Glioblastoma (GBM) is the most common malignant primary brain tumor with a poor 5-year survival rate. Autophagy is a conserved intracellular degradation system that plays a dual role in GBM ...pathogenesis and therapy. On one hand, stress can lead to unlimited autophagy to promote GBM cell death. On the other hand, elevated autophagy promotes the survival of glioblastoma stem cells against chemotherapy and radiation therapy. Ferroptosis is a type of lipid peroxidation-mediated regulated necrosis that initially differs from autophagy and other types of cell death in terms of cell morphology, biochemical characteristics, and the gene regulators involved. However, recent studies have challenged this view and demonstrated that the occurrence of ferroptosis is dependent on autophagy, and that many regulators of ferroptosis are involved in the control of autophagy machinery. Functionally, autophagy-dependent ferroptosis plays a unique role in tumorigenesis and therapeutic sensitivity. This mini-review will focus on the mechanisms and principles of autophagy-dependent ferroptosis and its emerging implications in GBM.
The nervous system with its complex organizational features and functions is well-known for its impressive ability to process information and drive countless biological processes. It has come to the ...surprise of many that the nervous system can also be intimately involved in an unwelcome area of human life: the initiation and progression of cancer. For brain tumors, the parallels to neurodevelopment and nervous system function can be found on multiple levels. First, cancer cells of incurable gliomas interconnect with long cellular extensions to a large communicating multicellular network. Second, indirect and direct neuronal input can generate, activate, and control brain tumor growth. Third, it is becoming increasingly clear that those features not only drive brain tumor progression but also the notorious resistance of these tumors against standard antitumor therapies. Remarkably, these recent insights have already generated novel ideas for better antitumor therapies.
Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for ...schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- and dose-dependent manner. At IC50, spheroid size and second-generation spheroid formation were significantly suppressed. Stemness factors, SOX2 and OCT4, were decreased. PFD treatment reduced cancer cell migration and invasion by reducing the Integrin α6 and uPAR levels and suppression of the expression of epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1. GLI1 was found to be involved in PFD-induced EMT inhibition. Furthermore, combinatorial treatment of PFD with temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo. Immunostaining revealed decreased expression of GLI1, SOX2, and vimentin in the PFD treatment group but not in the TMZ-only treatment group. Therefore, PFD can be effectively repurposed for the treatment of glioblastoma by combining it with TMZ.
Purpose: This study aimed to evaluate the predictability of survival in patients with glioblastoma using a machine learning (ML) model developed with tissue analysis features obtained through ...preoperative post-contrast T1-weighted images(T1WI). Materials and Methods: The radiomic features of tumors were obtained from postcontrast T1WI of 60 glioblastoma patients. Radiomic properties, density, shape, and textural properties obtained from six matrices were included in the analysis. The patients' three- and six-month survival rates were recorded. Five different ML algorithms were applied to create predictive models random forest, neural network, linear discriminant analysis(LDA), stochastic gradient descent (SGD), and support vector machine(SMV). Results: The mean survival time of the patients was 295.4 days, and the median value was 211.5 (17-1357) days. Among the models developed for three- and six-month survival prediction, the highest success was obtained from the LDA algorithm, in which the AUC values were calculated as 0.88 and 0.78, respectively. Conclusion: Using ML techniques, the success of predicting imaging-based patient survival was very high. With the development and widespread adoption of these techniques, ML models will be useful in deciding on treatment according to survival prediction in glioblastoma.
Amaç: Bu çalışma ameliyat öncesi kontrastlı T1 ağırlıklı görüntülerden(T1AG) elde edilen doku analizi(radyomiks) özellikleriyle geliştirilen makine öğrenimi(MÖ) modeli kullanılarak glioblastomlu hastalarda sağkalımın öngörülebilirliğini değerlendirmeyi amaçlamaktadır. Gereç ve Yöntem: Tümörlerin radyomiks özellikleri 60 glioblastoma hastasının kontrastlı T1AG’den elde edildi. Altı matristen elde edilen radyomik özellikler, yoğunluk, şekil ve dokusal özellikler analize dahil edilmiştir. Hastaların üç ve altı aylık sağkalım oranları kaydedildi. Tahmine dayalı modeller random forest, neural network, linear discriminant analysis(LDA), stochastic gradient descent (SGD), support vector machine(SMV) oluşturmak için beş farklı MÖ algoritması uygulandı. Bulgular: Hastaların ortalama sağkalım süresi 295,4 gün, medyan değeri 211,5 (17-1357) gündü. Üç ve altı aylık sağkalım tahmini için geliştirilen modellerden en yüksek başarı, EAA değerlerinin sırasıyla 0,88 ve 0,78 olarak hesaplandığı LDA algoritmasından elde edilmiştir. Sonuç: MÖ tekniklerini kullanarak, görüntülemeye dayalı hasta sağkalımını tahmin etme başarısı çok yüksekti. Bu tekniklerin gelişmesi ve yaygınlaşması ile MÖ modelleri, glioblastomda sağkalım tahminine göre tedaviye karar vermede faydalı olacaktır.
Glioblastoma multiforme (GBM) tumors are the most common type of brain tumors characterized by extensive angiogenesis that is mostly orchestrated by tumor hypoxia. The hypoxia induced factor-1 ...(HIF-1) transcriptional complex is the “master control switch” for hypoxia. Dysregulation of anterior gradient protein 2 (AGR2) expression is associated with tumor growth and metastasis. Whether AGR2 is a hypoxia-responsive factor and affects tumor progression via angiogenesis remains unknown. Here, we show that GBM cell lines, U87 and LN18, exhibited enhanced hypoxic responses compared with control normal human astrocytes, and a corresponding HIF-1-dependent increase in AGR2 mRNA and protein. Recombinant AGR2 and conditioned medium from GBM cells induced human umbilical vein endothelial cell (HUVEC) migration and tube formation, which were abrogated by anti-AGR2 neutralizing antibodies. Expression of the HIF-1α oxygen-dependent degradation domain mutant in cells resulted in elevated AGR2 levels and an increased ability to induce HUVEC migration and tube formation in vitro and enhanced growth and vascularity of tumor xenografts in vivo, which were prevented by AGR2 knockdown. Taken together, these results indicate that AGR2 expression is regulated by HIF-1 and plays an important role in control of glioblastoma growth and vascularity. Our findings suggest that inhibiting AGR2 may represent a new therapeutic target for anti-angiogenic cancer treatment.
Lysosomes of brain capillary endothelial cells are implicated in nicotine acetylcholine receptor (nAChR)‐mediated transcytosis and act as an enzymatic barrier for the transport of peptide ligands to ...the brain. A D‐peptide ligand of nAChRs (termed DCDX), which binds to nAChRs with an IC50 value of 84.5 nM, was developed by retro–inverso isomerization. DCDX displayed exceptional stability in lysosomal homogenate and serum, and demonstrated significantly higher transcytosis efficiency in an in vitro blood–brain barrier monolayer compared with the parent L‐peptide. When modified on liposomal surface, DCDX facilitated significant brain‐targeted delivery of liposomes. As a result, brain‐targeted delivery of DCDX modified liposomes enhanced therapeutic efficiency of encapsulated doxorubicin for glioblastoma. This study illustrates the importance of ligand stability in nAChRs‐mediated transcytosis, and paves the way for developing stable brain‐targeted entities.
Transportfähig: Die Wirkungsweise eines neu entwickelten D‐Peptid‐Liganden (DCDX) als Antagonist von Nicotinacetylcholin‐Rezeptoren (nAChRs) wurde experimentell und am Computer validiert. DCDX ist während der nAChR‐vermittelten Transzytose und der Blutzirkulation außergewöhnlich stabil und hat Potenzial für den gezielten Wirkstofftransport in das Gehirn zur Behandlung von Erkrankungen des Zentralnervensystems.
Cilj ove studije bio je pokazati ulogu angiogeneze i CD44 u glioblastomu (glioblastoma multiforme, GBM). Kao što su recentne studije pokazale da izraženost CD44 u nekim tumorima ima prognostičku ...vrijednost, postoje pojedini dokazi da je povećana izraženost CD44 povezana s lošijom prognozom bolesnika s glioblastomom. Poznato je da je CD44 široko izražen transmembranski stanični protein uključen u mnoge fi ziološke i patološke procese (adhezija matriksa, navođenje i aktivacija limfocita, cijeljenje rana, stanični rast, preživljavanje i migracija stanica, rast i metastaziranje tumora I dr.). Postoji veći broj potencijalnih mehanizama kojima CD44 može promicati malignost, npr. CD44 modulira čimbenike koji mogu dopustiti pokretanje tumora i metastatsku kaskadu (prianjanje, pokretljivost, degradacija matriksa, proliferacija i stanično preživljavanje). Specifi čno gledano, CD44 veže nekoliko izvanstaničnih tvari (hijaluronska kiselina, kolagen, fibronektin, osteopontin) što može olakšati vezanje i naknadni rast tumorskih stanica na drugim mjestima i izraženost CD44. S druge strane, pronađeno je da manja izraženost CD44 može biti povezana s većom vjerojatnošću recidiva i posljedično lošijim ishodom, što je potkrijepljeno praćenjem bolesnika s recidivom glioblastoma koji imaju bolje preživljavanje kod veće izraženosti CD44. Prema tome, veća izraženost CD44 vidljiva je u težim oblicima tumora, dok niže razine CD44 mogu ukazivati da su maligne stanice rezistentnije na kemoterapijske tvari.
Zusammenfassung
Die Betreuung von Menschen im Endstadium ihrer Karzinomerkrankung erfordert umfassende medizinische und pflegerische Ressourcen. Wenn aus finanziellen und privaten Gründen eine ...Aufnahme in ein Hospiz nicht möglich ist und die Betreuung zu Hause personell nicht zu schaffen ist, wäre – bei stabilen Allgemeinzustand und mit Unterstützung eines mobilen Palliativteams – eine Betreuung in einem Pflegeheim für manchen Patienten durchaus möglich. Neben einer durchführbaren Schmerztherapie und Symptomkontrolle ist die Flüssigkeits- und Nahrungszufuhr ein Kriterium für die Befürwortung einer möglichen Aufnahme in ein Pflegegeheim. Ist die Nahrungsaufnahme nur eingeschränkt bzw. gar nicht mehr möglich und liegt keine Patientenverfügung bzw. Vorsorgevollmacht vor, wird eine Aufnahme oft abgelehnt, da vor allem die in der Pflege tätigen Menschen trotz gegebener umfassender Information Angst haben, sich in einer ethisch und rechtlichen Streitsituation zu befinden.
Primary glioblastoma multiforme of cerebellar hemispheres in adults is a rare condition. Most of them result from dedifferentiation of astrocytoma to glioblastoma. We present two cases of unusual de ...novo cerebellar glioblastomas, one of which is the giant-cell variant. We review their clinical behaviour with conventional MR imaging features and discuss the key findings that can lead to the correct diagnosis in sight of new MR imaging technologies.
PDF
