The regulation of cysteine cathepsins and cystatins in human gliomas

Abstract

Cysteine cathepsins play an important role in shaping the highly infiltrative growth pattern of human gliomas. We have previously demonstrated that the activity of cysteine cathepsins is elevated in invasive glioblastoma (GBM) cells in vitro, in part due to attenuation of their endogenous inhibitors, the cystatins. To investigate this relationship in vivo, we established U87-MG xenografts in non-obese diabetic (NOD)/severe combined immunodeficiency (SCID)-enhanced green fluorescent protein (eGFP) mice. Here, tumor growth correlated with an elevated enzymatic activity of CatB both in the tumor core and at the periphery, whereas CatS and CatL levels were higher at the xenograft edge compared to the core. Reversely, StefB expression was detected in the tumor core, but it was generally absent in the tumor periphery, suggesting that downregulation of this inhibitor correlates with in vivo invasion. In human GBM samples, all cathepsins were elevated at the tumor periphery compared to brain parenchyma. CatB was also typically associated with angiogenic endothelia and necrotic areas. StefB was mainly detected in the tumor core, whereas CysC and StefA were evenly distributed, reflecting the observations in the xenografts. However, at the mRNA level, no differences in cathepsins and cystatins were observed between the tumor center and the periphery in both human biopsies and xenografts. Interestingly, in human tumors, cathepsin and stefin transcript levels correlated with CD68 and CXCR4 levels, but not with epidermal growth factor receptor (EGFR). Moreover, we reveal for the first time that an elevated StefA mRNA level is a highly significant prognostic factor for patient survival.

Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma

“…Recently, Sun et al [43] showed increased expression of stefin B in the nucleus of T98G astrocytoma cells that was associated with delay in cell cycle progression and stefin B was also found to inactivate caspase-3/7 in the nucleus. On the other hand, Gole et al [44] reported that expression of stefin B is decreased in invading GBM cells and at the periphery of the tumor in orthotopic xenografts of GBM in nude mice indicating differential expression of stefin B in different subpopulations of GBM cells within a tumor.…”

“…Cysteine cathepsins have been extensively investigated in glioma by our research groups [4], [6], [8], [41], [44], [48] and by others [3], [10]. CatB, CatL and CatS have been reported to be associated with glioma progression, and are highly overexpressed at mRNA, protein and activity levels in GBM.…”

“…However, our protease expression study indicates that CatK is much more overexpressed in GBM. CTSK that encodes for CatK may be the most interesting candidate gene that has never been associated with GBM, in contrast to other cysteine cathepsins [6], [44]. CatK is involved in collagenolytic activity in relationship with bone remodeling and is highly expressed in osteoclasts [48], [49].…”

Les tumeurs gliales diffuses de l’adulte

“…À l'intérieur même d'une sous-population tumorale, les cellules présentent de façon hétérogène des altérations moléculaires, telles que l'amplification de l'EGFR (points oranges), de la MET (points jaunes), du PDGFR (points verts) ou la méthylation du promoteur de MGMT (points bleus). B. Les différentes sous-populations tumorales expriment des gènes différents en faveur d'un comportement biologique différent [19][20][21][22][23][24][25][26][27][28][29] (voir Glossaire pour définition des abréviations).…”

“…GFAP et pERK [20] Nestine et pAKT [20] ASPHD2, NFE2L2, LAMC1, CD133 [24] ET-1, IL-8 [26] CD133 [19] IGFBP2 et vimentine [21] Autotaxine, éphrine B3, Bcl-w, PTK 2 [21] Hif1, IL-8 [25] E-sélectine [27] Nestine [28] Stéphine B [22] Cathepsines S et L [22] Gènes de la voie Notch [29] …”