Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo Journal Article


Authors: Wang, E. S.; Teruya-Feldstein, J.; Wu, Y.; Zhu, Z.; Hicklin, D. J.; Moore, M. A. S.
Article Title: Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo
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. © 2004 by The American Society of Hematology.
Keywords: immunohistochemistry; vasculotropin; controlled study; human cell; angiogenesis inhibitor; nonhuman; receptors, vascular endothelial growth factor; drug targeting; methotrexate; rituximab; cell proliferation; mouse; animals; mice; antineoplastic combined chemotherapy protocols; animal model; immunoglobulin; mice, scid; vasculotropin receptor 2; angiogenesis; vascular endothelial growth factor receptor-2; vascularization; monoclonal antibody; drug delivery systems; b cell lymphoma; cd20 antigen; antibodies, monoclonal; xenograft; messenger rna; immunocytochemistry; lymphoma, non-hodgkin; lymphoma cell; transplantation, heterologous; autocrine communication; large cell lymphoma; neoplasm transplantation; antigen binding; vascular endothelial growth factor receptor-1; antineoplastic antimetabolite; vasculotropin antibody; burkitt lymphoma; scid mouse; vasculotropin receptor 1; paracrine communication; diffuse large b cell lymphoma; lymphoma, large-cell, diffuse; humans; human; priority journal; article
Journal Title: Blood
Volume: 104
Issue: 9
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2004-11-01
Start Page: 2893
End Page: 2902
Language: English
DOI: 10.1182/blood-2004-01-0226
PROVIDER: scopus
PUBMED: 15238424
DOI/URL:
Notes: Blood -- Cited By (since 1996):101 -- Export Date: 16 June 2014 -- CODEN: BLOOA -- Source: Scopus
Altmetric Score
MSK Authors
  1. Julie T Feldstein
    288 Feldstein
  2. Eunice S Wang
    13 Wang
  3. Malcolm A S Moore
    427 Moore