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Cell and Tumor Biology |
Departments of 1 Genetic Medicine, 2 Medicine and Hematology-Medical Oncology, and 3 Obstetrics and Gynecology, Weill Medical College of Cornell University; and 4 ImClone Systems, Inc., New York, New York
Requests for reprints: Loïc Vincent and Shahin Rafii, Department of Medicine and Hematology-Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. Phone: 212-746-2070; E-mail: vincentloicny{at}yahoo.com and srafii{at}med.cornell.edu.
Induction of neoangiogenesis plays an important role in the pathogenesis of multiple myeloma. However, the mechanism by which expression of vascular endothelial growth factor (VEGF)-A and its receptors modulate the interaction of multiple myeloma cells with stromal cells is not known. Here, we describe a novel in vitro coculture system using fetal bone stromal cells as a feeder layer, which facilitates the survival and growth of human primary multiple myeloma cells. We show that stromal-dependent paracrine VEGF-A signaling promotes proliferation of human primary multiple myeloma cells. Primary multiple myeloma cells only expressed functional VEGF receptor (VEGFR)-1, but not VEGFR-2 or VEGFR-3. VEGFR-1 expression was detected in the cytoplasm and the nuclei of proliferating multiple myeloma cells. Inhibition of VEGFR-1 abrogated multiple myeloma cell proliferation and motility, suggesting that the functional interaction of VEGF-A with its cognate receptor is essential for the growth of primary multiple myeloma cells. Collectively, our results suggest that stromal-dependent paracrine and intracrine VEGF-A/VEGFR-1 signaling contributes to human primary multiple myeloma cell growth and therefore, VEGFR-1 blockade is a potential therapeutic strategy for the treatment of multiple myeloma.
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