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Vascular gene expression in nonneoplastic and malignant brain.

ABSTRACT: Malignant gliomas are uniformly lethal tumors whose morbidity is mediated in large part by the angiogenic response of the brain to the invading tumor. This profound angiogenic response leads to aggressive tumor invasion and destruction of surrounding brain tissue as well as blood-brain barrier breakdown and life-threatening cerebral edema. To investigate the molecular mechanisms governing the proliferation of abnormal microvasculature in malignant brain tumor patients, we have undertaken a cell-specific transcriptome analysis from surgically harvested nonneoplastic and tumor-associated endothelial cells. SAGE-derived endothelial cell gene expression patterns from glioma and nonneoplastic brain tissue reveal distinct gene expression patterns and consistent up-regulation of certain glioma endothelial marker genes across patient samples. We define the G-protein-coupled receptor RDC1 as a tumor endothelial marker whose expression is distinctly induced in tumor endothelial cells of both brain and peripheral vasculature. Further, we demonstrate that the glioma-induced gene, PV1, shows expression both restricted to endothelial cells and coincident with endothelial cell tube formation. As PV1 provides a framework for endothelial cell caveolar diaphragms, this protein may serve to enhance glioma-induced disruption of the blood-brain barrier and transendothelial exchange. Additional characterization of this extensive brain endothelial cell gene expression database will provide unique molecular insights into vascular gene expression.

SUBMITTER: Madden SL

PROVIDER: S-EPMC1618572 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Vascular gene expression in nonneoplastic and malignant brain.

Madden Stephen L SL Cook Brian P BP Nacht Mariana M Weber William D WD Callahan Michelle R MR Jiang Yide Y Dufault Michael R MR Zhang Xiaoming X Zhang Wen W Walter-Yohrling Jennifer J Rouleau Cecile C Akmaev Viatcheslav R VR Wang Clarence J CJ Cao Xiaohong X St Martin Thia B TB Roberts Bruce L BL Teicher Beverly A BA Klinger Katherine W KW Stan Radu-Virgil RV Lucey Brenden B Carson-Walter Eleanor B EB Laterra John J Walter Kevin A KA

The American journal of pathology 20040801 2

Malignant gliomas are uniformly lethal tumors whose morbidity is mediated in large part by the angiogenic response of the brain to the invading tumor. This profound angiogenic response leads to aggressive tumor invasion and destruction of surrounding brain tissue as well as blood-brain barrier breakdown and life-threatening cerebral edema. To investigate the molecular mechanisms governing the proliferation of abnormal microvasculature in malignant brain tumor patients, we have undertaken a cell- ...[more]

PMID: 15277233

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Project description:Background Dynamic contrast agent-enhanced (DCE) perfusion MRI may help differentiate between nonneoplastic and malignant lesions in the spine. Purpose To investigate the correlation between fractional plasma volume (Vp), a parameter derived from DCE perfusion MRI, and histopathologic diagnosis for spinal lesions. Materials and Methods In this retrospective study, patients who underwent DCE perfusion MRI and lesion biopsy between May 2015 and May 2018 were included. Inclusion criteria were short time interval (<30 days) between DCE perfusion MRI and biopsy, DCE perfusion MRI performed before biopsy, and DCE perfusion MRI performed at the same spine level as biopsy. Exclusion criteria were prior radiation treatment on vertebrae of interest, poor DCE perfusion MRI quality, nondiagnostic biopsy, and extensive spinal metastasis or prior kyphoplasty. One hundred thirty-four lesions were separated into a nonneoplastic group (n = 51) and a malignant group (n = 83) on the basis of histopathologic analysis. Two investigators manually defined regions of interest in the vertebrae. DCE perfusion MRI parameter Vp was calculated by using the Tofts pharmacokinetic two-compartment model. Vp was quantified, normalized to adjacent normal vertebrae, and compared between the two groups. A Mann-Whitney U test and receiver operating characteristic analysis was performed to verify the difference in Vp between the nonneoplastic and malignant groups. Reproducibility was assessed by calculating the Cohen κ coefficient. Results One hundred patients (mean age, 65 years ± 11 [standard deviation]; 52 men) were evaluated. Vp was lower in nonneoplastic lesions versus malignant lesions (1.6 ± 1.3 vs 4.2 ± 3.0, respectively; P < .001). The sensitivity of Vp was 93% (77 of 83; 95% confidence interval [CI]: 85%, 97%), specificity was 78% (40 of 51; 95% CI: 65%, 89%), and area under the receiver operating characteristic curve was 0.88 (95% CI: 0.82, 0.95). Cohen κ coefficient suggested substantial agreement in both intra- (κ = 0.72) and interreader (κ = 0.70) reproducibility. Conclusion This study indicated that dynamic contrast agent-enhanced perfusion MRI parameter, fractional plasma volume, was able to differentiate between nonneoplastic spinal lesions and malignant lesions. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Haller in this issue.

Project description:Recently, the overexpression of CD146 and its potential as a therapeutic target in high-grade gliomas, the most lethal type of brain cancer, was uncovered. In this study, we describe the generation of (89)Zr-Df-YY146, a novel (89)Zr-labeled monoclonal antibody (mAb) for the targeting and quantification of CD146 expression in a mouse model of glioblastoma, using noninvasive immunoPET imaging. YY146, a high affinity anti-CD146 mAb, was conjugated to deferoxamine (Df) for labeling with the long-lived positron emitter (89)Zr (t1/2: 78.4 h). In vitro assays, including flow cytometry, immunofluorescence microscopy, and Western blot, were performed with two glioblastoma cell lines, U87MG and U251, to determine their CD146 expression levels. Also, YY146 and Df-YY146's CD146-binding affinities were compared using flow cytometry. In vivo CD146-targeting of (89)Zr-Df-YY146 was evaluated by sequential PET imaging, in athymic nude mice bearing subcutaneously implanted U87MG or U251 tumors. CD146 blocking, ex vivo biodistribution, and histological studies were carried out to confirm (89)Zr-Df-YY146 specificity, as well as the accuracy of PET data. In vitro studies exposed elevated CD146 expression levels in U87MG cells, but negligible levels in U251 cells. Flow cytometry revealed no differences in affinity between YY146 and Df-YY146. (89)Zr labeling of Df-YY146 proceeded with excellent yield (?80%), radiochemical purity (>95%), and specific activity (?44 GBq/?mol). Longitudinal PET revealed prominent and persistent (89)Zr-Df-YY146 uptake in mice bearing U87MG tumors that peaked at 14.00 ± 3.28%ID/g (n = 4), 48 h post injection of the tracer. Conversely, uptake was significantly lower in CD146-negative U251 tumors (5.15 ± 0.99%ID/g, at 48 h p.i.; n = 4; P < 0.05). Uptake in U87MG tumors was effectively blocked in a competitive inhibition experiment, corroborating the CD146 specificity of (89)Zr-Df-YY146. Finally, ex vivo biodistribution validated the accuracy of PET data and histological examination successfully correlated tracer uptake with in situ CD146 expression. Prominent, persistent, and specific uptake of (89)Zr-Df-YY146 was observed in brain tumors, demonstrating the potential of this radiotracer for noninvasive PET imaging of CD146 expression. In a future clinical scenario, (89)Zr-Df-YY146 may serve as a tool to guide intervention and assess response to CD146-targeted therapies.

Dataset Information

Vascular gene expression in nonneoplastic and malignant brain.

Publications

Vascular gene expression in nonneoplastic and malignant brain.

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