Cysteine cathepsins B, X and K expression in peri-arteriolar glioblastoma stem cell niches

Abstract

Glioblastoma (GBM) is the most lethal brain tumor also due to malignant and therapy-resistant GBM stem cells (GSCs) that are localized in protecting hypoxic GSC niches. Some members of the cysteine cathepsin family of proteases have been found to be upregulated in GBM. Cathepsin K gene expression is highly elevated in GBM tissue versus normal brain and it has been suggested to regulate GSC migration out of the niches. Here, we investigated the cellular distribution of cathepsins B, X and K in GBM tissue and whether these cathepsins are co-localized in GSC niches. Therefore, we determined expression of these cathepsins in serial paraffin sections of 14 human GBM samples and serial cryostat sections of two samples using immunohistochemistry and metabolic mapping of cathepsin activity using selective fluorogenic substrates. We detected cathepsins B, X and K in peri-arteriolar GSC niches in 9 out of 16 GBM samples, which were defined by co-expression of the GSC marker CD133, the niche marker stromal-derived factor-1α (SDF-1α) and smooth muscle actin as a marker for arterioles. The expression of cathepsin B and X was detected in stromal cells and cancer cells throughout the GBM sections, whereas cathepsin K expression was more restricted to arteriole-rich regions in the GBM sections. Metabolic mapping showed that cathepsin B, but not cathepsin K is active in GSC niches. On the basis of these findings, it is concluded that cathepsins B, X and K have distinct functions in GBM and that cathepsin K is the most likely GSC niche-related cathepsin of the three cathepsins investigated.

Expression of Cathepsins B, D, and G in WHO Grade I Meningioma

“…Elevated expression of cathepsin B and cathepsin D has been observed in many tumor types such as infantile hemangioma (38), oral tongue squamous cell carcinoma (33), MG (39), and gliomas (40, 41) including GB (34). Interestingly, the cathepsin B expression pattern that we report here almost parallels that reported with GB cancer stem cells (31). Taken together, upregulation of cathepsin B within WHO grade 1 MG may indicate a growth phase in this tumor, although, this requires further investigation.…”

“…The expression of cathepsin B by the stem cell niche on the microvessels in GB has been reported recently (31), with this staining pattern being a negative prognostic factor (32). This study was aimed at investigating the expression of cathepsins B, D, and G in WHO grade I MG, in relation to the putative TSC population we have previously identified (17).…”

‘Patchiness’ and basic cancer research: unravelling the proteases

“…TI/TM/ECMD SCC, BC, G [44] S TI C, GAS [45] Z/X TG/TI/TM PC, HPC [46,47] A TI/TM MM [48] D TI/TM/ANG B, L, O [49] adenocarcinoma OCT4-positive cells [63]. In further developments, Cathepsin B activity was also found to be enriched in Glioblastoma stem cells from hypoxic niches using IHC and fluorogenic substrates in CD133-positive cells [64] indicating the possible importance of Cathepsin B as a potential marker in stem cell biology and cancer prognosis. Collectively, the potential involvement of the Cathepsins in cancer stem cell regulation appears to have significant and more research is therefore warranted in determining more precisely what mechanistic role they play in tumor signaling, progression and chemotherapeutic resistance in such systems.…”

Glioblastoma: Microenvironment and Niche Concept

“…A recent paper took into consideration all niche types described in the literature (perivascular, hypoxic, immune, extracellular matrix niches, etc.) concluding that they are not distinct from one another but they are parts of a single GSC niche, according to the hypoxic periarteriolar niche model [46,47] in which cathepsin K would play a functional role [48]. Roughly, they correspond to the one described as prototype of the PVN.…”