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Blood, 15 July 2007, Vol. 110, No. 2, pp. 624-631.
Prepublished online as a Blood First Edition Paper on March 21, 2007; DOI 10.1182/blood-2007-01-065714.
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Submitted January 5, 2007
Accepted March 12, 2007
Distinct roles of VEGFR-1 and -2 in the aberrant hematopoiesis associated with elevated levels of VEGF
Yuhui Huang, Xiaolan Chen, Mikhail M. Dikov, Sergey V Novitskiy, Claudio A. Mosse, Li Yang, and David P. Carbone*
Dept of Cancer Biology, Vanderbilt University, Nashville, TN, United States
Vanderbilt-Ingram Cancer Center, Dept of Medicine, Vanderbilt University, Nashville, TN, United States
Vanderbilt-Ingram Cancer Center, Dept of Pathology, Vanderbilt University, Nashville, TN, United States
* Corresponding author; email: d.carbone{at}vanderbilt.edu.
VEGF, a major factor in tumor-host interactions, plays critical roles in the aberrant hematopoiesis observed in cancer-bearing hosts. To dissect the roles of VEGFR-1 and VEGFR-2 in cancer-associated hematopoiesis in vivo, we selectively stimulated VEGFR-1 and VEGFR-2 by continuous infusion of receptor-specific ligands or selective blockade with VEGF receptor-specific antibodies in mice infused with recombinant VEGF at levels observed in tumor-bearing animals. We found that the effect of VEGF on the accumulation of Gr1+CD11b+ cells is mediated by VEGFR-2, but that the two receptors have opposite effects on lymphocyte development. Pathophysiologic levels of VEGF strongly inhibit T cell development via VEGFR-2, while VEGFR-1 signaling decreases this inhibition. VEGFR-1 and not VEGFR-2 signaling is responsible for the observed increase of splenic B cells. Both receptors are capable of inhibiting dendritic cell function. These data suggest that most of observed aberrant hematopoiesis caused by excess tumor-derived VEGF is mediated by VEGFR-2, and VEGFR-1 alone has very limited independent effects but clearly both positively and negatively modulates the effects of VEGFR-2. Our findings suggest that selective blockade of VEGFR-2 rather than of both receptors may optimally overcome the adverse hematologic consequences of elevated VEGF levels found in malignancy.
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