CD40 is a regulator for vascular endothelial growth factor in the tumor microenvironment of glioma.
ABSTRACT CD40 is expressed in many tumor cells, however, its role in tumor biology is yet to be demonstrated. In the present study, we investigated the role of CD40 in gliomas. In vivo, we evaluated CD40 expression in 95 glioma tissues and 10 non-tumorous brain tissues and investigated the relationship between histopathological parameters, vascular density, and vascular endothelial growth factor (VEGF) expressions. In vitro, we aimed to understand the biological relevance of CD40 and VEGF in glioma cell lines. The results clearly demonstrated that CD40 expression, including membranous and cytoplasmic staining, was significantly higher in poorly differentiated and well differentiated gliomas than in the non-tumorous brain tissues (P=0.045 and P=0.043, respectively). In gliomas, the expression of CD40 was significantly correlated with tumor size, VEGF expressions and microvessel density (MVD) (P=0.022, P=0.023 and P=0.0316, respectively). In the in vitro study, stimulation of human glioma cells by CD40 ligation induced the expression and secretion of VEGF and was blocked by anti-CD40 monoclonal antibody. These observations provide evidence that CD40 ligation supports the expression and secretion of VEGF and may be involved in neovascularization of gliomas, they also suggest that CD40 and VEGF may be useful biomarkers for evaluating the risk of developing gliomas, and may also be used as a target for therapy.
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ABSTRACT: Increasing evidence supports involvement of inflammation and immunity in atherogenesis. We report here that CD40 ligand (CD40L), an immunoregulatory signaling molecule heretofore considered largely restricted to recently activated CD4+ T lymphocytes, is expressed by human vascular endothelial cells (EC), smooth muscle cells (SMC), and human macrophages in vitro, and is coexpressed with its receptor CD40 on all three cells types in human atherosclerotic lesions in situ. Cultured human vascular EC, SMC, and human macrophages all constitutively expressed CD40L mRNA as well as protein. Stimulation with interleukin 1beta, tumor necrosis factor alpha, or interferon gamma increased surface levels and de novo synthesis of CD40L on all three cell types. CD40L expressed on EC, SMC, and macrophages exhibited biological activity, as it induced B7.2 expression on B cells. Human vascular SMC also constitutively expressed CD40, the receptor for CD40L, and through CD40 signaling, human recombinant CD40L induced expression of proinflammatory cytokines in these cells, identifying SMC as a target for CD40L. Human atherosclerotic lesions (n = 8) showed expression of immunoreactive CD40L on EC, SMC, and macrophages, while normal arterial tissues (n = 5) contained no CD40L. In atheroma CD40L+ cells often also expressed CD40. These observations establish human vascular EC, SMC, and human macrophages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of nonimmune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis.Proceedings of the National Academy of Sciences 04/1997; 94(5):1931-6. · 9.74 Impact Factor
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ABSTRACT: The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO 'Blue Book', the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.Acta Neuropathologica 09/2007; 114(2):97-109. · 9.73 Impact Factor
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ABSTRACT: We aimed to identify signaling pathways involved in the response and resistance to aromatase inhibitor therapy in patients with breast cancer. One hundred fourteen women with T2-4 N0-1, estrogen receptor (ER) alpha-positive tumors were randomly assigned to neoadjuvant letrozole or letrozole plus metronomic cyclophosphamide. Twenty-four tumor proteins involved in apoptosis, cell survival, hypoxia, angiogenesis, growth factor, and hormone signaling were assessed by immunohistochemistry in pretreatment samples (eg, caspase 3, phospho- mammalian target of rapamycin, hypoxia-inducible factor 1alpha [HIF-1alpha], vascular endothelial growth factor, mitogen-activated protein kinase [MAPK], phosphorylated epidermal growth factor receptor, phosphorylated ERalpha [pERalpha]). A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization. Ten-fold cross-validation and iterative leave-one-out were employed to validate and test the model, respectively. Tumor size, nodal status, age, tumor grade, histological type, and treatment were included in the analysis. Ninety-one patients (81%) attained a disease response, 48 achieved a complete clinical response (43%) whereas 22 did not respond (19%). Increased pERalpha and decreased p44/42 MAPK were significant factors for complete response to treatment in all leave-one-out iterations. Increased p44/42 MAPK and HIF-1alpha were significant factors for treatment resistance in all leave-one-out iterations. There was no significant interaction between these variables and treatment. Activated ERalpha form was an independent factor for sensitivity to chemoendocrine treatment, whereas HIF-1alpha and p44/42 MAPK were independent factors for resistance. Although further confirmatory analyses are needed, these findings have clear potential implications for future strategies in the management of clinical trials with aromatase inhibitors in the breast cancer.Journal of Clinical Oncology 01/2009; 27(2):227-34. · 18.04 Impact Factor