Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours

Abstract

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 RTpolymerase 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 477% tumours. Methylationspecific 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.

Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis

“…Our data are in line with our previous report showing that ADAMTS-12 inhibits the formation of vascular endothelial growth factor-induced tubular structures in BAE-1 cells (Llamazares et al, 2007). The finding of antiangiogenic effects for a member of the ADAMTS family is not unprecedented as it has also been described for ADAMTS-1 and ADAMTS-8 (Vazquez et al, 1999;Dunn et al, 2006). However, the originality of our findings relies on the identification of a key host ADAMTS-12 contribution in the host protection toward the angiogenic response induced by tumor cells.…”

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

“…These two proteases also cleave two other members of the lectican family, aggrecan [53] and versican [54], and have a restricted additional spectrum of ECM substrates [55][56][57]. Other members of the ADAMTS family have been shown or proposed to have aggrecanase activity (recently reviewed in [58]) but their expression in the CNS is low and there is currently no evidence for their role in B/b processing in gliomas [59][60][61][62][63].…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Brain tumours, often invading surrounding parenchyma, could thus display a modulated proteinase expression facilitating tumour cell infiltration and/ or angiogenesis. Some ADAMTS proteinases (ADAMTS-8 and ADAMTS-13) display lower levels of expression in brain tumours as compared to normal brain tissue [118,119]. In sharp contrast, ADAMTS-4 and TS-5 are overexpressed in human glioblastomas and could be responsible for brevican cleavage and contribute to invasiveness of glioblastoma cells [120].…”