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.
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
J R
JR
Dunn
J E
JE
Reed
D G
DG
du Plessis
E J
EJ
Shaw
P
P
Reeves
A L
AL
Gee
P
P
Warnke
C
C
Walker
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