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B Activation in Hemopoietic Progenitor Cells1
*
The Vanderbilt Cancer Center and Departments of Medicine and
Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; and
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75287
Vascular endothelial growth factor (VEGF), produced by almost all
tumor cells, affects the ability of hemopoietic progenitor cells (HPC)
to differentiate into functional dendritic cells (DC) during the early
stages of their maturation. In this study we demonstrate specific
binding of VEGF to HPC. This binding was efficiently competed by
placenta growth factor (PlGF), a ligand reportedly specific for the
Flt-1 receptor. The number of binding sites for VEGF decreased during
DC maturation in vitro associated with decreased levels of mRNA for
Flt-1. VEGF significantly inhibited nuclear factor-
B
(NF-B)-dependent activation of reporter gene transcription during
the first 24 h in culture. The presence of VEGF significantly
decreased the specific DNA binding of NF-B as early as 30 min after
induction with TNF-
. This was followed on days 7 to 10 by decreases
in the mRNA for RelB and c-Rel, two subunits of NF-B. Blockade of
NF-B activity in HPC at early stages of differentiation with an
adenovirus expressing a dominant IB inhibitor of NF-B reproduced
the pattern of effects observed with VEGF. Thus, NF-B plays an
important role in maturation of HPCs to DC, and VEGF activation of the
Flt-1 receptor is able to block the activation of NF-B in this
system. Blockade of NF-B activation in HPCs by tumor-derived factors
may therefore be a mechanism by which tumor cells can directly
down-modulate the ability of the immune system to generate effective
antitumor immune responses.
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B. R. Wong, R. Josien, S. Y. Lee, M. Vologodskaia, R. M. Steinman, and Y. Choi The TRAF Family of Signal Transducers Mediates NF-kappa B Activation by the TRANCE Receptor J. Biol. Chem., October 23, 1998; 273(43): 28355 - 28359. [Abstract] [Full Text] [PDF]
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 S. Rosic-Kablar, K. Chan, M. D. Reis, I. D. Dube, and M. R. Hough Induction of tolerance to immunogenic tumor antigens associated with lymphomagenesis in HOX11 transgenic mice PNAS, November 21, 2000; 97(24): 13300 - 13305. [Abstract] [Full Text] [PDF]
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