PlGF and VEGF-A Regulate Growth of High-Risk MYCN-Single Copy Neuroblastoma Xenografts via Different Mechanisms.
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and is a rapidly growing, highly-vascularized cancer. NBs frequently express angiogenic factors and high tumor angiogenesis has been associated with poor outcomes. Placental growth factor (PlGF) is an angiogenic protein belonging to the vascular endothelial growth factor (VEGF) family and is up-regulated mainly in pathologic conditions. Recently, PlGF was identified as a member of a gene expression signature characterizing highly malignant NB stem cells drawing attention as a potential therapeutic target in NB. In the present study, we sought to investigate the expression of PlGF in NB patients and the effect of PlGF inhibition on high-risk MYCN-non-amplified SK-N-AS NB xenografts. Human SK-N-AS cells, which are poorly differentiated and express PlGF and VEGF-A, were implanted subcutaneously in athymic nude mice. Treatment was done by intratumoral injection of replication-incompetent adenoviruses (Ad) expressing PlGF- or VEGF-specific short hairpin (sh)RNA, or soluble (s)VEGF receptor 2 (VEGFR2). The effect on tumor growth and angiogenesis was analyzed. High PlGF expression levels were observed in human advanced-stage NBs. Down-regulating PlGF significantly reduced NB growth in established NB xenografts by reducing cancer cell proliferation but did not suppress angiogenesis. In contrast, blocking VEGF by administration of Ad(sh)VEGF and Ad(s)VEGFR2 reduced tumor growth associated with decreased tumor vasculature. These findings suggest that PlGF and VEGF-A modulate MYCN-non-amplified NB tumors by different mechanisms and support a role for PlGF in NB biology.
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, A-1090 Vienna, Austria. karin.zins@meduniwien.ac.at.
Karin
K
Zins
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, A-1090 Vienna, Austria. zardinax@gmail.com.
Daniel
D
Kovatchki
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, A-1090 Vienna, Austria. trevor.lucas@meduniwien.ac.at.
Trevor
T
Lucas
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, A-1090 Vienna, Austria. dietmar.abraham@meduniwien.ac.at.|Comprehensive Cancer Center (CCC), Medical University of Vienna, A-1090 Vienna, Austria. dietmar.abraham@meduniwien.ac.at.
Dietmar
D
Abraham
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002675:Child, Preschool; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics*; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D000072483:Placenta Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D000071447:N-Myc Proto-Oncogene Protein; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2
neuroblastoma; placental growth factor; vascular endothelial growth factor A; vascular endothelial growth factor receptor 2; xenograft model
N Engl J Med. 2010 Jun 10;362(23):2202-11
20558371
Oncogene. 2008 Jun 26;27(28):3999-4007
18278068
Stem Cell Res. 2015 Sep;15(2):419-26
26342562
Endocr Relat Cancer. 2013 May 20;20(3):305-19
23463017
Nat Med. 2001 May;7(5):575-83
11329059
J Clin Oncol. 1996 Feb;14(2):405-14
8636750
J Cancer Res Clin Oncol. 2001 Dec;127(12):739-43
11768614
Semin Immunopathol. 2013 Sep;35(5):585-600
23657835
J Clin Oncol. 1993 Aug;11(8):1466-77
8336186
Int J Cancer. 1999 Mar 31;81(1):113-7
10077161
Int J Mol Sci. 2013 Sep 03;14 (9):17958-71
24005860
Cancer Treat Rev. 2005 Feb;31(1):27-34
15707702
J Clin Oncol. 2008 Jan 20;26(3):399-405
18202416
Cancer Res. 2001 Jan 15;61(2):679-86
11212268
Lancet Oncol. 2003 Aug;4(8):472-80
12901961
J Clin Oncol. 2007 Feb 1;25(4):376-83
17264333
Cancer Cell. 2011 Jun 14;19(6):740-53
21665148
FEBS Lett. 2005 Feb 14;579(5):1227-34
15710418
Clin Cancer Res. 2011 Mar 1;17 (5):976-88
21343374
Cell. 2010 Apr 2;141(1):166-77
20371352
Nat Med. 2003 Jun;9(6):669-76
12778165
Int J Cancer. 2002 Dec 1;102(4):351-4
12402304
N Engl J Med. 2008 May 8;358(19):2039-49
18463380
Cancer Lett. 2005 Oct 18;228(1-2):171-9
15927358
Eur J Cancer. 2002 Apr;38(6):750-7
11937307
J Reprod Immunol. 2003 Oct;60(1):53-60
14568677
J Clin Oncol. 2000 Jan;18(1):27-34
10623690
Int J Oncol. 2009 Feb;34(2):401-7
19148474
Am J Pathol. 2012 Oct;181(4):1115-25
22944600
Folia Neuropathol. 2007;45(1):1-8
17357004
Cell. 2010 Apr 2;141(1):178-90
20371353
Nat Rev Drug Discov. 2011 Jun;10(6):417-27
21629292
J Pediatr Surg. 2002 Apr;37(4):582-7
11912515
Clin Cancer Res. 2000 May;6(5):1900-8
10815914
Cancer Lett. 2003 Jul 18;197(1-2):47-52
12880959
Ann Oncol. 2008 Apr;19(4):807-13
18056650
Microvasc Res. 2012 Sep;84(2):155-60
22683469
Stem Cells. 2009 Sep;27(9):2342-52
19522014
Exp Mol Med. 2012 Jan 31;44(1):10-9
22217448
Cold Spring Harb Perspect Med. 2012 Aug 01;2(8):null
22908198
Blood. 2003 Aug 15;102(4):1515-24
12689930
Oncotarget. 2016 Jul 19;7(29):46668-46677
27081695
Eur J Cancer. 2008 Aug;44(12 ):1645-56
18614349
Cancer Res. 2006 Apr 15;66(8):4349-56
16618760
J Transl Med. 2013 Nov 27;11:295
24279335
Crit Rev Oncol Hematol. 2013 Jun;86(3):212-21
23273512
Clin Cancer Res. 2010 Mar 1;16(5):1431-41
20179233
Nat Rev Cancer. 2007 Jun;7(6):475-85
17522716
Oncotarget. 2016 Jul 19;7(29):46187-46202
27323822