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HB-EGF–EGFR Signaling in Bone Marrow Endothelial Cells Mediates Angiogenesis Associated with Multiple Myeloma

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Department of Biomedical Sciences and Human Oncology, Guido Baccelli Unit of Internal Medicine, University of Bari Medical School, 70124 Bari, Italy
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Department of Emergency and Organ Transplantations, Section of Pathological Anatomy, University of Bari Medical School, 70124 Bari, Italy
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Department of Interdisciplinary Medicine, University of Bari Medical School, 70124 Bari, Italy
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Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, 70124 Bari, Italy
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Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70124 Bari, Italy
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Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
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Bio-Proteomics Facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano (PN), Italy
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Vito Racanelli MD, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Policlinico, 11 Piazza G. Cesare, 70124 Bari, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(1), 173; https://doi.org/10.3390/cancers12010173
Received: 11 November 2019 / Revised: 2 January 2020 / Accepted: 8 January 2020 / Published: 10 January 2020
(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)
Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM. View Full-Text
Keywords: multiple myeloma; HB-EGF; EGFR; bone marrow angiogenesis; endothelial cells multiple myeloma; HB-EGF; EGFR; bone marrow angiogenesis; endothelial cells
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Rao, L.; Giannico, D.; Leone, P.; Solimando, A.G.; Maiorano, E.; Caporusso, C.; Duda, L.; Tamma, R.; Mallamaci, R.; Susca, N.; Buonavoglia, A.; Da Vià, M.C.; Ribatti, D.; De Re, V.; Vacca, A.; Racanelli, V. HB-EGF–EGFR Signaling in Bone Marrow Endothelial Cells Mediates Angiogenesis Associated with Multiple Myeloma. Cancers 2020, 12, 173.

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