Vascular endothelial growth factor (
VEGF) and its receptors (VEGFR) have been implicated in promoting solid
tumor growth and
metastasis via stimulating
tumor-associated angiogenesis. Here we show that certain "liquid"
tumors such as
acute myeloid leukemia not only produce
VEGF but also express functional VEGFR, resulting in an autocrine loop for
tumor growth and propagation. In addition, the
leukemia-derived
VEGF can also stimulate the production of
growth factors, including
interleukin 6 (
IL6) and
granulocyte-macrophage colony stimulating factor (
GM-CSF), by human endothelial cells, which in turn further promotes the growth of
leukemia cells (the paracrine loop). A fully human anti-VEGFR2 (or
kinase insert domain-containing receptor, KDR) antibody, IMC-2C6, strongly blocks KDR/
VEGF interaction and neutralizes
VEGF-stimulated activation of KDR in endothelial cells. In a system where
leukemia cells are co-cultured with endothelial cells, IMC-2C6 inhibits both the production of
IL6 and
GM-CSF by endothelial cells and the growth of
leukemia cells. Finally, IMC-2C6 effectively blocks
VEGF-induced migration of KDR+ human
leukemia cells, and when administered in vivo, significantly prolonged survival of mice inoculated with KDR+ human
leukemia cells. Taken together, our data suggest that anti-KDR
antibodies may have broad applications in the treatment of both solid
tumors and certain types of
leukemia.