Page 173 - 2021_07-Haematologica-web

Plasma Cell Disorders
Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression
Ferrata Storti Foundation
Haematologica 2021 Volume 106(7)1943-1956
Antonio G. Solimando,1,2,3 Matteo C. Da Viá,1,4,5 Patrizia Leone,3
Paola Borrelli,6 Giorgio A. Croci,7,8 Paula Tabares,1,9 Andreas Brandl,1,9 Giuseppe Di Lernia,3 Francesco P. Bianchi,10 Silvio Tafuri,10 Torsten Steinbrunn,1 Alessandra Balduini,11,12 Assunta Melaccio,3 Simona De Summa,13 Antonella Argentiero,2 Hilka Rauert-Wunderlich,14 Maria A. Frassanito,3 Paolo Ditonno,2 Erik Henke,15 Wolfram Klapper,7 Roberto Ria,3 Carolina Terragna,16 Leo Rasche,1 Andreas Rosenwald,14 K. Martin Kortüm,1 Michele Cavo,16 Domenico Ribatti,17 Vito Racanelli,3 Hermann Einsele,1 Angelo Vacca3 and Andreas Beilhack1,9
1Department of Medicine II, University Hospital of Würzburg, Würzburg, Germany; 2IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy; 3Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Aldo Moro Medical School, Bari, Italy; 4Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 5Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; 6Unit of Biostatistics and Clinical Epidemiology, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy; 7Department of Pathology, Hematopathology Section and Lymph Node Registry, University of Kiel/University Hospital Schleswig-Holstein, Kiel, Germany; 8Pathology Unit, Department of Pathophysiology and Transplantation, University of Milan and Fondazione IRCCS, Ca' Granda, Milan, Italy; 9Interdisciplinary Center for Clinical Research Laboratory, University Hospital of Würzburg, Würzburg, Germany; 10Section of Hygiene, Department of Biomedical Science and Human Oncology, University of Aldo Moro Medical School, Bari, Italy; 11Department of Molecular Medicine, University of Pavia, Pavia, Italy; 12Department of Biomedical Engineering, Tufts University, Medford, MA, USA; 13Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy; 14Institute of Pathology, University of Würzburg, Würzburg, Germany; 15Institute of Anatomy and Cell Biology, Julius-Maximilians Universität Würzburg, Würzburg, Germany; 16Institute of Hematology "L. and A. Seràgnoli", Bologna, Italy and 17Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Aldo Moro Medical School, Bari, Italy
ABSTRACT
Interactions of malignant multiple myeloma (MM) plasma cells with the microenvironment control MM plasma-cell growth, survival, drug-resis- tance and dissemination. As microvascular density increases in the bone marrow in MM, we investigated whether bone marrow MM endothelial cells control disease progression via the junctional adhesion molecule-A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MM endothelial cells in 111 patients with newly diagnosed MM and in 201 with relapsed/refractory MM compared to the levels in patients with mon- oclonal gammopathy of undetermined significance and healthy controls. Elevated membrane expression of JAM-A on MM endothelial cells predict- ed poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MM endothelial cells increased angiogenesis, whereas inhibition of this adhesion molecule impaired angiogenesis and MM growth in two-dimen- sional and three-dimensional in vitro cell cultures and chorioallantoic mem- brane assays. To corroborate these findings, we treated MM-bearing mice with a JAM-A-blocking monoclonal antibody and demonstrated impaired MM progression, corresponding to decreased MM-related vascularity. These findings support the concept that JAM-A is an important mediator of MM progression through facilitating MM-associated angiogenesis. Elevated
Correspondence:
ANDREAS BEILHACK
beilhack_a@klinik.uni-wuerzburg.de
Received: October 7, 2019. Accepted: April 28, 2020. Pre-published: June 4, 2020.
https://doi.org/10.3324/haematol.2019.239913
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2021; 106(7)
1943
ARTICLE