期刊
HAEMATOLOGICA
卷 106, 期 7, 页码 1943-1956出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2019.239913
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资金
- Bayerische Forschungsstiftung consortium FortiTher [WP2TP3]
- Deutsche Forschungsgemeinschaft mBone consortium [2084/1, 401253051]
- Italian Association for Cancer Research (AIRC) [20441]
- GLOBALDOC Project [CUP H96J17000160002]
- Puglia Region under the Action Plan for Cohesion [9]
- Apulian Regional Project Medicina di Precisione
- Wilhelm SanderStiftung [2014.903.1]
The interaction between malignant multiple myeloma (MM) plasma cells and the microenvironment, particularly bone marrow MM endothelial cells expressing junctional adhesion molecule-A (JAM-A), plays a crucial role in regulating MM progression. Elevated expression of JAM-A in MM endothelial cells is associated with poor clinical outcomes and advanced disease. Blocking JAM-A has shown to restrict angiogenesis and impede MM progression, suggesting it as a potential therapeutic target for halting neo-angiogenesis in MM.
Interactions 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.
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