VASCULAR ENDOTHELIAL GROWTH-FACTOR INHIBITS THE DEVELOPMENT OF DENDRITIC CELLS AND DRAMATICALLY AFFECTS THE DIFFERENTIATION OF MULTIPLE HEMATOPOIETIC LINEAGES IN-VIVO

Defective function of dendritic cells (DC) in cancer has been recently described and may represent one of the mechanisms of tumor evasion fr om immune system control. We have previously shown in vitro that vascu lar endothelial growth factor (VEGF), produced by almost all tumors, i s one of the tumor-derived factors responsible for the defective funct ion of these cells. In this study, we investigated whether in vivo inf usion of recombinant VEGF could reproduce the observed DC dysfunction. Continuous VEGF infusion, at rates as low as 50 ng/h (resulting in se rum VEGF concentrations of 120 to 160 pg/mL), resulted in a dramatic i nhibition of dendritic cell development, associated with an increase i n the production of B cells and immature Gr-1(+) myeloid cells. Infusi on of VEGF was associated with inhibition of the activity of the trans cription factor NF-kappa B in bone marrow progenitor cells. Experiment s in vitro showed that VEGF itself, and not factors released by VEGF-a ctivated endothelial cells, affected polypotent stem cells resulting i n the observed abnormal hematopoiesis. These data suggest that VEGF, a t pathologically relevant concentrations in vivo, may exert effects on pluripotent stem cells that result in blocked DC development as well as affect many other hematopoietic lineages. (C) 1998 by The American Society of Hematology.