Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade

Abstract

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-α (FAP-α) 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-α in human brain and astrocytic tumours. In parallel, expression of CXCR4, receptor for glioma cell growth stimulator chemokine SDF-1α 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-1α axis in glioma development.

Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas

“…1); for DPP-IV, the quantity determined by ELISA correlated with the DPP-IV enzymatic activity in tissue homogenates (r=0.79, P<0.05, data not shown). These data confirmed our previously reported results 11 in an independent patient cohort.…”

“…FAP immunopositivity was detectable by WB in most of the high-grade glioma samples, but was absent in the DPP-IV negative gliomas. This is consistent with ours as well as other authors' reports suggesting the coexpression and possible coregulation of DPP-IV and FAP in glioma cells and tissues 11,31 , human pancreatic alpha cells 37 and in some cancer cell lines 38 . The coexpression of DPP-IV and FAP was also described in endothelial cells, where both molecules are part of proteolytically active heteromeric aggregates with a molecular weight of 820 kDa, promoting cell migration and invasion 30 .…”

“…Both proteases are involved in the regulation of cell differentiation, adhesion and migration by their proteolytic activity and also non-hydrolytic interactions 9,10 . Our previous reports demonstrated that the expression DPP-IV and FAP is increased in glioblastomas 11,12 . The data on their pathogenetic role in brain tumors is limited-DPP-IV inhibits glioma cell growth, in large part independently of its enzymatic activity 13 , and FAP likely influences the interaction of glioma cells with the surrounding extracellular matrix (our unpublished results and ref.…”

Gene expression in oligodendroglial tumors

“…In clinical samples high levels of FAP expression have been associated with poor outcome in colorectal and ovarian cancer but improved outcome in invasive ductal breast carcinoma [1,10,50]. While expression of FAP in human astrocytic tumors has been reported, with increased expression correlating with increased grade [33], further investigation of this gene and its association with chemosensitivity is needed to reveal its role in gliomagenesis.…”

Ectoenzymes in Epithelial Ovarian Carcinoma: Potential Diagnostic Markers and Therapeutic Targets

“…In selected carcinoma tissues, CD26 is misexpressed and it can function either as an oncogene or as a tumour suppressor gene. Its expression is upregulated and associated with tumour aggressiveness in T and B lymphomas and leukaemias (Bauvois et al, 1999;Carbone et al, 1995;Dang et al, 2003), thyroid follicular tumours (de Micco et al, 2008), papillary carcinomas, astrocytic tumours (Stremenova et al, 2007) and gastrointestinal stromal tumours (Yamaguchi et al, 2008). Conversely, loss of CD26 occurs during malignant transformation of melanocytes into melanoma (Wesley et al, 1999), indicating a possible role of the molecule in suppressing the malignant transformation of melanocytes.…”