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Updated: Dec 9, 2025
Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
Published on: May 1, 2015
Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells
Maria Teresa Palano1, Domenica Giannandrea1, Natalia Platonova1
1Department of Health Sciences, Università degli Studi di Milano, 20142 Milano, Italy.
Abstract:
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.
Insights
Multiple myeloma (MM) progression involves increased angiogenesis. Jagged ligands from MM cells promote tumor angiogenesis and stimulate bone marrow stromal cells to enhance it, suggesting Jagged ligands as a therapeutic target.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Multiple myeloma (MM) is an incurable plasma cell cancer.
- MM progression involves changes in the bone marrow (BM) microenvironment, including increased angiogenesis.
- Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and is characterized by endothelial cell network formation, migration, and growth factor expression, such as vascular endothelial growth factor (VEGF).
Purpose of the Study:
- To investigate the role of Jagged1 and Jagged2 ligands in MM progression.
- To determine the impact of Jagged ligand dysregulation on the angiogenic potential of MM cells and bone marrow stromal cells (BMSCs).
- To explore the therapeutic potential of targeting Jagged ligands in MM.
Main Methods:
- Modulation of Jagged1-2 expression using RNA interference and soluble peptide administration.
- In vitro analysis of MM cell lines' ability to induce human pulmonary artery endothelial cell (HPAEC) angiogenesis.
- Assessment of the indirect effect on BMSC angiogenic potential.
- In vivo validation using a zebrafish model and analysis of MM patient BM biopsies.
Main Results:
- MM-derived Jagged ligands enhance tumor cell angiogenic potential.
- Jagged ligands directly trigger Notch activation in HPAECs, stimulating VEGF release.
- MM-derived Jagged ligands stimulate BMSCs to promote angiogenesis via VEGF secretion.
- Notch activation in the BM microenvironment during MM progression exhibits a pro-angiogenic effect.
Conclusions:
- Jagged ligands play a significant role in MM-associated angiogenesis.
- Targeting Jagged ligands may represent a promising therapeutic strategy for MM.
- Understanding the interaction between MM cells, BMSCs, and angiogenesis is crucial for developing effective treatments.
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