Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-grade gliomas constitute a group of aggressive CNS cancers that have high morbidity and mortality rates. Despite extensive research, current therapeutic approaches enable survival beyond 2 years in rare cases only. Thrombin and its main CNS target, protease-activated receptor-1, have been implicated in tumor progression and brain edema. Our aim was to study protease-activated receptor-1 (PAR-1) protein expression and thrombin-like activity levels in both in vitro and in vivo models of glioblastoma and correlate them with the volume of the surrounding edema. We measured the presence of PAR-1 protein using fluorescence immunohistochemistry and assessed thrombin activity in various glial and non-glial cell lines and in a CNS-1 glioma rat model using a thrombin-specific fluorescent assay. Thrombin activity was found to be highly elevated in various high-grade glioma cell lines as well as in non-glial malignant cell lines. In the CNS-1 glioma model, the level of PAR-1 fluorescence in the tumor was significantly elevated compared to adjacent regions of reactive gliosis or distant brain areas. The elevated level of thrombin activity observed in the high-grade glioma positively correlated with tumor-induced brain edema. In conclusion, thrombin is secreted from glioma cells and PAR-1 may be a new biological marker for high-grade gliomas.
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PMID:Thrombin Activity and Thrombin Receptor in Rat Glioblastoma Model: Possible Markers and Targets for Intervention? 2569 Nov 53

Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.
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PMID:Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas. 2664 82

Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood-brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs).
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PMID:Aquaporins and Brain Tumors. 2736 82

Background. New approaches are needed for patients newly diagnosed with bulky glioblastoma (GB) and/or with severe neurological impairment that cannot benefit from first line temozolomide (TMZ)-based chemoradiotherapy. Bevacizumab (BEV), an antiangiogenic anti-VEGF-R monoclonal antibody, has a rapid impact on tumor-related brain edema in recurrent GB. The present study reports the feasibility and efficacy of an induction treatment with TMZ and BEV to alleviate the initial neurological impairment and/or to reduce the tumor volume before a delayed chemoradiotherapy. Methods. We retrospectively analyzed tumor and target volumes and clinical neurological status in 39 patients with bulky GB and/or with severe neurological impairment after an induction treatment combining TMZ and BEV. Neurological and radiological responses were assessed according to RANO criteria. Calculating gross tumor and clinical target volumes (GTV and CTV) was done at diagnosis and before radiotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan Meier methods. Safety was reported according to NCTCAE. Results. A cohort of 39 patients was analyzed between December 2010 and April 2014. Upfront standard TMZ-based chemoradiotherapy was recused due either to tumor volume or impairment of neurological status and/or performance status. After TMZ/BEV induction (median time of 3 months), 6 (15%) patients achieved a partial response (PR), and 17 (44%) had a stable disease. 24 patients (62%) received a radical-intent chemoradiotherapy. TMZ-BEV induced median reduction of the clinical target volume (CTV) was 25.9% [-84.4%; - 4.8%]. The median PFS and OS were 8.4 months [95% CI: (6.6 - 9.9)] and 11.0 months [95% CI: (9.3 - 13.7)], respectively in the whole cohort and 10.8 [95% CI: (9.3 - 12.9)] and 15.0 [95% CI: (13.2 - 17.8)] for irradiated patients. Induction treatment led to corticosteroid dose reduction or cessation in 21 patients (54%). KPS improvement was observed in 38% of patients. Toxicity was mild with only 7/39 (18%) grade III-IV toxicity, including 1 digestive bleeding and 1 epistaxis. Conclusion. TMZ-BEV induction led to CTV reduction allowing for optimal chemoradiotherapy in a majority (62%) of patients for which radiotherapy was initially recused. A clinical benefit was obtained with improved KPS and a decrease in steroid dose.
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PMID:Temozolomide and Bevacizumab Induction before Chemoradiotherapy in Patients with Bulky Glioblastoma and/or with Severe Neurological Impairment. 2863 56

Glioblastoma (GBM) is a highly malignant CNS tumor with very poor survival despite intervention with conventional therapeutic strategies. Although the CNS is separated from the immune system by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier, emerging evidence of immune surveillance and the selective infiltration of GBMs by immune suppressive cells indicates that there is breakdown or compromise of these physical barriers. This in turn offers hope that immunotherapy can be applied to specifically target and reduce tumor burden. One of the major setbacks in translating immunotherapy strategies is the hostile microenvironment of the tumor that inhibits trafficking of effector immune cells such as cytotoxic T lymphocytes into the CNS. Incorporating important findings from autoimmune disorders such as multiple sclerosis to understand and thereby enhance cytotoxic lymphocyte infiltration into GBM could augment immunotherapy strategies to treat this disease. However, although these therapies are designed to evoke a potent immune response, limited space in the brain and cranial vault reduces tolerance for immune therapy-induced inflammation and resultant brain edema. Therefore, successful immunotherapy requires that a delicate balance be maintained between activating and retaining lasting antitumor immunity.
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PMID:Immunotherapy in CNS cancers: the role of immune cell trafficking. 2977 86

In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate-aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST-expressing gliomas showing that these tumors exhibit increased glutamate concentration compared to GLAST-depleted glioma. Despite their GLAST expression, GBM stem-like cells (GSCs) released rather than taking up glutamate due to their lack of Na+/K+-ATPase. Overexpression of Na+/K+-ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH-101. In glioma-bearing mice, a single intratumoral injection of UCPH-101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target.
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PMID:Altered function of the glutamate-aspartate transporter GLAST, a potential therapeutic target in glioblastoma. 3041 68

Subcortical bleeding from brain tumors is not rare. In the majority of cases, tumors are revealed within a few months after bleeding. We herein report a relatively rare case of glioblastoma(GBM)that appeared one year after the removal of a subcortical hematoma. A 70-year-old woman suddenly began experiencing headache, vomiting, and aphasia. CT revealed a subcortical hematoma in the left superior temporal lobe and subarachnoid bleeding. Neither aneurysms nor abnormal signs suggesting a malignant tumor were noted during cerebral angiography. The hematoma was completely removed via craniotomy, and she was discharged with no neurological deficit.(MRI performed seven months after the surgery showed neither space-occupying lesions in the left temporal lobe nor brain edema. Twelve months after the initial surgery, she had aphasia again. CT and MRI revealed an enhanced mass lesion in the left temporal lobe. Positron emission tomography findings strongly indicated the presence of a malignant tumor. Histology of the tumor after removal showed GBM HDH-1 wild-type with an MIB-1 labelling index of approximately 50%. After the surgery, she underwent extensive local radiation therapy(50 Gy)with chemotherapy(temozolomide). The pathological mechanism underlying the appearance of GBM at the site where subcortical bleeding was previously observed is unclear. GBM may have caused bleeding or may have originated from the brain tissue that was damaged during the first surgery. Follow-up using neuroimaging for one year may be needed when subcortical bleeding is observed.
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PMID:[A Case of Glioblastoma that Appeared One Year after the Removal of Subcortical Hematoma]. 3123 70


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