Association of Angiogenic Cells in the Tumour Microenvironment and the Circulating Matured Endothelial Cells in Astrocytic Glioma

Introduction: Astrocytic gliomas are the most common and lethal intracranial brain tumours and rely on angiogenesis for the tumour development. Endothelial progenitor cells (EPCs) contribute to the angiogenesis of glioma tumour. Objectives: The study aimed to investigate the matured circulating endothelial cells population in the peripheral blood mononuclear cells (PBMCs) and its associations with tissue resident angiogenic cells in astrocytic glioma patients. Methods: A total of 22 astrocytic glioma patients were recruited from Hospital Universiti Sains Malaysia. Tumour were sliced and stained with CD133+ and VEGFA+ for angiogenic cells (n=22). The circulating (CD133-/VEGFR2+) matured endothelial cells in PBMCs (n=22) were quantified using FACS. The paired t-test and Pearson correlation test were used for the data analysis. Results: The angiogenic cells in brain tumour tissue were significantly higher compared to adjacent normal brain tissue (median 1.07±0.96% vs. median 0.69±0.68%; Wilcoxon signed rank test Z=-3.100; p=0.002). Positive correlation was found between the angiogenic cells of brain tumour tissue and adjacent normal brain tissue (Spearman’s rho correlation test, r=0.56; p=0.007). Significant positive correlation was found between matured endothelial cells in peripheral circulating systems and angiogenic cells in tumour of astrocytic glioma patients (Pearson correlation test, r=0.60, p=0.003).Conclusion:The findings of the study give support to the possible roles of EPCs in astrocytic glioma patients. Thus targeting tissue resident angiogenic cells and matured circulating endothelial cells by antiangiogenic treatment might be useful to prevent the tumour growth.

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Abstract TMP120: Autoantigen(s) Trigger a Robust Immune Response in Cerebral Cavernous Malformations

Stroke ◽

10.1161/str.51.suppl_1.tmp120 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Dongdong Zhang ◽

Abhinav Srinath ◽

Andrew J Kinloch ◽

Robert Shenkar ◽

Le Shen ◽

...

Keyword(s):

Mass Spectrometry ◽

Endothelial Cells ◽

B Cell ◽

Brain Tissue ◽

Glial Cells ◽

Plasma Cells ◽

Normal Brain ◽

Normal Brain Tissue ◽

Cell Lysates ◽

Mass Spectrometry Identification

Introduction: Previous studies have reported robust inflammatory cell infiltration, selective synthesis of IgG, B-cell clonal expansion, and deposition of immune complexes and complement within Cerebral Cavernous Malformation (CCM) lesions. Furthermore,B-cell depletion has been shown to reduce the maturation of CCM in murine models. We hypothesize that specific autoantigen(s) within the lesional milieu trigger the pathogenetic immune responses in CCMs. This study aims to identify those putative autoantigen(s) using recombinant antibodies (rAbs) derived from plasma cells found in surgical human CCM lesions. Methods: CD138 + plasma cells were laser captured from fresh frozen surgically resected human CCM lesions. Clonally expanded immunoglobulin heavy- and light-chain variable region pairs were cloned into IgG expression vectors and expressed as monoclonal antibodies. Purified rAbs were assayed by immunofluorescence with CCM lesion tissue and normal brain tissue sections. rAbs assayed by immunocytochemistry with human primary cell line were used to further define the staining pattern. The cell lysates were immunoprecipitated with rAb, after protein purification by SDS-PAGE, and analyzed by Mass spectrometry. Results: In normal brain tissue, rAbs stained endothelial cells with limited staining of glial cells. In CCM lesional tissue, rAbs stained endothelial cells, glial cells as well as structures in the acellular matrix adjacent to caverns. In cultured Human Brain Microvascular Endothelial Cells (HBMECs) and Human Astrocytes (HAs), rAbs co-localized with cytoplasmic components. After HBMEC and HA cell lysates were immunoprecipitated with rAb, a Coomassie Stain detected bands of approximately 50 kDa. Conclusions: Our results suggest that autoantigen(s) in human CCM lesions are cytoplasmic components present in lesional tissue as well as in normal brain tissue. Molecular level identification of the triggering antigen is still ongoing by mass spectrometry. Identification of the autoantigen(s) in the lesional milieu might explain the propensity of lesion development from leaky endothelium in the neuroglial parenchyma. Characterization of the autoantigen triggers will open new venues for therapy or vaccine in this disease.

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Maximum Lesion-To-Contralateral Normal Brain Tissue Ratio of 11C-Methionine PET as a Prognostic Imaging Biomarker for Newly Diagnosed and Untreated Astrocytic Glioma

10.21203/rs.3.rs-729587/v1 ◽

2021 ◽

Author(s):

Kosuke Nakajo ◽

Takehiro Uda ◽

Toshiyuki Kawashima ◽

Yuzo Terakawa ◽

Kenichi Ishibashi ◽

...

Keyword(s):

Brain Tissue ◽

Cox Regression ◽

Surgical Excision ◽

World Health ◽

Imaging Biomarker ◽

Normal Brain ◽

Newly Diagnosed ◽

Normal Brain Tissue ◽

Astrocytic Glioma ◽

Contralateral Normal Brain

Abstract Purpose: This study aimed whether the uptake of amino tracer positron emissiontomography (PET) can be used as an additional imaging biomarker to estimatethe prognosis of glioma.Methods: Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) gradeⅡ-Ⅳ astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution.Results: Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (PFS) (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, p<0.0001), whereas histology (anaplastic astrocytoma: HR 5.30, 95%CI 1.23-22.8, p=0.025; glioblastoma: HR 11.52, 95%CI 2.27-58.47, p=0.0032), preoperative KPS≥80 (HR 0.23, 95%CI 0.09-0.62, p=0.004), maximum lesion-to-contralateral normal brain tissue (LN max)≥4.03 (HR 0.24, 95%CI 0.08-0.71, p=0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95%CI 1.81-109.2, p=0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max≥ 4.03 (29.3 months) than in patients with LN max<4.03 (not reached; p=0.03). OS differed significantly between patients with IDH mutant/LN max<4.03 and patients with IDH mutant/LN max ≥4.03.Conclusions: LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO gradeⅡ-Ⅳ astrocytic glioma.

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Types of Endothelium in Normal and Neoplastic Brain Tissue

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100067480 ◽

1970 ◽

Vol 28 ◽

pp. 98-99

Author(s):

Milton W. Brightman ◽

Thomas S. Reese

Keyword(s):

Endothelial Cells ◽

Horseradish Peroxidase ◽

Tight Junctions ◽

Brain Tissue ◽

Normal Brain ◽

Cerebral Ventricles ◽

Normal Brain Tissue ◽

Capillary Lumen ◽

Cerebral Capillaries

The junctions between adjacent endothelial cells of the cerebral capillaries in normal vertebrates determine whether or not proteins can leave the capillary lumen to move into the parenchymal interspaces. In rodents (mice and hamsters), these junctions are of the tight variety, such as that shown in Fig.2(TJ), and are typical of endothelium in normal brain tissue. Such tight junctions appear to form circumferential belts of occlusion between contiguous endothelial cells. A protein such as horseradish peroxidase, when injected into the blood, is thereby prevented from leaving the capillary lumen to enter the extracellular clefts of the neuropil. The same tight junctions also stop peroxidase from entering the capillary lumen after this protein has been injected into the cerebral ventricles and has moved throughout the extracellular clefts.

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Observations of intracranial neoplasms treated with gamma knife radiosurgery

Journal of Neurosurgery ◽

10.3171/jns.2002.97.supplement_5.0623 ◽

2002 ◽

Vol 97 ◽

pp. 623-626 ◽

Cited By ~ 25

Author(s):

György T. Szeifert ◽

Nicolas Massager ◽

Daniel DeVriendt ◽

Philippe David ◽

Françoise De Smedt ◽

...

Keyword(s):

Endothelial Cells ◽

Brain Tissue ◽

Gamma Knife ◽

Tumor Tissue ◽

Gamma Knife Radiosurgery ◽

Normal Brain ◽

Vascular Endothelial ◽

Normal Brain Tissue ◽

Content Type ◽

Fine Print

Object. The purpose of this study was to compare histopathological changes with imaging findings in different tumors after gamma knife radiosurgery (GKS). Methods. Five patients of a series of 220 treated with GKS underwent craniotomy for tumor removal 3 to 12 months after radiosurgery. There were two patients with multiple cerebral metastases, one with vestibular schwannoma, one with malignant glioma, and one with meningioma. A portion of normal brain tissue outside the prescription dose volume was acquired wherever possible to facilitate examination of the effects of radiosurgery. Histopathological and immunohistochemical investigations were performed. In addition to the routine hematoxylin and eosin and Mallory trichrome stains, immunohistochemical reactions were also performed for Factor VIII—associated antigen (FVIII) and CD34 antigen to study vascular endothelial effects of the irradiation. Endothelial cells of vessels in the normal brain tissue covering the tumor, outside of the prescription isodose volume, expressed marked CD34 and FVIII positivity. In the irradiated targeted tumor tissue samples, however, both reactions decreased remarkably. Conclusions. The results of the present immunohistochemical study provide support to the experimental hypothesis that vascular endothelial cells are the principal targets of single high-dose irradiation. The loss of central contrast enhancement of tumor tissue following radiosurgery might be consequence of the vascular damage.

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Maximum Lesion-to-contralateral Normal Brain Tissue Ration of 11C-methionine PET as a Prognostic Imaging Biomarker for Newly Diagnosed and Untreated Astrocytic Glioma

10.21203/rs.3.rs-596317/v1 ◽

2021 ◽

Author(s):

Kosuke Nakajo ◽

Takehiro Uda ◽

Toshiyuki Kawashima ◽

Yuzo Terakawa ◽

Kenichi Ishibashi ◽

...

Keyword(s):

Brain Tissue ◽

Cox Regression ◽

Surgical Excision ◽

World Health ◽

Imaging Biomarker ◽

Normal Brain ◽

Newly Diagnosed ◽

Normal Brain Tissue ◽

Astrocytic Glioma ◽

Contralateral Normal Brain

Abstract Purpose: This study aimed whether the uptake of amino tracer positron emission tomography (PET) can be used as an additional imaging biomarker to estimate the prognosis of glioma.Methods: Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) gradeⅡ-Ⅳ astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution.Results: Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (PFS) (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10-0.41, p<0.0001), whereas histology (anaplastic astrocytoma: HR 5.30, 95%CI 1.23-22.8, p=0.025; glioblastoma: HR 11.52, 95%CI 2.27-58.47, p=0.0032), preoperative KPS≥80 (HR 0.23, 95%CI 0.09-0.62, p=0.004), maximum lesion-to-contralateral normal brain tissue (LN max)≥4.03 (HR 0.24, 95%CI 0.08-0.71, p=0.01), and isocitrate dehydrogenase (IDH) status (HR 14.06, 95%CI 1.81-109.2, p=0.011) were factors influencing overall survival (OS) in multivariate Cox regression. OS was shorter in patients with LN max≥ 4.03 (29.3 months) than in patients with LN max<4.03 (not reached; p=0.03). OS differed significantly between patients with IDH mutant/LN max<4.03 and patients with IDH mutant/LN max ≥4.03.Conclusions: LN max using 11C-methionine PET may be used in prognostic markers for newly identified and untreated WHO gradeⅡ-Ⅳ astrocytic glioma.

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Neuroinflammatory changes of the normal brain tissue in cured mice following combined radiation and anti-PD-1 blockade therapy for glioma

Scientific Reports ◽

10.1038/s41598-021-84600-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mariano Guardia Clausi ◽

Alexander M. Stessin ◽

Zirun Zhao ◽

Stella E. Tsirka ◽

Samuel Ryu

Keyword(s):

Brain Tissue ◽

Cranial Irradiation ◽

Subcortical White Matter ◽

Glioma Cell Line ◽

Hippocampal Neurogenesis ◽

Normal Brain ◽

Long Term Effects ◽

Normal Brain Tissue ◽

Molecule Inhibitor

AbstractThe efficacy of combining radiation therapy with immune checkpoint inhibitor blockade to treat brain tumors is currently the subject of multiple investigations and holds significant therapeutic promise. However, the long-term effects of this combination therapy on the normal brain tissue are unknown. Here, we examined mice that were intracranially implanted with murine glioma cell line and became long-term survivors after treatment with a combination of 10 Gy cranial irradiation (RT) and anti-PD-1 checkpoint blockade (aPD-1). Post-mortem analysis of the cerebral hemisphere contralateral to tumor implantation showed complete abolishment of hippocampal neurogenesis, but neural stem cells were well preserved in subventricular zone. In addition, we observed a drastic reduction in the number of mature oligodendrocytes in the subcortical white matter. Importantly, this observation was evident specifically in the combined (RT + aPD-1) treatment group but not in the single treatment arm of either RT alone or aPD-1 alone. Elimination of microglia with a small molecule inhibitor of colony stimulated factor-1 receptor (PLX5622) prevented the loss of mature oligodendrocytes. These results identify for the first time a unique pattern of normal tissue changes in the brain secondary to combination treatment with radiotherapy and immunotherapy. The results also suggest a role for microglia as key mediators of the adverse treatment effect.

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Quantitative Measurements of Regional Glucose Utilization and Rate of Valine Incorporation into Proteins by Double-Tracer Autoradiography in the Rat Brain Tumor Model

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1989.12 ◽

1989 ◽

Vol 9 (1) ◽

pp. 87-95 ◽

Cited By ~ 22

Author(s):

Michihiro Kirikae ◽

Mirko Diksic ◽

Y. Lucas Yamamoto

Keyword(s):

Protein Synthesis ◽

Brain Tumor ◽

Rat Brain ◽

Brain Tissue ◽

Glucose Utilization ◽

Tumor Model ◽

Normal Brain ◽

Normal Brain Tissue ◽

Rat Brain Tumor ◽

Brain Tumor Model

We examined the rate of glucose utilization and the rate of valine incorporation into proteins using 2-[18F]fluoro-2-deoxyglucose and L-[1-14C]-valine in a rat brain tumor model by quantitative double-tracer autoradiography. We found that in the implanted tumor the rate of valine incorporation into proteins was about 22 times and the rate of glucose utilization was about 1.5 times that in the contralateral cortex. (In the ipsilateral cortex, the tumor had a profound effect on glucose utilization but no effect on the rate of valine incorporation into proteins.) Our findings suggest that it is more useful to measure protein synthesis than glucose utilization to assess the effectiveness of antitumor agents and their toxicity to normal brain tissue. We compared two methods to estimate the rate of valine incorporation: “kinetic” (quantitation done using an operational equation and the average brain rate coefficients) and “washed slices” (unbound labeled valine removed by washing brain slices in 10% thrichloroacetic acid). The results were the same using either method. It would seem that the kinetic method can thus be used for quantitative measurement of protein synthesis in brain tumors and normal brain tissue using [11C]-valine with positron emission tomography.

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PET Study of Methionine Accumulation in Glioma and Normal Brain Tissue

Journal of Computer Assisted Tomography ◽

10.1097/00004728-198703000-00002 ◽

1987 ◽

Vol 11 (2) ◽

pp. 208-213 ◽

Cited By ~ 71

Author(s):

Mats Bergström ◽

Kaj Ericson ◽

Lars Hagenfeldt ◽

Mikael Mosskin ◽

Hans von Holst ◽

...

Keyword(s):

Brain Tissue ◽

Normal Brain ◽

Normal Brain Tissue

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Quantitative Analysis of Mobile Proteins in Normal Brain Tissue by Amide Proton Transfer Imaging

Journal of Computer Assisted Tomography ◽

10.1097/rct.0000000000001141 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Kazuaki Sugawara ◽

Tosiaki Miyati ◽

Ryo Ueda ◽

Daisuke Yoshimaru ◽

Masanobu Nakamura ◽

...

Keyword(s):

Quantitative Analysis ◽

Proton Transfer ◽

Brain Tissue ◽

Amide Proton ◽

Normal Brain ◽

Normal Brain Tissue ◽

Amide Proton Transfer ◽

Amide Proton Transfer Imaging

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Glutathione S-Transferases and Cytochrome P450 Enzyme Expression in Patients with Intracranial Tumors: Preliminary Report of 55 Patients

Medical Principles and Practice ◽

10.1159/000494496 ◽

2018 ◽

Vol 28 (1) ◽

pp. 56-62

Author(s):

Cahit Kural ◽

Arzu Kaya Kocdogan ◽

Gulcin Güler Şimşek ◽

Serpil Oğuztüzün ◽

Pınar Kaygın ◽

...

Keyword(s):

Cytochrome P450 ◽

Brain Tissue ◽

Pituitary Adenomas ◽

Normal Brain ◽

Cytochrome P450 Enzyme ◽

Intracranial Tumors ◽

Glutathione S Transferase ◽

Normal Brain Tissue ◽

Tissue Samples ◽

P450 Enzyme

Objective: Intracranial tumors are one of the most frightening and difficult-to-treat tumor types. In addition to surgery, protocols such as chemotherapy and radiotherapy also take place in the treatment. Glutathione S-transferase (GST) and cytochrome P450 (CYP) enzymes are prominent drug-metabolizing enzymes in the human body. The aim of this study is to show the expression of GSTP1, GSTM1, CYP1A1, and CYP1B1 in different types of brain tumors and compare our results with those in the literature. Subjects and Methods: The expression of GSTP1, GSTM1, CYP1A1, and CYP1B1 was analyzed using immunostaining in 55 patients with intracranial tumors in 2016–2017. For GST and CYP expression in normal brain tissue, samples of a portion of surrounding normal brain tissue as well as a matched far neighbor of tumor tissue were used. The demographic features of the patients were documented and the expression results compared. Results: The mean age of the patients was 46.72 years; 29 patients were female and 26 were male. Fifty-seven specimens were obtained from 55 patients. Among them, meningioma was diagnosed in 12, metastases in 12, glioblastoma in 9, and pituitary adenoma in 5. The highest GSTP1, GSTM1, and CYP1A1 expressions were observed in pituitary adenomas. The lowest GSTP1 expression was detected in glioblastomas and the lowest CYP1B1 expression in pituitary adenomas. Conclusion: GSTP1 and CYP expression is increased in intracranial tumors. These results should be confirmed with a larger series and different enzyme subtypes.

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