Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets.
The invasive phenotype of glioblastoma multiforme (GBM) is a hallmark of malignant process, yet molecular mechanisms that dictate this locally invasive behavior remain poorly understood. Gene expression profiles of human glioma cells were assessed from laser capture-microdissected GBM cells collected from paired patient tumor cores and white matter-invading cell populations. Changes in gene expression in invading GBM cells were validated by quantitative reverse transcription polymerase chain reaction (QRT-PCR) and immunohistochemistry in an independent sample set. QRT-PCR confirmed the differential expression in 19 of 21 genes tested. Immunohistochemical analyses of autotaxin (ATX), ephrin B3, B-cell lymphoma-w (BCLW), and protein tyrosine kinase 2 beta showed them to be expressed in invasive glioma cells. The known GBM markers, insulin-like growth factor binding protein 2 and vimentin, were robustly expressed in the tumor core. A glioma invasion tissue microarray confirmed the expression of ATX and BCLW in invasive cells of tumors of various grades. GBM phenotypic and genotypic heterogeneity is well documented. In this study, we show an additional layer of complexity: transcriptional differences between cells of tumor core and invasive cells located in the brain parenchyma. Gene products supporting invasion may be novel targets for manipulation of brain tumor behavior with consequences on treatment outcome.
Hoelzinger
Dominique B
DB
Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
Mariani
Luigi
L
Weis
Joachim
J
Woyke
Tanja
T
Berens
Theresa J
TJ
McDonough
Wendy S
WS
Sloan
Andrew
A
Coons
Stephen W
SW
Berens
Michael E
ME
D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007834:Lasers; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D012333:RNA, Messenger
Nat Immunol. 2001 Jun;2(6):493-500
11376335
Genes Dev. 2001 Jun 1;15(11):1311-33
11390353
Clin Cancer Res. 2001 Aug;7(8):2480-9
11489830
Am J Pathol. 2001 Sep;159(3):779-86
11549567
Cancer Res. 2001 Sep 15;61(18):6885-91
11559565
Brain Pathol. 2002 Jan;12(1):87-94
11770904
Brain Pathol. 2002 Jan;12(1):108-16
11771519
J Neuropathol Exp Neurol. 2002 Mar;61(3):215-25; discussion 226-9
11895036
Biochimie. 2002 Feb-Mar;84(2-3):195-201
12022950
Clin Exp Metastasis. 2002;19(3):225-32
12067203
Neuro Oncol. 2002 Jul;4(3):179-86
12084348
Front Biosci. 2002 Aug 1;7:e339-53
12133814
Physiol Rev. 2002 Oct;82(4):893-922
12270947
Am J Physiol Regul Integr Comp Physiol. 2002 Nov;283(5):R1104-17
12376404
Cancer Res. 2002 Nov 1;62(21):6278-88
12414658
Mol Cancer Ther. 2002 Nov;1(13):1229-36
12479704
Clin Exp Metastasis. 2002;19(7):603-8
12498389
Nature. 2003 Jan 2;421(6918):83-7
12511959
Brain Pathol. 2003 Jan;13(1):52-61
12580545
J Cell Biol. 2003 Feb 17;160(4):565-75
12578912
Cancer Res. 2003 Mar 1;63(5):1093-100
12615727
Mol Cancer Res. 2003 Mar;1(5):323-32
12651906
Cancer Res. 2003 Apr 1;63(7):1602-7
12670911
Science. 2003 Apr 4;300(5616):135-9
12624178
J Clin Oncol. 2003 Apr 15;21(8):1624-36
12697889
Oncogene. 2003 Apr 17;22(15):2361-73
12700671
J Exp Clin Cancer Res. 2003 Jun;22(2):299-306
12866581
Cancer J. 2003 May-Jun;9(3):180-8
12952303
J Cell Sci. 2003 Nov 1;116(Pt 21):4409-17
13130092
Acta Neurochir Suppl. 2003;88:153-62
14531573
Int J Oncol. 2003 Dec;23(6):1697-702
14612943
J Neurol Neurosurg Psychiatry. 1999 Dec;67(6):763-8
10567494
Biochem Cell Biol. 2000;78(5):569-75
11103947
Cancer Res. 2000 Dec 1;60(23):6617-22
11118044
Int J Oncol. 2001 Feb;18(2):287-95
11172594
Cancer Res. 2001 May 15;61(10):4190-6
11358844
J Neurosci. 2001 May 15;21(10):3360-8
11331365
Cell Motil Cytoskeleton. 2004 Feb;57(2):84-95
14691948
J Biol Chem. 2004 Feb 6;279(6):4136-43
14627715
J Neurosurg. 1983 Feb;58(2):159-69
6294260
Cancer. 1989 Jul 15;64(2):442-7
2736491
J Biol Chem. 1992 Feb 5;267(4):2524-9
1733949
J Biol Chem. 1993 May 25;268(15):10709-12
8496137
Cancer. 1995 Jun 15;75(12):2904-9
7773941
Int J Cancer. 1996 Jul 17;67(2):275-82
8760599
Mol Cell Biol. 1996 Sep;16(9):5069-80
8756665
J Neurosurg. 1997 Sep;87(3):420-30
9285609
Acta Neurochir (Wien). 1997;139(9):845-50
9351989
Anticancer Res. 1997 Nov-Dec;17(6B):4145-9
9428348
Nat Med. 1998 Jul;4(7):844-7
9662379
Cancer Res. 1999 Sep 1;59(17):4228-32
10485462
J Neuropathol Exp Neurol. 1999 Oct;58(10):1029-40
10515226