DigitalUM :: Browsing by Subject "Glioblastoma"

Browsing by Subject "Glioblastoma"

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Open Access
Activation of alternative pathways of angiogenesis and involvement of stem cells following anti-angiogenesis treatment in glioma
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Arbab, Ali S.
Malignant gliomas are hypervascular tumors that are highly resistant to all the currently available multimodal treatments. Therefore, anti-angiogenic therapies targeting VEGF or VEGF receptors (VEGFRs) were designed and thought to be an effective tool for controlling the growth of malignant gliomas. However, recent results of early clinical trials using humanized monoclonal antibodies against VEGF (Bevacizumab), as well as small-molecule tyrosine kinase inhibitors that target different VEGF receptors (VEGFRs) (Vatalanib, Vandetanib, Sunitinib, Sorafenib, etc) alone or in combination with other therapeutic agents demonstrated differing outcomes, with the majority of reports indicating that glioma developed resistance to the employed anti-angiogenic treatments. It has been noted that continued anti-angiogenic therapy targeting only the VEGF-VEGFR system might affect pro-angiogenic factors other than VEGF, such as basic fibroblast growth factor (bFGF), stromal derived factor 1 (SDF-1) and Tie-2. These factors may in turn stimulate angiogenesis by mobilizing bone marrow derived precursor cells, such as endothelial progenitor cells (EPCs), which are known to promote angiogenesis and vasculogenesis. In this short review, the current antiangiogenic treatments, possible mechanisms of activation of alternative pathways of angiogenesis, and possible involvement of bone marrow derived progenitor cells in the failure of anti-angiogenic treatments are discussed
Open Access
Autophagy in the immunosuppressive perivascular microenvironment of glioblastoma
(MDPI, 2019-12-31) Molina Gallego, María Luisa; Martínez Pérez, Salvador; García Bernal, David; Valdor Alonso, Rut; Bioquímica y Biología Molecular B e Inmunología
Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions.
Open Access
Chaperone-mediated autophagy ablation in pericytes reveals new glioblastoma prognostic markers and efficient treatment against tumor progression
(2022-03-18) Molina Gallego, María Luisa; Aparicio, Pedro; Moraleda, José M.; Martínez, Salvador; García Bernal, David; Rubio Pedraza, Gonzalo; Salinas Hidalgo, María Dolores; Valdor Alonso, Rut; Bioquímica y Biología Molecular B e Inmunología
Background: The lack of knowledge of the progression mechanisms of glioblastoma (GB), the most aggressive brain tumor, contributes to the absence of successful therapeutic strategies. Our team has recently demonstrated a crucial new role for chaperone-mediated autophagy (CMA) in pericytes (PC)-acquired immunosuppressive function, which prevents anti-tumor immune responses and facilitates GB progression. The possible impact that GB-induced CMA in PC has on other functions that might be useful for future GB prognosis/treatment, has not been explored yet. Thus, we proposed to analyze the contribution of CMA to other GB-induced changes in PC biology and determine if CMA ablation in PC is a key target mechanism for GB treatment. Methods: Studies of RNA-seq and secretome analysis were done in GB-conditioned PC with and without CMA (from knockout mice for LAMP-2A) and compared to control PC. Different therapeutic strategies in a GB mouse model were compared. Results: We found several gene expression pathways enriched in LAMP2A-KO PC and affected by GB-induced CMA in PC that correlate with our previous findings. Phagosome formation, cellular senescence, focal adhesion and the effector function to promote anti-tumor immune responses were the most affected pathways, revealing a transcriptomic profiling of specific target functions useful for future therapies. In addition, several molecules associated with tumor mechanisms and related to tumor immune responses such as gelsolin, periostin, osteopontin, lumican and vitamin D, were identified in the PC secretome dependent on GB-induced CMA. The CMA ablation in PC with GB cells showed an expected immunogenic phenotype able to phagocyte GB cells and a key strategy to develop future therapeutic strategies against GB tumor progression. A novel intravenous therapy using exofucosylated CMA-deficient PC was efficient to make PC reach the tumor niche and facilitate tumor elimination. Conclusion: Our results corroborate previous findings on the impaired immunogenic function of PC with GB-induced CMA, driving to other altered PC functions and the identifications of new target markers related to the tumor immune responses and useful for GB prognosis/therapy. Our work demonstrates CMA ablation in PC as a key target mechanism to develop a successful therapy against GB progression.
Open Access
Chaperone-Mediated Autophagy in Pericytes: A Key Target for the Development of New Treatments against Glioblastoma Progression
(MDPI, 2022-08-10) Salinas Hidalgo, María Dolores; Valdor Alonso, Rut; Bioquímica y Biología Molecular B e Inmunología
Open Access
circRNA-SMO upregulates CEP85 to promote proliferation and migration of glioblastoma via sponging miR-326
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Wu, Bin; Xia, Liang; Zhang, Shuyuan; Jin, Kai; Li, Liwen; Sun, Caixing; Xia, Ting; Chen, Gao
Circular RNAs (circRNAs) play an important role in cancer development by sponging microRNAs (miRNAs) to regulate the signaling axis. However, more comprehensive mechanisms of circRNAs in glioblastoma need to be elucidated. RT-qPCR was used to detect the expression levels of circRNA-SMO and miR-326. Dual-luciferase reporter assays were conducted to verify the interaction among circRNA-SMO, miR-326, and CEP85. Flow cytometric analysis was performed to detect apoptosis. Western blotting was used to determine the protein levels of the different molecules. Animal xenograft experiments were performed to evaluate the role of circRNA-SMO in vivo. CircRNA-SMO was upregulated in glioblastoma tissues and glioblastoma cells. CircRNA-SMO downregulation inhibited the viability and colonyforming ability of the glioblastoma cells. In addition, miR-326 was downregulated in glioblastoma cells, which was verified to sponge circRNA-SMO and interact with CEP85. Moreover, circRNA-SMO inhibition induced the elevation of miR-326 and apoptosis, accompanied by a decrease in CEP85. CircRNA-SMO knockdown-mediated tumor inhibition was prevented by an miR-326 inhibitor. Furthermore, circRNA-SMO inhibition inhibited tumor growth in vivo, accompanied by an increase in miR-326 and a decline in CEP85 in tumor tissues. Conclusions. CircRNA-SMO sponges miR-326 to promote glioblastoma proliferation and migration by upregulating CEP85 expression. This study clarified the role of circRNA-SMO in the development of glioblastoma, providing novel insights for its treatment.
Open Access
Dataset of the project: Una Posible Diana Terapeutica para Bloquear la Progresión del Glioblastoma: la Autofagia Mediada por Chaperonas en Pericitos (PID2020-114010RB-I00)
(2026-02-09) Rodríguez, Pablo; Rubio Pedraza, Gonzalo; Valdor Alonso, Rut; Salinas Hidalgo, María Dolores; Bioquímica y Biología Molecular B e Inmunología
Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers due to its complex tumor microenvironment (TME). We previously showed that GB progression is dependent on the aberrant induction of chaperone-mediated autophagy (CMA) in pericytes (PCs), which promotes TME immunosuppression through the PC secretome
Open Access
Datos de investigación Proyecto Estudio de la Biología del Pericito Dependiente de Autofagia Mediada por Chaperonas Como Diana Clave para el Desarrrollo de Terapias en Glioblastoma (PID2023-149111OB-I00)
(2026-05-19) Salinas Hidalgo, María Dolores; Naranjo Sánchez, Elena; Valdor Alonso, Rut; Martínez González, Isabel María; Bioquímica y Biología Molecular B e Inmunología; Facultades de la UMU::Facultad de Medicina
Open Access
Diagnostic markers for glioblastoma
(F. Hernández y J.F. Madrid. Murcia: Universidad de Murcia, Departamento de Biología Celular e Histología., 2011) Jung, C.S.; Unterberg, A.W.; Hartmann, C.
Glioblastoma (GBM) is the most malignant form of cerebral gliomas, and despite distinct progress in surgical resection, radiation and chemotherapy, the prognosis of patients with GBM is still very poor. In the past decades knowledge of genomics and proteomics and of diagnostic, prognostic, predictive and pharmakodynamic markers measured in cerebrospinal-fluid (CSF), serum, or tumor tissue biomarkers has improved. This review briefly compiles our concepts on diagnostic markers for GBM, focusing on the latest developments.
Open Access
Expression of lumican and osteopontin in perivascular areas of the glioblastoma peritumoral niche and its value for prognosis
(MDPI, 2024-12-29) Rodríguez, Pablo; Rubio Pedraza, Gonzalo; Salinas Hidalgo, María Dolores; Valdor Alonso, Rut; Bioquímica y Biología Molecular B e Inmunología
Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers due to its complex tumor microenvironment (TME). We previously showed that GB progression is dependent on the aberrant induction of chaperone-mediated autophagy (CMA) in pericytes (PCs), which promotes TME immunosuppression through the PC secretome. The secretion of extracellular matrix (ECM) proteins with anti-tumor (Lumican) and pro-tumoral (Osteopontin, OPN) properties was shown to be dependent on the regulation of GB-induced CMA in PCs. As biomarkers are rarely studied in TME, in this work, we aimed to validate Lumican and OPN as prognostic markers in the perivascular areas of the peritumoral niche of a cohort of GB patients. Previously, we had validated their expression in GB xenografted mice presenting GB infiltration (OPN) or GB elimination (Lumican) dependent on competent or deficient CMA PCs, respectively. Then, patient sample classification by GB infiltration into the peritumoral brain parenchyma was related to GB-induced CMA in microvasculature PCs, analyzing the expression of the lysosomal receptor, LAMP-2A. Our results revealed a correlation between GB-induced CMA activity in peritumoral PCs and GB patients’ outcomes, identifying three degrees of severity. The perivascular expression of both immune activation markers, Iba1 and CD68, was related to CMA-dependent PC immune function and determined as useful for efficient GB prognosis. Lumican expression was identified in perivascular areas of patients with less severe outcome and partially co-localizing with PCs presenting low CMA activity, while OPN was primarily found in perivascular areas of patients with poor outcome and partially co-localizing with PCs presenting high CMA activity. Importantly, we found sex differences in the incidence of middle-aged patients, being significantly higher in men but with worse prognosis in women. Our results confirmed that Lumican and OPN in perivascular areas of the GB peritumoral niche are effective predictive biomarkers for evaluating prognosis and monitoring possible therapeutic immune responses dependent on PCs in tumor progression.
Open Access
Facilitating tailored therapeutic strategies for glioblastoma through an orthotopic patient-derived xenograft platform
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Lee, Hye Won; Lee, Kyoungmin; Kim, Dong Geon; Yang, Hee Kyoung; Nam, Do-Hyun
Despite years of research into its pathobiology and continuing clinical trials for novel therapies, the prognosis for patients with glioblastoma (GBM) remains dismal. An important obstacle against treatment efficacy may be a high degree of intra- and inter-tumoral heterogeneity within GBMs, which may be caused by the presence of self-renewing GBM stem cells (GSCs). Recent advances in multi-omics technology introduce new possibilities for applying personalized strategies to GBM therapy. As drug discovery is accelerating with the transition from non-selective, cytotoxic therapy to a precision, targeted approach, the appropriate in vivo platform for GBM is critical for validating drug targets and prioritizing candidates for clinical studies, for co-development of companion diagnostics and, ultimately, for drug approval. Here we will describe GBM orthotopic patient-derived xenografts (PDXs) as more useful, clinically relevant resources for individually tailored strategies for GBM.
Open Access
Growth pattern of experimental glioblastoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Ahlstedt, Jonatan; Förnvik, Karolina; Helms, Gunther; Salford, Leif G.; Ceberg, Crister; Skagerberg, Gunnar; Redebrandt, Henrietta Nittby
Glioblastoma multiforme (GBM) is an aggressive primary brain malignancy with a very poor prognosis. Researchers employ animal models to develop potential therapies. It is important that these models have clinical relevance. This means that old models, propagated for decades in cultures, should be questioned. Parameters to be evaluated include whether animals are immune competent or not, the infiltrative growth pattern of the tumor, tumor volume resulting in symptoms and growth rate. We here describe the growth pattern of an experimental glioblastoma model in detail with GFP positive glioblastoma cells in fully immune competent animals and study tumor growth rate and tumor mass as a function of time from inoculation. We were able to correlate findings made with classical immunohistochemistry and MR findings. The tumor growth rate was fitted by a Gompertz function. The model predicted the time until onset of symptoms for 5000 inoculated cells to 18.7±0.4 days, and the tumor mass at days 10 and 14, which are commonly used as the start of treatment in therapeutic studies, were 5.97±0.62 mg and 29.1±3.0 mg, respectively. We want to raise the question regarding the clinical relevance of the outline of glioblastoma experiments, where treatment is often initiated at a very early stage. The approach presented here could potentially be modified to gain information also from other tumor models.
Open Access
Histological heterogeneity of human glioblastomas investigated with an unsupervised neural network (SOM)
(Murcia : F. Hernández, 2005) Iglesias-Rozas, J.R.; Hopf, N.
The histological variability of Glioblastomas (GB) precludes the modern assimilation of theses tumors into a single histological tumor group. As an alternative to statistical histological evaluation, we investigated 1489 human GB in order to discover whether they could be correctly classified using Self- Organizing Maps (SOM). In all tumors 50 histological features, as well as the age and sex of the patients, were examined. Four clusters of GB with a significance of 52 (maximal significance 60) were found. Cluster C1 contained 37.47% of all GB and 41.09% of all polymorphic glioblastomas (PG). Cluster C2 included 35.06% of all GB and 44.96% of all giant cell glioblastomas (GCG). Cluster C3 contained 16.45% of all GB with a significant component of astroblasts, glioblasts and oligodendroglia. Cluster C4 included 11.01% of all GB, 87.80% of the gliosarcomas (GS) and 36.72% of all GCG. Placing a series of component windows with their maps side by side allows the immediate recognition of the dependencies on variables and the determination of variables necessary to build the specific clusters. The SOM allow a realistic histological classification, comparable to the actual classification by the WHO. In addition, we found new, small subclusters of human GB which may have a clinical significance. With SOM one can learn to discriminate, discard and delete data, select histological and clinical or genetic variables that are meaningful, and consequently influence the result of patient management.
Open Access
Immunohistopathological and neuroimaging characterization of murine orthotopic xenograft models of glioblastoma multiforme recapitulating the most salient features of human disease
(Murcia : F. Hernández, 2009) Radaelli, E.; Ceruti, R.; Patton, V.; Russo, M.; Degrassi, A.; Croci, V.; Caprera, F.; Stortini, G.; Scanziani, E.; Pesenti, E.; Alzani, R.
Tumorigenesis in human glioblastoma multiforme (GBM) is driven by several genetic abnormalities with disruption of important molecular pathways, such as p53/MDM2/p14ARF and EGFR/PTEN/Akt/mTOR. The malignant progression of human GBM is also primarily associated with a peculiar multistep pathophysiological process characterized by intratumoral ischemic necrosis (i.e. pseudopalisading necrosis) and activation of the hypoxia-inducible factor (HIF)-1a pathway with consequent peritumoral microvascular proliferation and infiltrative behaviour. Predictable preclinical animal models of GBM should recapitulate the main pathobiological hallmarks of the human disease. In this study we describe two murine orthotopic xenograft models using U87MG and U251 human cell lines. Ten Balb/c nude male mice were orthotopically implanted with either U87MG (5 mice) or U251 (5 mice) cell lines. Intracranial tumor growth was monitored through Magnetic Resonance Imaging (MRI). Immunohistopathological examination of the whole cranium was performed 30 days after implantation. U251 orthotopic xenografts recapitulated the salient pathobiological features described for human GBM, including invasive behaviour, wide areas of pseudopalisading necrosis, florid peripheral angiogenesis, GFAP and vimentin expression, nonfunctional p53 expression, striking active-caspase-3 and HIF-1a expression along pseudopalisades. U87MG orthotopic xenografts proved to be very dissimilar from human GBM, showing expansile growth, occasional necrotic foci without pseudopalisades, intratumoral lacunar pattern of angiogenesis, lack of GFAP expression, fuctional p53 expression and inconsistent HIF-1a expression. Expression of pAkt was upregulated in both models. The results obtained suggest that the U251 orthotopic model may be proposed as a predictive and reliable tool in preclinical studies since it recapitulates the most salient pathobiological features reported for human GBM.
Open Access
MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue
(Murcia : F. Hernández, 2009) Preusser, Matthias
Evidence from several studies supports that the epigenetic, transcriptional and translational regulation and expression of O6-methylguaninemethyltransferase (MGMT) is relevant for prognostic and predictive considerations in glioblastoma patients. MGMT status is being used as a stratifying factor or eligibility criterion in ongoing and accruing clinical glioblastoma trials. In some cases, there is also interest in MGMT assessment of glioblastoma tissue in the dayto- day clinical setting. However, a number of different methods and protocols have been used for MGMT analysis and it is unclear which methods harbour the greatest potential for translation into routine clinical use. This article reviews methods that have been used for MGMT assessment at DNA-, RNA- and protein-level in glioblastoma with a focus on their potential clinical utility. Conclusions. (1) DNA-based methods for MGMT analysis seem more promising for translation into the clinical setting than RNA- or protein-based methods. However, at present there is lack of data to base recommendations for a specific method or protocol for MGMT testing on. There is a strong need for systematic comparisons and validation of intra- and interlaboratory reproducibility and clinical performance of different methods for MGMT assessment to identify the best method for clinical MGMT testing. (2) The current practice of formalin-fixation of neurosurgical specimens considerably limits the spectrum of methods that can be applied for molecular diagnosis in clinical neurooncology. Further studies may be helpful to establish more appropriate protocols for tumour tissue preservation (e.g. identification of alternative fixatives that do not deteriorate DNA and RNA quality).
Open Access
Predicting short-term survival after gross total or near total resection in glioblastomas by machine learning-based radiomic analysis of preoperative MRI
(MDPI, 2021-10-09) Cepeda, Santiago; Pérez Núñez, Ángel; García García, Sergio; García Pérez, Daniel; Arese, Ignacio; Jiménez Roldán, Luis; García Galindo, Manuel; González, Pedro; Velasco Casares, María; Zamora, Tomás; Sarabia, Rosario; Farmacología; Facultades de la UMU::Facultad de Medicina
Radiomics, in combination with artificial intelligence, has emerged as a powerful tool for the development of predictive models in neuro-oncology. Our study aims to find an answer to a clinically relevant question: is there a radiomic profile that can identify glioblastoma (GBM) patients with short-term survival after complete tumor resection? A retrospective study of GBM patients who underwent surgery was conducted in two institutions between January 2019 and January 2020, along with cases from public databases. Cases with gross total or near total tumor resection were included. Preoperative structural multiparametric magnetic resonance imaging (mpMRI) sequences were pre-processed, and a total of 15,720 radiomic features were extracted. After feature reduction, machine learning-based classifiers were used to predict early mortality (<6 months). Additionally, a survival analysis was performed using the random survival forest (RSF) algorithm. A total of 203 patients were enrolled in this study. In the classification task, the naive Bayes classifier obtained the best results in the test data set, with an area under the curve (AUC) of 0.769 and classification accuracy of 80%. The RSF model allowed the stratification of patients into low- and high-risk groups. In the test data set, this model obtained values of C-Index = 0.61, IBS = 0.123 and integrated AUC at six months of 0.761. In this study, we developed a reliable predictive model of short-term survival in GBM by applying open-source and user-friendly computational means. These new tools will assist clinicians in adapting our therapeutic approach considering individual patient characteristics.
Open Access
PTPIP51, a positive modulator of the MAPK/Erk pathway, is upregulated in glioblastoma and interacts with 14-3-3ß and PTP1B in situ
(F. Hernández y J.F. Madrid. Murcia: Universidad de Murcia, Departamento de Biología Celular e Histología., 2011) Petri, M.K.; Stenzinger, A.; Kuchelmeister, K.; Nestler, U.; Paradowska, A.; Steger, K.; Brobeil, A.; Viard, M.; Wimmer, M.
Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumour. Protein tyrosine phosphatase interacting protein 51 (PTPIP51) is an interaction partner of 14-3-3ß, which correlates with the grade of malignancy in gliomas. In this study PTPIP51 and its interacting partners 14-3-3ß, PTP1B, c-Src, Raf-1 as well as EGFR were investigated in human glioblastoma. Twenty glioblastoma samples were analyzed on transcriptional and translational level by immunohisto-chemistry, in situ hybridization and RT-PCR. To compare PTPIP51 expression in gliomas of different malignancies, quantitative RT-PCR for grade II astrocytoma and GBM samples was employed. Additionally, we analyzed the correlation between PTPIP51 and 14-3-3ß transcription, and checked for in situ interaction between PTPIP51 and 14-3-3ß and PTP1B, respectively. PTPIP51 and 14-3-3ß mRNA showed a tumour grade dependent upregulation in gliomas. Glioblastoma cells displayed a strong immunoreaction of PTPIP51, which co-localized with 14-3-3ß and PTP1B. The duolink proximity ligation assay corroborated a direct in situ interaction of PTPIP51 with both proteins, known to interact with PTPIP51 in vitro. The in vitro interacting partners Raf-1 and c-Src showed a partial co-localization. Besides, immune cells located in capillaries or infiltrating the tumour tissue and endothelial cells of pseudoglomerular vessels revealed a high PTPIP51 expression. The upregulation of PTPIP51 and its connection with the EGFR/MAPK pathway by 14-3-3ß via Raf-1 and by PTP1B via c-Src, argue for a functional role of PTPIP51 in the pathogenesis of human glioblastoma.
Open Access
Short-term neuropathological aspects of in vivo suicide gene transfer to the F98 rat glioblastoma using liposomal and viral vectors
(Murcia : F. Hernández, 2001) von Eckardstein, K.; Patt, Stephan; Zhu, J.; Zhang, L.; Cervós-Navarro, J.; Reszka, R.
To date, only few preclinical protocols on liposomal suicide gene transfer in tumors have been published, none of which directly compared viral to liposomal vectors in terms of immunoreactivity and efficacy. We thus studied the neuropathological alterations in 80 rats being treated for glioblastoma using liposomal and, for comparison, adenoviral and retroviral suicide gene transfer approaches to identify vectorassociated efficacy and toxicity for further clinical studies. 62 rats served as controls. F98 tumors were established in Fisher rats and transfected in vivo with the thymidine kinase gene of herpes simplex virus (HSVtk) by a single intratumoral application and an implanted intratumoral continuous delivery system. Three days later ganciclovir was given intraperitoneally for 14 days. The animals were sacrificed 17 days post completed gene transfer. Brains were examined histologically and immunohistochemically using markers for immunocompetent cells. Ten animals showed complete tumor regression; they al1 belonged to the liposomal and adenoviral groups. In 6 of 10 experimental groups considerable numbers of lymphocytes along the margins of the regression cavities could be observed. Control animals of the liposomal and adenoviral groups showed only little lymphocytic infiltration, underlining the minimal immunogenicity of these carriers. In contrast, the retroviral control group featured a high lymphocyte infiltration. In summary, this study indicates that, in terms of both efficacy and immunoreaction, liposomes are as appropriate as adenoviruses in the treatment of rat glial tumors using suicide gene transfer strategies.
Open Access
Spontaneous intracerebral hemorrhage as presentation of atypical central neurocytoma: the role of angiogenesis through the characterization of tumor endothelial cells
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Marfia, Giovanni; Pirola, Elena; Navone, Stefania Elena; Beretta, Matteo; Guarnaccia, Laura; Trombetta, Elena; Franzini, Andrea; Rampini, Paolo; Campanella, Rolando
A 36-year-old white man presented with sudden-onset headache and rapid deterioration of consciousness. Computer tomography revealed a right capsular intra-parenchimal hemorrhage with an intraventricular component; therefore, emergency surgery was performed. Once the hematoma was evacuated, the cause of the hemorrhage was identified as a tumor mass and it was resected. Histopathological and immunohistochemical examinations of the surgical specimen disclosed a diagnosis of atypical central neurocytoma. By using a protocol recently set up in our laboratory, we succeeded in isolating and propagating, for the first time, human endothelial cells from central neurocytoma (CN-ECs). Different analyses revealed that isolated CNECs consist of a pure endothelial cell population, with the expression of endothelial markers (CD31, CD309/VEGFR2, CD105, eNOS) and with angiogenic properties, such as the uptake of LDL. Moreover, CNECs spontaneously organize in a vascular-like structure. The goal of this case report is to stress the need for further studies focused on understanding the causes of the onset of an intra-parenchimal hemorrhage in the presence of an atypical central neurocytoma in order to tailor treatments to each single patient and achieve the best clinical outcome.
Embargo
The effect of Glioblastoma on Pericytes
(2020-10-29) Molina Gallego, María Luisa; Valdor Alonso, Rut; Bioquímica y Biología Molecular B e Inmunología
Purpose of the Review: Intratumoral pericytes (PC) do not share the same tumor niche as peritumoral PC. Furthermore, glioblastoma multiforme (GB) cells do not seem to affect them equally. Therefore, for a better understanding of the effects of GB on PC, in this chapter, we will classify them according to whether they are intratumoral or peritumoral PC, focusing mainly on peritumoral effects, which seem to have better future prospects for finding effective therapies in GB cancer. Recent Findings: Recently, it has been shown that PC could be the main target of the tumor infiltration front and have a fundamental role in the proliferation, expansion, and survival of the tumor, as well as in the regulation of anti-tumor immune responses. Modulation of the immune function of PC through molecular mechanisms such as chaperone-mediated autophagy (CMA) seems to be essential to prevent an immunosuppressive microenviroment that facilitates tumor growth. Summary: GB is the most frequent and aggressive brain tumor. In the last years, PC have been gaining special attention due to their role in GB progression. GB cells infiltrate away from the tumor core more often and faster when they are associated with perivascular cells. However, to find targeted therapies against PC to promote their brain defense function and improve anti-tumor immune responses requires a better understanding of the heterogeneity, markers, and distribution of PC at origin.
Open Access
The emerging role of mTOR up-regulation in brain astrocytoma
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Ryskalin, Larisa; Limanaqi, Fiona; Biagioni, Francesca; Frati, Alessandro; Esposito, Vincenzo; Calierno, Maria Teresa; Lenzi, Paola; Fornai, Francesco
The present manuscript is an overview of various effects of mTOR up-regulation in astrocytoma with an emphasis on its deleterious effects on the proliferation of Glioblastoma Multiforme. The manuscript reports consistent evidence indicating the occurrence of mTOR up-regulation both in experimental and human astrocytoma. The grading of human astrocytoma is discussed in relationship with mTOR upregulation. In the second part of the manuscript, the biochemical pathways under the influence of mTOR are translated to cell phenotypes which are generated by mTOR up-regulation and reverted by its inhibition. A special section is dedicated to the prominent role of autophagy in mediating the effects of mTOR in glioblastoma. In detail, autophagy inhibition produced by mTOR up-regulation determines the fate of cancer stem cells. On the other hand, biochemical findings disclose the remarkable effects of autophagy activators as powerful inducers of cell differentiation with a strong prevalence towards neuronal phenotypes. Thus, mTOR modulation acts on the neurobiology of glioblastoma just like it operates in vivo at the level of brain stem cell niches by altering autophagy-dependent cell differentiation. In the light of such a critical role of autophagy we analyzed the ubiquitin proteasome system. The merging between autophagy and proteasome generates a novel organelle, named autophagoproteasome which is strongly induced by mTOR inhibitors in glioblastoma cells. Remarkably, when mTOR is maximally inhibited the proteasome component selectively moves within autophagy vacuoles, thus making the proteasome activity dependent on the entry within autophagy compartment.

Browsing by Subject "Glioblastoma"

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