γ-Glutamyltranspeptidase (GGT, syn. γ-Glutamyltransferase) and dipeptidylpeptidase-IV (DPP-IV) activity participates in metabolic and growth control of normal and tumor cells by processing biologically active peptides. Here, we report on up-regulation of these enzymes in human brain gliomas determined by catalytic enzyme histochemistry and immunocytochemistry. Higher activity of GGT was found in 50%, 68% and 81% of WHO grade II, III and IV tumors, respectively. The process started at/near the microvasculature, from where it spread to the parenchyma. On average, the enzyme activity in grade II, III and IV gliomas exceeded controls 2.0, 3.0 and 3.5-fold, respectively. Up-regulation of DPP-IV-like activity also started at the microvasculature, but mainly in pericytes and mononuclear-like cells around the vessels and dispersed in the parenchyma. Marked elevation of this enzyme activity, comprising also tumor parenchyma, occurred only in grade IV glioblastomas (65% patients; 3.6 times above controls) which can, therefore, help in their differentiation from grade III gliomas. The increase of total DPP-IV-like activity also included its two enzymatic homologs, the canonical DPP-IV/CD26 and FAP-1α. The increase in GGT is supposed to be a tumor grade dependent response of microvasculature and tumor astrocytes to stress induced by tissue hypoxia and/or the metabolic aberrancies. The increase in DPP-IV-like activity in high-grade tumors can be attributed to inflammatory/scavenging processes performed by the mononuclear-like cells and, in glioblastomas, also to regressive changes in the structure and function of the microvasculature and tumor parenchyma, including astrocyte stress response. The inverse relationship between DPP-IV-like activity and Ki67 in most glioblastomas and shorter survival time of patients with low activity of this enzyme also suggest its anti-oncogenic effects.
- MeSH
- dipeptidylpeptidasa 4 biosyntéza MeSH
- dospělí MeSH
- gama-glutamyltransferasa biosyntéza MeSH
- gliom enzymologie patologie MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádorové biomarkery analýza MeSH
- nádory mozku enzymologie patologie MeSH
- prognóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň nádoru MeSH
- upregulace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Meningiomas are tumors derived from arachnoid cap cells that represent approximately 30% of all intracranial tumors. In this study, we investigated 22 human meningiomas for the expression of dipeptidyl peptidase (DPP)-IV activity and/or structure homologs (DASH), including canonical DPP-IV/CD26, fibroblast activation protein-alpha (FAPalpha), DPP8 and DPP9. DPP-IV-like enzymatic activity, including all enzymatically-active DASH molecules, was found in all 18 benign meningiomas WHO grade I and IV atypical meningiomas WHO grade II by continuous rate fluorimetric assay in tissue homogenates and catalytic enzyme histochemistry in situ. In atypical meningiomas, this activity was significantly higher and was associated with higher cell proliferation as detected by Ki67 antigen immunohistochemistry. The expression of DPP-IV/CD26 and FAPalpha demonstrated by real-time RT-PCR and immunohistochemistry was low. As shown histochemically, it occurred most often on the surface of fibrous bundles and whorls rich in extracellular matrix. Compared to DPP-IV/CD26 and FAPalpha, the expression of DPP8 and DPP9 was higher and, in addition, it was present also in the cells inside these structures. Expression of CXCR4, the receptor of pro-proliferative chemokine stromal cell-derived factor-1alpha (SDF-1alpha), DPP-IV substrate, was found in all tumors, suggesting higher values in atypical grade II samples. This is the first report on the expression status of dipeptidyl peptidase-IV and related molecules in meningiomas. It shows that DPP8 and DPP9 prevail over canonical DPP-IV/CD26 and FAPalpha in all examined patients. In addition, the study suggests an increase of DPP-IV-like enzymatic activity in these tumors of WHO grade II.
- MeSH
- dipeptidasy genetika metabolismus MeSH
- dipeptidylpeptidasa 4 genetika metabolismus MeSH
- dipeptidylpeptidasy a tripeptidylpeptidasy genetika metabolismus MeSH
- dospělí MeSH
- exprese genu MeSH
- imunohistochemie MeSH
- izoenzymy genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové proteiny genetika metabolismus MeSH
- meningeální nádory enzymologie genetika patologie MeSH
- meningeom enzymologie genetika patologie MeSH
- messenger RNA analýza MeSH
- nádorové biomarkery analýza MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- senioři MeSH
- serinové endopeptidasy genetika metabolismus MeSH
- stanovení celkové genové exprese MeSH
- želatinasy genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Alterations in dipeptidyl peptidase-IV (DPP-IV) enzymatic activity are characteristic of malignant transformation. Through its well-characterized functionality in regulating the activity of bioactive peptides by removal of the N-terminal dipeptide, DPP-IV activity may have profound effects upon metastatic potential and cell growth. Although DPP-IV/CD26 (EC 3.4.14.5) is the canonical representative of the group, a number of other proteins including DPP-7, 8, 9, and seprase/fibroblast activation protein-alpha (FAP-alpha) have been shown to have similar enzymatic activity. This study was set up to address the relative representation and enzymatic activity of plasma membrane localized DPP-IV/CD26 and FAP-alpha in human brain and astrocytic tumours. In parallel, expression of CXCR4, receptor for glioma cell growth stimulator chemokine SDF-1alpha known to be a DPP-IV substrate, was investigated. This is the first report showing that non-malignant brain tissue contains a DPP-IV-like enzymatic activity attributable mostly to DPP-8/9, while the substantial part of the activity in glioma is due to increased DPP-IV/CD26, localized in both the vascular and parenchymal compartments. DPP-IV enzymatic activity increased dramatically with tumour grade severity. A grade-related increase in CXCR4 receptor paralleled the rise in DPP-IV expression and activity. These data might support a role for DPP-IV regulation of the CXCR4-SDF-1alpha axis in glioma development.
- MeSH
- antigeny nádorové genetika metabolismus MeSH
- astrocytom enzymologie genetika patologie MeSH
- buněčná membrána metabolismus MeSH
- dipeptidylpeptidasa 4 genetika metabolismus MeSH
- dospělí MeSH
- financování organizované MeSH
- imunoenzymatické techniky MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorové buňky kultivované MeSH
- nádory mozku enzymologie genetika patologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- receptory CXCR4 genetika metabolismus MeSH
- regulace genové exprese enzymů fyziologie MeSH
- RNA nádorová genetika metabolismus MeSH
- senioři MeSH
- serinové endopeptidasy genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
PURPOSE: Our study is focused on the magnetic resonance imaging (MRI) observation of lesion development and hippocampus related functional impairments in rats after irradiation with a Leksell Gamma knife (LGK). MATERIALS AND METHODS: We exposed 32 three-month-old Long-Evans rats to various radiation doses (25 Gy, 50 Gy or 75 Gy). The rats were scanned by a 4.7 T magnetic resonance (MR) spectrometer at several timepoints (1 - 18 months) after irradiation. The lesion size was evaluated by manual segmentation; the animals were behaviorally tested in a Morris water maze and examined histologically. RESULTS: We found that a dose of 25 Gy induced no edema, necrosis or behavioral change. The response of the rats to higher doses was not uniform; the first occurrence of lesions in the rat brains irradiated with 50 and 75 Gy was detected six months post-irradiation. Functional impairment correlated well with the lesion size and histology. CONCLUSIONS: Rat brains showed the development of expanding delayed lesions after 50 or 75 Gy doses from the LGK during the first year after irradiation.
- MeSH
- dávka záření MeSH
- financování organizované MeSH
- hipokampus patologie zranění MeSH
- krysa rodu rattus MeSH
- magnetická rezonanční tomografie MeSH
- poranění mozku etiologie patologie MeSH
- potkani Long-Evans MeSH
- radiační poranění etiologie patologie MeSH
- radiochirurgie škodlivé účinky MeSH
- vztah dávky záření a odpovědi MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
