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Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration
Sergio Dias, … , M.A.S. Moore, Shahin Rafii
Sergio Dias, … , M.A.S. Moore, Shahin Rafii
Published August 15, 2000
Citation Information: J Clin Invest. 2000;106(4):511-521. https://doi.org/10.1172/JCI8978.
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Article

Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration

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Abstract

Emerging data suggest that VEGF receptors are expressed by endothelial cells as well as hematopoietic stem cells. Therefore, we hypothesized that functional VEGF receptors may also be expressed in malignant counterparts of hematopoietic stem cells such as leukemias. We demonstrate that certain leukemias not only produce VEGF but also express functional VEGFR-2 in vivo and in vitro, resulting in the generation of an autocrine loop that may support leukemic cell survival and proliferation. Approximately 50% of freshly isolated leukemias expressed mRNA and protein for VEGFR-2. VEGF165 induced phosphorylation of VEGFR-2 and increased proliferation of leukemic cells, demonstrating these receptors were functional. VEGF165 also induced the expression of MMP-9 by leukemic cells and promoted their migration through reconstituted basement membrane. The neutralizing mAb IMC-1C11, specific to human VEGFR-2, inhibited leukemic cell survival in vitro and blocked VEGF165-mediated proliferation of leukemic cells and VEGF-induced leukemic cell migration. Xenotransplantation of primary leukemias and leukemic cell lines into immunocompromised nonobese diabetic mice resulted in significant elevation of human, but not murine, VEGF in plasma and death of inoculated mice within 3 weeks. Injection of IMC-1C11 inhibited proliferation of xenotransplanted human leukemias and significantly increased the survival of inoculated mice. Interruption of signaling by VEGFRs, particularly VEGFR-2, may provide a novel strategy for inhibiting leukemic cell proliferation.

Authors

Sergio Dias, Koichi Hattori, Zhenping Zhu, Beate Heissig, Margaret Choy, William Lane, Yan Wu, Amy Chadburn, Elizabeth Hyjek, Muhammad Gill, Daniel J. Hicklin, Larry Witte, M.A.S. Moore, Shahin Rafii

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Figure 10

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(a) Leukemic cell engraftment (%) in the bone marrow of HL-60– and HEL-i...
(a) Leukemic cell engraftment (%) in the bone marrow of HL-60– and HEL-inoculated mice. Day 15 after the start of the experiment, bone marrow cells from inoculated mice were stained for human CD15 and human VEGFR-2/KDR and quantified by flow cytometry. IMC-1C11–treated mice had a significantly lower percentage of human cells in the bone marrow than untreated mice (P < 0.001). These results are representative of three mice per cell line. (b) Quantification of primary leukemic cells in the peripheral blood of inoculated mice. PBMCs from primary leukemia-inoculated mice were stained for human CD45 and human VEGFR-2 and quantified by flow cytometry, as described in Methods. Fourteen days after the start of treatment, IMC-1C11–treated mice had significantly less circulating CD45+VEGFR-2+ human leukemic cells than untreated mice (P < 0.05). These results are representative of three mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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