title: Fetal stromal-dependent paracrine and intracrine vascular endothelial growth factor-a/vascular endothelial growth factor receptor-1 signaling promotes proliferation and motility of human primary myeloma cells.
abstract: 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.
authors.affiliation: Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA. vincentloicny@yahoo.com
authors.forename: Loïc
authors.initials: L
authors.lastname: Vincent
authors.forename: David K
authors.initials: DK
authors.lastname: Jin
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Karajannis
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: William K
authors.initials: WK
authors.lastname: Rashbaum
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Peter
authors.initials: P
authors.lastname: Bohlen
authors.forename: Ruben
authors.initials: R
authors.lastname: Niesvizky
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1