Gliomagenesis induces profound changes in the composition of the extracellular matrix (ECM) of the brain. In this study, we identified a cellular population responsible for the increased deposition of collagen I and fibronectin in glioblastoma. Elevated levels of the fibrillar proteins collagen I and fibronectin were associated with the expression of fibroblast activation protein (FAP), which is predominantly found in pericyte-like cells in glioblastoma. FAP+ pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in the GBM microenvironment. Using mass spectrometry, we demonstrated that 3D matrices produced by FAP+ pericyte-like cells are rich in collagen I and fibronectin and contain several basement membrane proteins. This expression pattern differed markedly from glioma cells. Finally, we have shown that ECM produced by FAP+ pericyte-like cells enhances the migration of glioma cells including glioma stem-like cells, promotes their adhesion, and activates focal adhesion kinase (FAK) signaling. Taken together, our findings establish FAP+ pericyte-like cells as crucial producers of a complex ECM rich in collagen I and fibronectin, facilitating the dissemination of glioma cells through FAK activation.
- MeSH
- endopeptidasy MeSH
- extracelulární matrix * metabolismus patologie MeSH
- fibronektiny * metabolismus MeSH
- glioblastom patologie metabolismus MeSH
- gliom * patologie metabolismus MeSH
- kolagen typu I metabolismus MeSH
- lidé MeSH
- membránové proteiny metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí fyziologie MeSH
- nádory mozku * patologie metabolismus MeSH
- pericyty * metabolismus patologie MeSH
- pohyb buněk fyziologie MeSH
- serinové endopeptidasy metabolismus MeSH
- želatinasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference 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.
- Publikační typ
- časopisecké články MeSH
The proline-specific serine protease fibroblast activation protein (FAP) can participate in the progression of malignant tumors and represents a potential diagnostic and therapeutic target. Recently, we demonstrated an increased expression of FAP in glioblastomas, particularly those of the mesenchymal subtype. Factors controlling FAP expression in glioblastomas are unknown, but evidence suggests that transforming growth factor beta (TGFbeta) can trigger mesenchymal changes in these tumors. Here, we investigated whether TGFbeta promotes FAP expression in transformed and stromal cells constituting the glioblastoma microenvironment. We found that both FAP and TGFbeta-1 are upregulated in glioblastomas and display a significant positive correlation. We detected TGFbeta-1 immunopositivity broadly in glioblastoma tissues, including tumor parenchyma regions in the immediate vicinity of FAP-immunopositive perivascular stromal cells. Wedemonstrate for the first time that TGFbeta-1 induces expression of FAP in non-stem glioma cells, pericytes, and glioblastoma-derived endothelial and FAP+ mesenchymal cells, but not in glioma stem-like cells. In glioma cells, this effect is mediated by the TGFbeta type I receptor and canonical Smad signaling and involves activation of FAP gene transcription. We further present evidence of FAP regulation by TGFbeta-1 secreted by glioma cells. Our results provide insight into the previously unrecognized regulation of FAP expression by autocrine and paracrine TGFbeta-1 signaling in a broad spectrum of cell types present in the glioblastoma microenvironment.
- MeSH
- endopeptidasy genetika metabolismus MeSH
- fluorescenční protilátková technika MeSH
- fosforylace MeSH
- glioblastom etiologie metabolismus patologie MeSH
- imunohistochemie MeSH
- kultivované buňky MeSH
- lidé MeSH
- membránové proteiny genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí účinky léků genetika MeSH
- regulace genové exprese u nádorů * účinky léků MeSH
- transformující růstový faktor beta1 metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- farmakoterapie klasifikace MeSH
- intrakraniální hypertenze diagnóza MeSH
- látky ovlivňující centrální nervový systém aplikace a dávkování klasifikace MeSH
- lidé MeSH
- nádory mozku * diagnostické zobrazování farmakoterapie klasifikace patologie terapie MeSH
- terapie klasifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- akutní nemoc * MeSH
- anamnéza MeSH
- antifosfolipidový syndrom diagnóza klasifikace patologie terapie MeSH
- artritida diagnóza klasifikace MeSH
- bolesti zad diagnóza klasifikace terapie MeSH
- diferenciální diagnóza MeSH
- dnavá artritida diagnóza terapie MeSH
- lidé MeSH
- obrovskobuněčná arteritida diagnóza patologie terapie MeSH
- renální insuficience MeSH
- revmatické nemoci * diagnóza klasifikace terapie MeSH
- syndrom vzplanutí nemoci MeSH
- systémová sklerodermie klasifikace komplikace patologie MeSH
- systémový lupus erythematodes diagnóza chemicky indukované klasifikace patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
