Abstract
Simple SummaryThe Jagged family of ligands are aberrantly expressed during multiple myeloma progression and contributes to activate Notch signaling both in myeloma cells and in the nearby bone marrow cell populations activating several pro-tumor effects. This work elucidates, in vitro, in vivo as well as in patients’ bone marrow biopsies, different mechanisms by which tumor cell-derived Jagged1 and 2 contribute to myeloma-associated angiogenesis. These include the ability to induce myeloma and bone marrow stromal cell secretion of VEGF along with a direct activation of the pro-angiogenic Notch signaling pathway in endothelial cells. This research provides a rational for a Jagged-directed therapy in multiple myeloma.Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1–2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines’ ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients’ BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.
Highlights
Multiple myeloma (MM) is a plasma cell malignancy mainly settled in the bone marrow (BM)where it establishes tight communication with the stromal cell populations, including BM stromal cells (BMSCs) and endothelial cells (ECs), and promotes a pro-tumor microenvironment (TME), inducing the angiogenic switch [1] and favoring MM growth and progression [2].MM may rise as an asymptomatic monoclonal gammopathy of undetermined significance (MGUS), a benign avascular phase of the disease [3]
To assess the involvement of MM cell-derived Jagged ligands in angiogenesis promotion, we knocked down (KD) the ligands in two human myeloma cell lines (HMCLs), namely RPMI8226 and
An ELISA assay (Figure 2E) confirmed that the down-modulation of vascular endothelial growth factor (VEGF)-A mRNA affected the protein secretion. These results indicated that the HMCLs may promote angiogenesis by activating the Notch signaling in ECs via heterotypic Jagged-mediated Notch activation and, HMCL-mediated secretion of pro-angiogenic VEGF-A is influenced by homotypic activation of the Notch signaling induced by the Jagged ligands
Summary
Multiple myeloma (MM) is a plasma cell malignancy mainly settled in the bone marrow (BM)where it establishes tight communication with the stromal cell populations, including BM stromal cells (BMSCs) and endothelial cells (ECs), and promotes a pro-tumor microenvironment (TME), inducing the angiogenic switch [1] and favoring MM growth and progression [2].MM may rise as an asymptomatic monoclonal gammopathy of undetermined significance (MGUS), a benign avascular phase of the disease [3]. Where it establishes tight communication with the stromal cell populations, including BM stromal cells (BMSCs) and endothelial cells (ECs), and promotes a pro-tumor microenvironment (TME), inducing the angiogenic switch [1] and favoring MM growth and progression [2]. The progression from MGUS to MM is characterized by clonal expansion of tumor cells within the BM (infiltrating a cell number higher than 10%) and it is coupled with an angiogenic switch that brings forth neo-vessels formation throughout the BM [4]. MM-associated endothelial cells (MM-ECs) differ from MGUS-ECs due to their higher intrinsic angiogenic capability [5,6]. The interaction between the ligand and receptor induces two proteolytic cleavages that releases the intracellular portion of Notch, which in turn activates the transcription of the Notch-responsive genes [9]
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