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

Emerging data suggest that VEGF receptors are expressed by endothelial cell s as well as hematopoietic stem cells. Therefore, we hypothesized that func tional VEGF receptors may also be expressed in malignant counterparts of he matopoietic stem cells such as leukemias. We demonstrate that certain leuke mias 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 iso lated leukemias expressed mRNA and protein for VEGFR-2. VEGF(165) induced p hosphorylation of VEGFR-2 and increased proliferation of leukemic cells, de monstrating these receptors were functional. VEGF(165) also induced the exp ression of MMP-9 by leukemic cells and promoted their migration through rec onstituted basement membrane. The neutralizing mAb IMC-1C11, specific to hu man VEGFR-2, inhibited leukemic cell survival in vitro and blocked VEGF(165 )-mediated proliferation of leukemic cells and VEGF-induced leukemic cell m igration. Xenotransplantation of primary leukemias and leukemic cell lines into immunocompromised nonobese diabetic mice resulted in significant eleva tion of human, but not murine, VEGF in plasma and death of inoculated mice within 3 weeks. Injection of IMC-1C11 inhibited proliferation of xenotransp lanted human leukemias and significantly increased the survival of inoculat ed mice. Interruption of signaling by VEGFR-2, particularly VEGFR-2, may pr ovide a novel strategy for inhibiting leukemic cell proliferation.