodies
Neoplasms
Flow Cytometry

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells. / la Rocca, Francesco; Airoldi, Irma; Di Carlo, Emma; Marotta, Pina; Falco, Geppino; Simeon, Vittorio; Laurenzana, Ilaria; Trino, Stefania; de Luca, Luciana; Todoerti, Katia; Villani, Oreste; Lackmann, Martin; D’Auria, Fiorella; Frassoni, Francesco; Neri, Antonino; Del Vecchio, Luigi; Musto, Pellegrino; Cilloni, Daniela; Caivano, Antonella.

In: Cellular Oncology, Vol. 40, No. 5, 2017, p. 483-496.

Research output: Contribution to journalArticle

la Rocca, F, Airoldi, I, Di Carlo, E, Marotta, P, Falco, G, Simeon, V, Laurenzana, I, Trino, S, de Luca, L, Todoerti, K, Villani, O, Lackmann, M, D’Auria, F, Frassoni, F, Neri, A, Del Vecchio, L, Musto, P, Cilloni, D & Caivano, A 2017, 'EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells', Cellular Oncology, vol. 40, no. 5, pp. 483-496. https://doi.org/10.1007/s13402-017-0338-4
la Rocca, Francesco ; Airoldi, Irma ; Di Carlo, Emma ; Marotta, Pina ; Falco, Geppino ; Simeon, Vittorio ; Laurenzana, Ilaria ; Trino, Stefania ; de Luca, Luciana ; Todoerti, Katia ; Villani, Oreste ; Lackmann, Martin ; D’Auria, Fiorella ; Frassoni, Francesco ; Neri, Antonino ; Del Vecchio, Luigi ; Musto, Pellegrino ; Cilloni, Daniela ; Caivano, Antonella. / EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells. In: Cellular Oncology. 2017 ; Vol. 40, No. 5. pp. 483-496.
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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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T1 - EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells

AU - la Rocca, Francesco

AU - Airoldi, Irma

AU - Di Carlo, Emma

AU - Marotta, Pina

AU - Falco, Geppino

AU - Simeon, Vittorio

AU - Laurenzana, Ilaria

AU - Trino, Stefania

AU - de Luca, Luciana

AU - Todoerti, Katia

AU - Villani, Oreste

AU - Lackmann, Martin

AU - D’Auria, Fiorella

AU - Frassoni, Francesco

AU - Neri, Antonino

AU - Del Vecchio, Luigi

AU - Musto, Pellegrino

AU - Cilloni, Daniela

AU - Caivano, Antonella

PY - 2017

Y1 - 2017

N2 - 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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