Abstract |
The role of angiogenesis in lymphoproliferative diseases is not well established. We demonstrate here that human lymphoma cells secrete vascular endothelial growth factor ( VEGF) and express VEGF receptor 1 (VEGFR-1) and VEGFR-2. Proliferation of non-Hodgkin lymphoma (NHL) cells under serum-free conditions was enhanced by the addition of VEGF and was blocked by VEGFR-1- and VEGFR-2-specific antibodies. To differentiate between VEGF-mediated autocrine and paracrine effects on lymphoma growth, NOD/SCID mice engrafted with human diffuse large B-cell lymphoma (DLBCL) were treated with species-specific antibodies against human VEGFR-1 (6.12), human VEGFR-2 (IMC-1C11), murine VEGFR-1 (MF-1), or murine VEGFR-2 (DC101). Treatment with 6.12 or DC101 (targeting tumor VEGFR-1 and host VEGFR-2) reduced established DLBCL xenograft growth, whereas treatment with IMC-1C11 or MF-1 (targeting tumor VEGFR-1 and host VEGFR-1) had no effect. Decreased tumor volumes after 6.12 and DC101 treatment correlated with increased tumor apoptosis and reduced vascularization, respectively, supporting the presence of autocrine VEGFR-1- and paracrine VEGFR-2-mediated pathways in lymphomagenesis. Inhibition of paracrine VEGF interactions (DC101) in these models was equivalent to their inhibition with rituximab. Combining DC101 with therapeutic agents ( rituximab, 6.12, methotrexate) consistently improved tumor responses over those of single-agent therapy. These data support the further clinical development of VEGFR-targeted approaches for the therapy of aggressive DLBCL.
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Authors | Eunice S Wang, Julie Teruya-Feldstein, Yan Wu, Zhenping Zhu, Daniel J Hicklin, Malcolm A S Moore |
Journal | Blood
(Blood)
Vol. 104
Issue 9
Pg. 2893-902
(Nov 01 2004)
ISSN: 0006-4971 [Print] United States |
PMID | 15238424
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antibodies, Monoclonal
- Receptors, Vascular Endothelial Growth Factor
- Vascular Endothelial Growth Factor Receptor-1
- Vascular Endothelial Growth Factor Receptor-2
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Topics |
- Animals
- Antibodies, Monoclonal
(pharmacology, therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, therapeutic use)
- Autocrine Communication
(drug effects, physiology)
- Cell Proliferation
(drug effects)
- Drug Delivery Systems
- Humans
- Lymphoma, Large B-Cell, Diffuse
(drug therapy, pathology)
- Lymphoma, Non-Hodgkin
(drug therapy, pathology)
- Mice
- Mice, SCID
- Neoplasm Transplantation
- Paracrine Communication
(drug effects, physiology)
- Receptors, Vascular Endothelial Growth Factor
(immunology, metabolism)
- Transplantation, Heterologous
- Vascular Endothelial Growth Factor Receptor-1
(immunology, metabolism)
- Vascular Endothelial Growth Factor Receptor-2
(immunology, metabolism)
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