title: Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis.
abstract: The potential role of osteoblasts in bone and bone marrow (BM) metastases in neuroblastoma (NBL) remains unclear. In this study, we examined the effect of NBL cells on the osteoblastic differentiation of BM-derived mesenchymal stromal cells (BMMSC). We show that the presence of NBL cells enhanced the osteoblastic differentiation of BMMSC driven by bone morphogenetic protein (BMP)-4, in the absence of any effect on NBL cell proliferation. Expression profiles of BMMSC driven toward osteoblastic differentiation revealed an increase in vascular endothelial growth factor A (Vegfa) expression in the presence of NBL cells. We demonstrated that NBL cells increased BMMSC-derived VEGFA mRNA and protein and that this was enhanced by BMP-4. However, in similar conditions, neither the addition of an mVEGFA blocking antibody nor exogenous recombinant (r) mVEGFA affected osteoblastic differentiation. In contrast, siRNA- mediated knock-down of VEGFA in BMMSC prevented osteoblastic differentiation in BMP-4-treated cocultures, an effect that was not reversed in the presence of rmVEGFA. An analysis of murine bones injected with hNBL cells revealed an increase of mVEGFA producing cells near tumor cells concomitantly with an increase in Vegfa and Runx2 mRNA. This coincided with an increase in osteoclasts, in Rankl/Opg mRNA ratio and with the formation of osteolytic lesions. Thus NBL cells promote osteoblastogenesis in the BM by increasing VEGFA expression in BMMSC. Our study provides a new insight into the role of VEGFA in NBL metastases by pointing to the role of stroma-derived intracrine VEGFA in osteoblastogenesis.
authors: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.|Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Southern California Keck School of Medicine, Los Angeles, CA.|Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors: Josephine H
authors: JH
authors: HaDuong
authors: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.|Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Southern California Keck School of Medicine, Los Angeles, CA.|Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors: Laurence
authors: L
authors: Blavier
authors: Department of Orthopedic Surgery, University of Southern California, Los Angeles, CA.
authors: Sanjeev K
authors: SK
authors: Baniwal
authors: Department of Orthopedic Surgery, University of Southern California, Los Angeles, CA.|Department of Biochemistry & Molecular Biology, University of Southern California, Los Angeles, CA.
authors: Baruch
authors: B
authors: Frenkel
authors: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.
authors: Jemily
authors: J
authors: Malvar
authors: Norris Comprehensive Cancer Center Bioinformatics Core and Division of Hematology, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors: Vasu
authors: V
authors: Punj
authors: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.|Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Southern California Keck School of Medicine, Los Angeles, CA.|Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors: Richard
authors: R
authors: Sposto
authors: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA.|Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Southern California Keck School of Medicine, Los Angeles, CA.|Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA.|Department of Biochemistry & Molecular Biology, University of Southern California, Los Angeles, CA.
authors: Yves A
authors: YA
authors: DeClerck
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000008:administration & dosage; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D053244:Osteoprotegerin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D055415:Bone Morphogenetic Protein 4; D050659:Core Binding Factor Alpha 1 Subunit; D053244:Osteoprotegerin; D012333:RNA, Messenger; C493716:Runx2 protein, mouse; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: VEGFA; mesenchymal cells; neuroblastoma; osteoblastogenesis
references: Cancer Metastasis Rev. 2006 Dec;25(4):551-8
references: 17160558
references: Mol Cancer Ther. 2014 Apr;13(4):962-75
references: 24502925
references: J Biol Chem. 2008 Jul 4;283(27):18573-81
references: 18450743
references: J Clin Oncol. 1999 Mar;17(3):846-54
references: 10071275
references: Br J Cancer. 1999 May;80(5-6):898-903
references: 10360672
references: Cancer Res. 2005 Sep 1;65(17):7554-60
references: 16140917
references: J Bone Miner Res. 2006 Apr;21(4):637-46
references: 16598384
references: J Cell Biochem. 2004 Feb 1;91(2):265-76
references: 14743387
references: Cancer Res. 2012 May 1;72(9):2228-38
references: 22389450
references: Clin Exp Metastasis. 2004;21(5):427-35
references: 15672867
references: J Biochem. 2012 Mar;151(3):247-54
references: 22253449
references: N Engl J Med. 2004 Apr 15;350(16):1655-64
references: 15084698
references: Int J Cancer. 2004 Oct 10;111(6):829-38
references: 15300794
references: J Clin Oncol. 2001 Aug 1;19(15):3562-71
references: 11481364
references: Anticancer Drugs. 2014 Jan;25(1):1-7
references: 24100278
references: Cancer Cell. 2011 Feb 15;19(2):192-205
references: 21295524
references: Cancer Res. 2009 Jan 1;69(1):329-37
references: 19118018
references: Osteoporos Int. 2012 Apr;23(4):1399-413
references: 21881969
references: Nature. 2010 Aug 12;466(7308):829-34
references: 20703299
references: J Clin Invest. 2000 Apr;105(8):R15-24
references: 10772661
references: Int J Cancer. 2008 Sep 1;123(5):1034-42
references: 18546262
references: Cancer Res. 2005 Aug 15;65(16):7267-75
references: 16103078
references: Cancer Res. 2001 Feb 15;61(4):1637-44
references: 11245477
references: Lancet. 2007 Jun 23;369(9579):2106-20
references: 17586306
references: Nat Rev Cancer. 2005 Jan;5(1):21-8
references: 15630412
references: J Biol Chem. 2012 Jan 13;287(3):1671-8
references: 22110141
references: J Mol Med (Berl). 2013 Jan;91(1):83-94
references: 22864925
references: Development. 2002 Apr;129(8):1893-904
references: 11934855
references: Cancer Res. 2005 Feb 15;65(4):1129-35
references: 15734993
references: J Clin Invest. 2012 Sep;122(9):3101-13
references: 22886301
references: Endocr Rev. 1998 Feb;19(1):18-54
references: 9494779
references: Eur J Cancer. 2000 Jun;36(10):1248-57
references: 10882863
references: Cancer. 2003 Feb 1;97(3 Suppl):834-9
references: 12548583
references: Cancer Lett. 2005 Oct 18;228(1-2):203-9
references: 15975706
references: J Biol Chem. 2002 Jul 5;277(27):24571-8
references: 11964407
references: Mol Endocrinol. 1993 Feb;7(2):189-98
references: 8385738
references: Curr Top Dev Biol. 2005;65:169-87
references: 15642383
references: N Engl J Med. 2003 Dec 25;349(26):2483-94
references: 14695408
references: J Natl Cancer Inst. 1997 Jun 18;89(12):881-6
references: 9196255
references: Gene. 2005 Aug 29;357(1):1-8
references: 16125875
references: Nat Rev Cancer. 2013 Jun;13(6):397-411
references: 23702928
references: Cancer Res. 2003 Jun 15;63(12 ):3026-31
references: 12810621
references: Nat Rev Cancer. 2011 Jun;11(6):411-25
references: 21593787
references: Bone. 2002 Mar;30(3):472-7
references: 11882460