Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours.
Angiogenesis and extracellular matrix degradation are key events in tumour progression, and factors regulating stromal-epithelial interactions and matrix composition are potential targets for the development of novel anti-invasive/antiangiogenic therapies. Here, we examine the expression of ADAMTS-8, a secreted protease with antiangiogenic properties, in brain tissues. Using quantitative RT-polymerase chain reaction (PCR), high, equivalent expression of ADAMTS-8 was found in normal whole brain, cerebral cortex, frontal lobe, cerebellum and meninges. ADAMTS-8 expression in 34 brain tumours (including 22 high-grade gliomas) and four glioma cell lines indicated at least two-fold reduction in mRNA compared to normal whole brain in all neoplastic tissues, and no detectable expression in 14 out of 34 (41%) tumours or four out of four (100%) cell lines. In contrast, differential expression of TSP1 and VEGF was seen in nine out of 15 (60%) and seven out of 13 (54%) tumours, with no relationship in the expression of these genes. Immunohistochemistry and Western analysis indicated downregulation of ADAMTS-8 protein in >77% tumours. Methylation-specific PCR analysis of ADAMTS-8 indicated promoter hypermethylation in one out of 24 brain tumours (a metastasis) and three out of four glioma cell lines suggesting an alternative mechanism of downregulation. These data suggest a role for ADAMTS-8 in brain tumorigenesis, warranting further investigation into its role in regulation of tumour angiogenesis and local invasion.
Dunn
J R
JR
JK Douglas Cancer Research Laboratories, Clatterbridge Hospital, Bebington, Wirral CH64 3JY, and Department of Neurological Science, University of Liverpool, UK. julie.dunn@ccrt.nhs.uk
Reed
J E
JE
du Plessis
D G
DG
Shaw
E J
EJ
Reeves
P
P
Gee
A L
AL
Warnke
P
P
Walker
C
C
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000071096:ADAMTS Proteins; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D018797:Cell Cycle Proteins; D012333:RNA, Messenger; C497749:TSPY1 protein, human; D042461:Vascular Endothelial Growth Factor A; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C120807:ADAMTS8 protein, human