DigitalUM :: Browsing by Subject "Glioblastoma"

Browsing by Subject "Glioblastoma"

Now showing 1 - 10 of 10

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
Chaperone-mediated autophagy ablation in pericytes reveals new glioblastoma prognostic markers and efficient treatment against tumor progression
(2022-03-18) Molina Gallego, María Luisa; García-Bernal, David; Salinas, María Dolores; Rubio, Gonzalo; Aparicio, Pedro; Moraleda, José M.; Martínez, Salvador; Valdor, 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
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
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
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.
Embargo
The effect of Glioblastoma on Pericytes
(2020-10-29) Molina Gallego, María Luisa; Valdor, 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
Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Angara, Kartik; Rashid, Mohammad H.; Shankar, Adarsh; Ara, Roxan; Iskander, Asm; Borin, Thaiz F.; Jain, Meenu; Achyut, Bhagelu R.; Arbab, Ali S.
Glioblastoma (GBM) is one hypervascular and hypoxic tumor known among solid tumors. Antiangiogenic therapeutics (AATs) have been tested as an adjuvant to normalize blood vessels and control abnormal vasculature. Evidence of relapse exemplified in the progressive tumor growth following AAT reflects development of resistance to AATs. Here, we identified that GBM following AAT (Vatalanib) acquired an alternate mechanism to support tumor growth, called vascular mimicry (VM). We observed that Vatalanib induced VM vessels are positive for periodic acid-Schiff (PAS) matrix but devoid of any endothelium on the inner side and lined by tumor cells on the outer-side. The PAS+ matrix is positive for basal laminae (laminin) indicating vascular structures. Vatalanib treated GBM displayed various stages of VM such as initiation (mosaic), sustenance, and full-blown VM. Mature VM structures contain red blood cells (RBC) and bear semblance to the functional blood vessel-like structures, which provide all growth factors to favor tumor growth. Vatalanib treatment significantly increased VM especially in the core of the tumor, where HIF-1α was highly expressed in tumor cells. VM vessels correlate with hypoxia and are characterized by co-localized MHC-1+ tumor and HIF-1α expression. Interestingly, 20-HETE synthesis inhibitor HET0016 significantly decreased GBM tumors through decreasing VM structures both at the core and at periphery of the tumors. In summary, AAT induced resistance characterized by VM is an alternative mechanism adopted by tumors to make functional vessels by transdifferentiation of tumor cells into endothelial-like cells to supply nutrients in the event of hypoxia. AAT induced VM is a potential therapeutic target of the novel formulation of HET0016. Our present study suggests that HET0016 has a potential to target therapeutic resistance and can be combined with other antitumor agents in preclinical and clinical trials.

Browsing by Subject "Glioblastoma"

Results Per Page

Sort Options