Halting the vicious cycle within the multiple myeloma ecosystem: Blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression
Solimando AG, Da Via MC, Leone P, Borrelli P, Croci GA, Tabares P, Brandl A, Di Lernia G, Bianchi FP, Tafuri S, Steinbrunn T, Balduini A, Melaccio A, De Summa S, Argentiero A, Rauert-Wunderlich H, Frassanito MA, Ditonno P, Henke E, Klapper W, Ria R, Terragna C, Rasche L, Rosenwald A, Kortum KM, Cavo M, Ribatti D, Racanelli V, Einsele H, Vacca A, Beilhack A (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 106
Pages Range: 1943-1956
Journal Issue: 7
DOI: 10.3324/haematol.2019.239913
Abstract
nteractions of malignant multiple myeloma (MM) plasma cells with the microenvironment control MM plasma-cell growth, survival, drug-resistance 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 monoclonal gammopathy of undetermined significance and healthy controls. Elevated membrane expression of JAM-A on MM endothelial cells predicted 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-dimensional and three-dimensional in vitro cell cultures and chorioallantoic membrane 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 JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for the survival of both patients with newly diagnosed MM and those with relapsed/refractory MM. Blocking JAM-A restricts angiogenesis in vitro, in utero and in vivo and represents a suitable druggable molecule to halt neo-angiogenesis and MM progression.
Involved external institutions
University of Bari Aldo Moro / Università degli Studi di Bari Aldo Moro
Italy (IT)
Universitätsklinikum Würzburg
Germany (DE)
Hospital Giovanni Paolo II
Italy (IT)
Julius-Maximilians-Universität Würzburg
Germany (DE)
Università degli Studi di Pavia
Italy (IT)
Universitätsklinikum Schleswig-Holstein (UKSH)
Germany (DE)
Italy (IT)
Universitätsklinikum Würzburg
Germany (DE)
Hospital Giovanni Paolo II
Italy (IT)
Julius-Maximilians-Universität Würzburg
Germany (DE)
Università degli Studi di Pavia
Italy (IT)
Universitätsklinikum Schleswig-Holstein (UKSH)
Germany (DE)
How to cite
APA:
Solimando, A.G., Da Via, M.C., Leone, P., Borrelli, P., Croci, G.A., Tabares, P.,... Beilhack, A. (2021). Halting the vicious cycle within the multiple myeloma ecosystem: Blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression. Haematologica, 106(7), 1943-1956. https://doi.org/10.3324/haematol.2019.239913
MLA:
Solimando, Antonio G., et al. "Halting the vicious cycle within the multiple myeloma ecosystem: Blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression." Haematologica 106.7 (2021): 1943-1956.
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