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

TitleAutocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration.
Publication TypeJournal Article
Year of Publication2000
AuthorsDias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, Moore MA, Rafii S
JournalJ Clin Invest
Date Published2000 Aug
KeywordsAnimals, Antibodies, Monoclonal, Base Sequence, Cell Division, Cell Movement, DNA Primers, Endothelial Growth Factors, Gene Expression, Graft Survival, Humans, Leukemia, Lymphokines, Matrix Metalloproteinase 9, Mice, Mice, Inbred NOD, Neoplasm Transplantation, Neoplastic Cells, Circulating, Receptor Protein-Tyrosine Kinases, Receptors, Growth Factor, Receptors, Vascular Endothelial Growth Factor, RNA, Messenger, RNA, Neoplasm, Signal Transduction, Transplantation, Heterologous, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors

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. VEGF(165) induced phosphorylation of VEGFR-2 and increased proliferation of leukemic cells, demonstrating these receptors were functional. VEGF(165) 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 VEGF(165)-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.

Alternate JournalJ Clin Invest
PubMed ID10953026
PubMed Central IDPMC380247
Grant ListR01 HL061849 / HL / NHLBI NIH HHS / United States
R01HL58707 / HL / NHLBI NIH HHS / United States
R01HL61401 / HL / NHLBI NIH HHS / United States
R01HL61849 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Amy Chadburn, M.D.

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