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Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias

Division of Hematology-Oncology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2001; 98(19):10857-10862. DOI: 10.1073/pnas.191117498

ABSTRACT Antiangiogenic agents block the effects of tumor-derived angiogenic factors (paracrine factors), such as vascular endothelial
growth factor (VEGF), on endothelial cells (EC), inhibiting the growth of solid tumors. However, whether inhibition of angiogenesis
also may play a role in liquid tumors is not well established. We recently have shown that certain leukemias not only produce
VEGF but also selectively express functional VEGF receptors (VEGFRs), such as VEGFR-2 (Flk-1, KDR) and VEGFR1 (Flt1), resulting
in the generation of an autocrine loop. Here, we examined the relative contribution of paracrine (EC-dependent) and autocrine
(EC-independent) VEGF/VEGFR signaling pathways, by using a human leukemia model, where autocrine and paracrine VEGF/VEGFR
loops could be selectively inhibited by neutralizing mAbs specific for murine EC (paracrine pathway) or human tumor (autocrine)
VEGFRs. Blocking either the paracrine or the autocrine VEGF/VEGFR-2 pathway delayed leukemic growth and engraftment in vivo, but failed to cure inoculated mice. Long-term remission with no evidence of disease was achieved only if mice were treated
with mAbs against both murine and human VEGFR-2, whereas mAbs against human or murine VEGFR-1 had no effect on mice survival.
Therefore, effective antiangiogenic therapies to treat VEGF-producing, VEGFR-expressing leukemias may require blocking both
paracrine and autocrine VEGF/VEGFR-2 angiogenic loops to achieve remission and long-term cure.

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    • "). Inhibition of VEGF receptors reduces angiogenic activity and appears to either directly or indirectly inhibit the growth of leukaemic cells (Dias et al, 2001; Zhu et al, 2003). The findings of the present study add new elements and complexity to our understanding of the cell signalling generated by the activation of VEGF-R in AML cells, showing a cross-talk between VEGF-R from one side and IL-3R and GM-CSFR from the other side. "
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