Compartment- and malignance-dependent up-regulation of γ-glutamyltranspeptidase and dipetidylpeptidase-IV activity in human brain gliomas.
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.
The Joint Laboratory of Cancer Cell Biology of the Institute of Physiology of the Academy of Sciences of the Czech Republic, v.v.i. and the 1st Medical Faculty, Charles University in Prague, Czech Republic. maresv@biomed.cas.cz
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V
Mareš
J
J
Stremeňová
V
V
Lisá
H
H
Kozáková
J
J
Marek
M
M
Syrůček
O
O
Šoula
A
A
Šedo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis*; D005260:Female; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D015854:Up-Regulation; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D005723:gamma-Glutamyltransferase; C554782:gamma-glutamyltransferase, human; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4