Functional VEGF and VEGF receptors are expressed in human medulloblastomas.
Vascular endothelial growth factor (VEGF) is one of the key regulators of tumor neoangiogenesis. It acts through two types of high-affinity tyrosine kinase receptors (VEGF receptor-1 [VEGFR-1]/fms-related tyrosine kinase 1 [Flt-1] and VEGFR-2/kinase domain receptor [KDR]) expressed on endothelial cells. VEGFRs have also been detected on cancer cells, suggesting a possible autocrine effect of VEGF on their growth. We studied the expression of VEGF, VEGFR-1, and VEGFR-2 in human medulloblastoma cell lines (DAOY, D283Med, and D341Med) and investigated the possible autocrine mechanisms of VEGF on medulloblastoma cell proliferation. Reverse transcriptase PCR analysis showed the presence of VEGF and VEGFR mRNAs in all cell lines studied. Of the three VEGF isoforms, VEGF(121) and VEGF(189) were detected by Western blot analysis in all three medulloblastoma cell lines, whereas VEGF(165) was identified only in DAOY cells. Medulloblastoma cell lines expressed both VEGFR-1 and VEGFR-2. We also demonstrated expression of VEGF and its receptors in medulloblastoma tumor specimens. Exogenous VEGFR-2 inhibitor reduced the VEGF-dependent cell proliferation of DAOY and D283Med cells. In DAOY cells, VEGF(165) induced phosphorylation of VEGFR-2/KDR and of downstream proteins in the signal transduction pathway. These data suggest a possible autocrine role for VEGF in medulloblastoma growth. Targeting VEGF signaling may represent a new therapeutic option in the treatment of medulloblastoma.
Slongo
M Liliana
ML
Department of Experimental Biomedical Sciences, Division of Hematology-Oncology, University-Hospital of Padua, Via Giustiniani 3, 35128 Padua, Italy.
Molena
Beatrice
B
Brunati
Anna Maria
AM
Frasson
Martina
M
Gardiman
Marina
M
Carli
Modesto
M
Perilongo
Giorgio
G
Rosolen
Angelo
A
Onisto
Maurizio
M
D000293:Adolescent; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor
Lab Invest. 1999 Dec;79(12):1573-82
10616207
EMBO J. 2000 Apr 3;19(7):1525-33
10747021
J Clin Invest. 2000 Aug;106(4):511-21
10953026
J Invest Dermatol. 2000 Dec;115(6):1000-7
11121133
Cell Growth Differ. 2001 Mar;12(3):129-35
11306513
J Neurosci. 2001 May 15;21(10):3332-41
11331362
Blood. 2001 Sep 15;98(6):1904-13
11535528
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10857-62
11553814
Eur J Cancer. 2001 Nov;37(16):2064-72
11597385
Mol Cell Proteomics. 2002 Apr;1(4):304-13
12096112
Proteomics. 2002 Sep;2(9):1267-76
12362345
Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8
12516034
Nat Med. 2003 Jun;9(6):669-76
12778165
J Neurooncol. 2004 Jan;66(1-2):129-38
15015778
Lancet Oncol. 2004 Apr;5(4):209-18
15050952
Pathol Res Pract. 2004;200(7-8):501-9
15462497
Semin Oncol. 2004 Oct;31(5):666-75
15497120
Science. 1983 Feb 25;219(4587):983-5
6823562
J Neuropathol Exp Neurol. 1989 Jan;48(1):48-68
2535715
Science. 1989 Dec 8;246(4935):1306-9
2479986
Curr Opin Oncol. 1997 May;9(3):223-9
9229143
Cancer Res. 1999 Feb 1;59(3):728-33
9973224
Cancer Res. 1999 Jul 15;59(14):3374-8
10416597
Urology. 1999 Sep;54(3):567-72
10475375
Oncogene. 2005 Jan 27;24(5):790-800
15592523
J Clin Oncol. 2005 Feb 10;23(5):1011-27
15585754
Cancer. 2005 Jul 15;104(2):427-38
15952180
Int J Oncol. 2005 Sep;27(3):791-8
16077930
Oncogene. 2005 Dec 1;24(54):8025-37
16116481
Nature. 2005 Dec 15;438(7070):967-74
16355214
J Cell Mol Med. 2005 Oct-Dec;9(4):777-94
16364190
Nature. 2006 May 25;441(7092):457-62
16724058