Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments.

• Klíčová slova
• cancer, chemokine, drug repurposing, gliptin, immune response, stem cells, stromal cell-derived factor, tumor microenvironment,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.

• Klíčová slova
• angiogenesis, angiopoietin, fibroblast activation protein, glioblastoma, microenvironment, seprase, vessel destabilisation,
• Publikační typ
• časopisecké články MeSH

Glioblastomas are deadly neoplasms resistant to current treatment modalities. Fibroblast activation protein (FAP) is a protease which is not expressed in most of the normal adult tissues but is characteristically present in the stroma of extracranial malignancies. FAP is considered a potential therapeutic target and is associated with a worse patient outcome in some cancers. The FAP localization in the glioma microenvironment and its relation to patient survival are unknown. By analyzing 56 gliomas and 15 non-tumorous brain samples, we demonstrate increased FAP expression in a subgroup of high-grade gliomas, in particular on the protein level. FAP expression was most elevated in the mesenchymal subtype of glioblastoma. It was neither associated with glioblastoma patient survival in our patient cohort nor in publicly available datasets. FAP was expressed in both transformed and stromal cells; the latter were frequently localized around dysplastic blood vessels and commonly expressed mesenchymal markers. In a mouse xenotransplantation model, FAP was expressed in glioma cells in a subgroup of tumors that typically did not express the astrocytic marker GFAP. Endogenous FAP was frequently upregulated and part of the FAP+ host cells coexpressed the CXCR4 chemokine receptor. In summary, FAP is expressed by several constituents of the glioblastoma microenvironment, including stromal non-malignant mesenchymal cells recruited to and/or activated in response to glioma growth. The limited expression of FAP in healthy tissues together with its presence in both transformed and stromal cells suggests that FAP may be a candidate target for specific delivery of therapeutic agents in glioblastoma.

• Klíčová slova
• Fibroblast activation protein α, Glioma, Seprase, Serine protease, Stromal cells,
• MeSH
• apoptóza MeSH
• buňky stromatu metabolismus   patologie   MeSH
• dospělí MeSH
• endopeptidasy MeSH
• fibroblasty metabolismus   patologie   MeSH
• glioblastom genetika   metabolismus   patologie   MeSH
• imunoenzymatické techniky MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• messenger RNA genetika   MeSH
• mezoderm metabolismus   patologie   MeSH
• míra přežití MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buňky kultivované MeSH
• následné studie MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• prognóza MeSH
• proliferace buněk MeSH
• senioři MeSH
• serinové endopeptidasy genetika   metabolismus   MeSH
• staging nádorů MeSH
• studie případů a kontrol MeSH
• transformované buněčné linie metabolismus   patologie   MeSH
• western blotting MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• želatinasy genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• endopeptidasy MeSH
• fibroblast activation protein alpha MeSH Prohlížeč
• membránové proteiny MeSH
• messenger RNA MeSH
• nádorové biomarkery MeSH
• serinové endopeptidasy MeSH
• želatinasy MeSH

Dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein-α (FAP) are speculated to participate in the regulation of multiple biological processes, because of their unique enzymatic activity, as well as by non-hydrolytic molecular interactions. At present, the role of DPP-IV and FAP in the development and progression of various types of tumors, including glioblastoma, is intensively studied, and their functional crosstalk is hypothesized. In this article, we describe the correlative expression of DPP-IV and FAP mRNA in primary cell cultures derived from human glioblastoma and associated expression dynamics of both molecules in astrocytoma cell lines depending on culture conditions. Although the molecular mechanisms of DPP-IV and FAP co-regulations remain unclear, uncoupled expression of transgenic DPP-IV and the endogenous FAP suggests that it occurs rather at the transcriptional than at the posttranscriptional level. Understanding of the expressional and functional coordinations of DPP-IV and FAP may help clarify the mechanisms of biological roles of both molecules in transformed astrocytic cells.

• MeSH
• buněčná diferenciace MeSH
• buněčné extrakty chemie   MeSH
• buněčné kultury MeSH
• dipeptidylpeptidasa 4 genetika   metabolismus   MeSH
• endopeptidasy MeSH
• enzymatické testy MeSH
• genetická transkripce * MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• messenger RNA genetika   metabolismus   MeSH
• neuroglie enzymologie   metabolismus   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• serinové endopeptidasy genetika   metabolismus   MeSH
• transformované buněčné linie MeSH
• želatinasy genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• buněčné extrakty MeSH
• dipeptidylpeptidasa 4 MeSH
• endopeptidasy MeSH
• fibroblast activation protein alpha MeSH Prohlížeč
• membránové proteiny MeSH
• messenger RNA MeSH
• rekombinantní proteiny MeSH
• serinové endopeptidasy MeSH
• želatinasy MeSH