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
Brain metastases are a very common and serious complication of oncological diseases. Despite the vast progress in multimodality treatment, brain metastases significantly decrease the quality of life and prognosis of patients. Therefore, identifying new targets in the microenvironment of brain metastases is desirable. Fibroblast activation protein (FAP) is a transmembrane serine protease typically expressed in tumour-associated stromal cells. Due to its characteristic presence in the tumour microenvironment, FAP represents an attractive theranostic target in oncology. However, there is little information on FAP expression in brain metastases. In this study, we quantified FAP expression in samples of brain metastases of various primary origin and characterised FAP-expressing cells. We have shown that FAP expression is significantly higher in brain metastases in comparison to non-tumorous brain tissues, both at the protein and enzymatic activity levels. FAP immunopositivity was localised in regions rich in collagen and containing blood vessels. We have further shown that FAP is predominantly confined to stromal cells expressing markers typical of cancer-associated fibroblasts (CAFs). We have also observed FAP immunopositivity on tumour cells in a portion of brain metastases, mainly originating from melanoma, lung, breast, and renal cancer, and sarcoma. There were no significant differences in the quantity of FAP protein, enzymatic activity, and FAP+ stromal cells among brain metastasis samples of various origins, suggesting that there is no association of FAP expression and/or presence of FAP+ stromal cells with the histological type of brain metastases. In summary, we are the first to establish the expression of FAP and characterise FAP-expressing cells in the microenvironment of brain metastases. The frequent upregulation of FAP and its presence on both stromal and tumour cells support the use of FAP as a promising theranostic target in brain metastases.
- MeSH
- fibroblasty patologie MeSH
- individualizovaná medicína MeSH
- karcinom z renálních buněk * patologie MeSH
- kvalita života MeSH
- lidé MeSH
- membránové proteiny metabolismus MeSH
- nádorové mikroprostředí MeSH
- nádory ledvin * patologie MeSH
- nádory mozku * patologie MeSH
- serinové endopeptidasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th-April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017-2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017-2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community ́s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.
- MeSH
- chronický subdurální hematom * MeSH
- COVID-19 * MeSH
- lidé MeSH
- neurochirurgické výkony MeSH
- pandemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa 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 world currently faces the novel severe acute respiratory syndrome coronavirus 2 pandemic. Little is known about the effects of a pandemic on non-elective neurosurgical practices, which have continued under modified conditions to reduce the spread of COVID-19. This knowledge might be critical for the ongoing second coronavirus wave and potential restrictions on health care. We aimed to determine the incidence and 30-day mortality rate of various non-elective neurosurgical procedures during the COVID-19 pandemic. A retrospective, multi-centre observational cohort study among neurosurgical centres within Austria, the Czech Republic, and Switzerland was performed. Incidence of neurosurgical emergencies and related 30-day mortality rates were determined for a period reflecting the peak pandemic of the first wave in all participating countries (i.e. March 16th-April 15th, 2020), and compared to the same period in prior years (2017, 2018, and 2019). A total of 4,752 emergency neurosurgical cases were reviewed over a 4-year period. In 2020, during the COVID-19 pandemic, there was a general decline in the incidence of non-elective neurosurgical cases, which was driven by a reduced number of traumatic brain injuries, spine conditions, and chronic subdural hematomas. Thirty-day mortality did not significantly increase overall or for any of the conditions examined during the peak of the pandemic. The neurosurgical community in these three European countries observed a decrease in the incidence of some neurosurgical emergencies with 30-day mortality rates comparable to previous years (2017-2019). Lower incidence of neurosurgical cases is likely related to restrictions placed on mobility within countries, but may also involve delayed patient presentation.
- MeSH
- COVID-19 mortalita MeSH
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- neurochirurgické výkony mortalita trendy MeSH
- neurochirurgie metody MeSH
- novorozenec MeSH
- pandemie statistika a číselné údaje MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- Geografické názvy
- Evropa MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
Nestr.
Fibroblastový aktivační protein (FAP) je proteasa selektivně exprimovaná v mikroprostředí řady nádorů, včetně gliomů vysokého stupně malignity (HGG). FAP je minimálně exprimován ve zdravých tkáních a představuje proto potenciální cíl protinádorové léčby. Naše předchozí práce prokázala zvýšenou expresi FAP v transformovaných gliálních buňkách a v perivaskulárně lokalizovaných stromálních buňkách s mezenchymálními charakteristikami u nově diagnostikovaných gliomů. V rámci projektu budou FAP a FAP+ mezenchymální buňky zkoumány jako potenciální terapeutické cíle v HGG a to za využití párových vzorků tkání od pacientů operovaných pro nově diagnostikovaný a následně recidivující HGG, in vitro studií a myších modelů včetně zvířat s vyřazenou expresí FAP. Současně bude studována možná tumorigenní role FAP indukovaného radioterapií. Na základě molekulárních mechanizmů role FAP a FAP+ mezenchymálních buněk v gliomagenezi budou připraveny a v in vitro a in vivo modelech otestovány nové proprietární látky využívající specifické inhibitory FAP ke specifickému cílení nádorového mikroprostředí.; Fibroblast activation protein (FAP) is a protease selectively expressed in the microenvironment of several tumors including high grade gliomas (HGG). Due to its minimal expression in healthy tissues, the protease is a proposed therapeutic target in extracranial malignancies. Our previous work demonstrated increased expression of FAP in transformed glial cells and in host perivascularly localized stromal cells with mesenchymal features in newly diagnosed glioblastomas. In this project, paired bioptic material from primary and recurrent HGG from the same patient, in vitro studies and mouse models including FAP knockout animals will be utilized to validate FAP itself and FAP+ mesenchymal cells as potential therapeutic targets in HGG. In parallel, the putative tumor promoting effect of FAP induced by radiotherapy will be examined. Based on the molecular mechanisms of the role of FAP and FAP+ mesenchymal cells in gliomagenesis, novel proprietary compounds utilizing FAP inhibitors as a targeting moiety will be synthesized and tested using glioma models in vitro and in vivo.
- MeSH
- cílená molekulární terapie metody MeSH
- glioblastom farmakoterapie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádorové mikroprostředí MeSH
- proteasy škodlivé účinky účinky léků MeSH
- transformující růstový faktor beta1 MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- onkologie
- farmakoterapie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
Cíl: Nekrvácející mozkové výdutě (unruptured intracranial aneurysms; UIA) se vzhledem ke stoupající dostupnosti a lepší kvalitě zobrazovacích metod stávají stále častější diagnózou v neurologické a neurochirurgické praxi. Vzhledem k existenci rizika ruptury a krvácení, je na místě zvážit jejich uzávěr. Na indikaci vyřazení výdutě z cirkulace a způsob vyřazení nejsou zcela jednotné názory. Prezentujeme výsledky pacientů s UIA operovaných na našem oddělení v průběhu posledních 9 let a náš pohled na tuto problematiku. Soubor a metodika: Pacienti s UIA operovaní na našem oddělení byli zahrnuti do souboru, který jsme retrospektivně analyzovali s důrazem na hodnocení bezpečnosti výkonu a úplnosti vyřazení výdutě. Výsledky: Za 9 let bylo operováno 146 pacientů se 184 incidentálními nebo koincidentálními výdutěmi. Nejčastěji byly výdutě lokalizovány na střední mozkové tepně (40 %). Perioperační komplikace se vyskytly u 10 % pacientů a celková chirurgická morbidita/mortalita byla 3,5/0 %. U 143 pacientů byla provedena kontrolní CTA, která potvrdila úplnou obliteraci výdutě v 99 %. Průměrný follow-up pacientů byl 4,5 roku. Závěr: Naše výsledky ukazují, že mikrochirurgická léčba UIA je bezpečnou, dlouhodobě účinnou léčbou, dobře tolerovanou pacienty. Zejména v případě UIA, kde hlavním smyslem léčebné intervence je trvalá eliminace rizika krvácení, by měla být vždy zvažována jako léčebná modalita.
Aim: Unruptured intracranial aneurysms (UIA) are getting more frequently diagnosed in neurology and neurosurgery clinics as the quality and availability of diagnostic radiology methods increases. Due to the risk of rupture and bleeding, aneurysm occlusion should be considered. The indication and the way of treatment are not yet fully agreed upon. We present results for UIA surgeries that were done during the last 9 years at our department and our approach on this topic. Patients and methods: Patients with UIA that were operated on at our department were retrospectively analyzed with special consideration of procedure safety and full obliteration of the aneurysm. Results: 146 patients with 184 incidental or coincidental aneurysms were operated on during the last 9 years. The most common localization was on the middle cerebral artery (40%). Perioperative complication occurred in 10% of cases and total surgery morbidity/mortality was 3.5/0%. CTA examination performed in 143 patients proved full obliteration of the aneurysm in 99% cases. The average follow-up of the patients was 4.5 years. Conclusion: Our results demonstrated that microsurgical treatment of UIAs was safe, effective in the long term and tolerated well by patients. Preferentially in UIA cases, where the main goal is to eliminate the risk of bleeding, surgery should always be considered as a therapeutic modality.
