Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of chemokine receptors and chemokine production by adult human non-transformed astrocytes, grade III astrocytoma and grade IV glioblastoma tumour cell lines were determined. Here, we show an increased expression of CXCR3 and CXCR4, and a decreased expression of CXCR1 and CCR4 by glioma cells compared to adult human astrocytes. Glioma cells showed increased production of CXCL10, whereas production of other chemokines was decreased (CXCL8, CCL2, CCL5, and CCL22). CXCL10 induced an ERK1/2-dependent increase in [(3)H] thymidine uptake. These results suggest that expression of chemokine receptor/ligand pairs such as CXCR3/CXCL10 have an important role in the proliferation of glioma cells.
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PMID:Chemokine production and chemokine receptor expression by human glioma cells: role of CXCL10 in tumour cell proliferation. 1853 64

The morphological patterns of glioma cell invasion are known as the secondary structures of Scherer. In this report, we propose a biologically based mechanism for the nonrandom formation of Scherer's secondary structures based on the differential expression of stromal cell-derived factor (SDF)-1alpha and CXCR4 at the invading edge of glioblastomas. The chemokine SDF-1alpha was highly expressed in neurons, blood vessels, subpial regions, and white matter tracts that form the basis of Scherer's secondary structures. In contrast, the SDF-1alpha receptor, CXCR4, was highly expressed in invading glioma cells organized around neurons and blood vessels, in subpial regions, and along white matter tracts. Neuronal and endothelial cells exposed to vascular endothelial growth factor up-regulated the expression of SDF-1alpha. CXCR4-positive tumor cells migrated toward a SDF-1alpha gradient in vitro, whereas inhibition of CXCR4 expression decreased their migration. Similarly, inhibition of CXCR4 decreased levels of SDF-1alpha-induced phosphorylation of FAK, AKT, and ERK1/2, suggesting CXCR4 involvement in glioma invasion signaling. These studies offer one plausible molecular basis and explanation of the formation of Scherer's structures in glioma patients.
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PMID:Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer's structures. 1859 7

The tumor microenvironment affects tumor initiation, progression, and metastasis. However, it is still not clear how stromal cells interact with the tumor cells. By using a cytokine array immunoblot assay, we showed that interleukin (IL)-8, IL-6, and RANTES (regulated upon activation normal T-cell expressed and secreted) proteins were up-regulated in GBM8401 glioma cells after coculture with human THP-1-derived macrophages. IL-8 is a chemokine with leukocyte chemotactic, tumorigenic, and proangiogenic properties. To evaluate the correlation of IL-8 expression with tumor-associated macrophages and angiogenesis, 43 glioma specimens were studied. The results showed that the IL-8 mRNA expression and microvessel count in glioma surgical specimens correlated positively with the density of tumor-associated macrophages. We further showed that IL-8 mRNA expression in GBM8401 cells increased dramatically, by 2(8)-2(10)-fold, after being cocultured with macrophages. This increase could also be induced by macrophage-conditioned medium, tumor necrosis factor-alpha, IL-1alpha, and IL-1beta, and could be suppressed by anti-inflammatory agents including pyrrolidine dithiocarbamate, pentoxifylline, or dexamethasone. These findings imply that macrophage infiltration may be the common feature shared by cancer and inflammation, and macrophages could play a role in promoting glioma growth and angiogenesis by inducing IL-8 expression in glioma cells via inflammatory stimuli or the nuclear factor kappa B pathway.
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PMID:Induced interleukin-8 expression in gliomas by tumor-associated macrophages. 1915 59

The monocyte chemotactic protein 3 (MCP-3) belongs to the MCP subgroup of the CC chemokines and promotes chemotaxis of immune cells. MCP-1 is believed to play an important role in monocyte infiltration into tumor tissues; however, the relationship between tumor-infiltrating macrophage/microglia (TIM/M) and the expression of chemokines has not been investigated in detail in human glioma samples; therefore, we first examined the expression of several chemokines and chemokine receptors in human tumor cell lines, which included glioma lines, using real-time PCR. We found that several glioma lines expressed MCP-3 predominantly, and not MCP-1. In order to assess the significance of MCP-3 expression in human glioma tissues, we then examined the number of CD68+ TIM/M, the percentage of TIM/M in the total cell population, and the expression of MCP-1 and MCP-3 in glioma tissues. There was a correlation between the percentage of TIM/M and MCP-3 expression levels; however, there was no correlation between the percentage of TIM/M and MCP-1 expression. There was no correlation between the number of TIM/M and prognosis of patients. These data indicate that tumor cell-derived MCP-3, but not MCP-1, facilitates the infiltration of macrophage/microglia into tumor tissues. This is the first study that clearly compared the significance of MCP-3 with that of MCP-1 in the tumor infiltration rates of TIM/M.
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PMID:Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. 1942 80

Today several findings indicate that a multifactorial strategy is the best strategy for treating cancer. Although radiotherapy, chemotherapy and surgery have been differently applied to treat human gliomas, no substantial improvement in life expectancy has been observed. Starting from 1992, the goal of our studies was to obtain new biological data on malignant astrocytomas to better understand the basic biology of the tumour and these are reviewed here. Immunotherapy may represent an available method in addition to the traditional therapeutic approaches. Starting from 1991, we set up a cellular model of lymphocytes obtained from peripheral blood of healthy patients treated with interleukin-2 (IL-2) in order to study the role of IL-2 in regulating lymphocytes activation. The lymphocytes responding to IL-2 treatment, named lymphokine-activated killer (LAK) cells, have a killer non MHC restricted activity, and are able to kill autologous and allogenic glioma cells. The interaction of LAK cells with various normal and transformed targets indicates that LAK cells recognize surface structures present both on normal and transformed cells. However, only the interaction with transformed cells induces lytic events and LAK cells can act as "surgical weapons" against tumour cells independently from their cell cycle. Much recent effort has focused on identifying the immune escape mechanisms used by glioma cells, in particular the modulation of the human leukocyte antigen (HLA) and antigen processing machinery component expression. Finally, another interesting field of research that will be presented is that of new tumour biomarkers of proliferation and apoptosis, cytokine/chemokine release and cytokine/chemokine receptors.
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PMID:Immunobiological and experimental aspects of malignant astrocytoma. 1959 14

Malignant gliomas manifest frequent tumor recurrence after surgical resection and/or other treatment because of their nature of invasiveness and dissemination. The recognized brain tumor-tracking property of neural progenitor/stem cells opened the possibility of targeting malignant brain tumors using neural progenitor/stem cells. We and others have previously shown that fetal neural progenitor/stem cells can be used to deliver therapeutic molecules to brain tumors. Our recent work has further shown that gene delivery by bone marrow-derived neural progenitor/stem cells achieves therapeutic effects in a glioma model. In this study, we isolate and characterize bone marrow-derived neural progenitor/stem cells, which also express the chemokine receptor chemokine CXC receptor 4 (CXCR4). We show that CXCR4 is required for their chemotaxis and extracellular matrix invasion against a gradient of glioma soluble factors. Furthermore, beta-galactosidase-labeled bone marrow-derived neural progenitor/stem cells implanted in the contralateral side of the brain were shown to track gliomas as early as day 1 and increased through days 3 and 7. Intracranial glioma tracking by bone marrow-derived neural progenitor/stem cells is significantly inhibited by preincubation of bone marrow-derived neural progenitor/stem cells with a blocking anti-CXCR4 antibody, suggesting a CXCR4-dependent tracking mechanism. Glioma tracking bone marrow-derived neural progenitor/stem cells were found to express progenitor/stem cell markers, as well as CXCR4. Although bromodeoxyuridine incorporation assays and proliferating antigen staining indicated that tumor tracking bone marrow-derived neural progenitor/stem cells were mostly nonproliferating, these cells survive in the local tumor environment with little apoptosis. Elucidating the molecular mechanism of brain tumor tracking by adult source stem cells may provide basis for the development of future targeted therapy for malignant brain tumors.
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PMID:Chemokine CXC receptor 4--mediated glioma tumor tracking by bone marrow--derived neural progenitor/stem cells. 1972 78

Pulmonary activation-regulated chemokine (PARC) now designated CC-chemokine ligand 18 (CCL18) has been shown to play a significant role in the pathogenesis of various tissue injuries and diseases in a proinflammatory or immune suppressive way to limit or support the inflammation or disease. While much is known about the roles of CCL18/PARC in non-neural tissues, its expression in the CNS has remained largely unexplored and controversial. Using reverse transcription polymerase chain reaction (RT-PCR) and double immunohistochemical staining, we analyzed the expression of CCL18/PARC in the human brain with special reference to traumatic brain injuries and tumors. The RT-PCR analysis revealed the expression of CCL18/PARC mRNA both in the traumatic brain and glioma tissues examined. Immunoexpression of CCL18/PARC protein was consistently detected in all cases of traumatic brain injuries examined by immunohistochemical staining. Double immunofluorescence labeling has extended the study that CCL18/PARC positive cells were macrophages/microglia, astrocytes or neurons. The CCL18/PARC expression was localized in macrophage-like cells in two of eight glioblastoma tissues whose cancer cells were CCL18/PARC negative. Unexpectedly, CCL18/PARC mRNA weakly and constitutively expressed by glioblastoma cell line was upregulated after endotoxin stimulation. The present results indicated a significant production of CCL18/PARC in different CNS traumatic and neoplasm tissues by specific cellular elements expressing the chemokine. An anti-inflammatory mechanism jointly exerted by these cells via CCL18/PARC may be involved in the CNS immunity after traumatic injury and tumorigenesis.
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PMID:CC-chemokine ligand 18/pulmonary activation-regulated chemokine expression in the CNS with special reference to traumatic brain injuries and neoplastic disorders. 1995 19

The transmembrane chemokine CX3CL1 and its receptor CX3CR1 are thought to be involved in the trafficking of immune cells during an immune response and in the pathology of various human diseases including cancer. However, little is known about the expression and function of CX3CR1 in human glioma-infiltrating microglia/macrophages (GIMs), representing the major cellular stroma component of highly malignant gliomas. Here, we show that CX3CR1 is overexpressed at both the mRNA and protein level in solid human astrocytomas of different malignancy grades and in glioblastomas. CX3CR1 was localized in ionized calcium-binding adapter molecule 1 (Iba1) and CD11b/c positive GIMs in situ as shown by fluorescence microscopy. In accordance with this, freshly isolated human GIM-enriched fractions separated by CD11b MACS technology displayed high Iba1 and CX3CR1 mRNA expression levels in vitro. Moreover, cultured human GIMs responded to CX3CL1-triggered activation of CX3CR1 with adhesion and migration in vitro. Besides an increase in motility, CX3CL1 also enhanced expression of matrix metalloproteases 2, 9, and 14 in GIM fractions in vitro. These data indicate that the CX3CL1/CX3CR1 system has a crucial tumor-promoting role in human glioblastomas via its impact on glioma-infiltrating immune subsets.
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PMID:CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). 2018 83

The chemokine CXCL12/stromal cell-derived factor-1 and its receptor CXCR4 play a major role in tumor invasion, proliferation, and metastasis. Recently, CXCR7 was identified as a novel, alternate receptor for CXCL12 and CXCL11/I-TAC. Because both chemokines are expressed abundantly in human astrocytomas and glioblastomas, we investigated the occurrence and function of both receptors in astroglial tumors. In situ, CXCR7 is highly expressed on tumor endothelial, microglial, and glioma cells whereas CXCR4 has a much more restricted localization; CXCL12 is often colocalized with CXCR7. CXCR7 transcription in tumor homogenates increased with malignancy. In vitro, CXCR7 was highly expressed in all glioma cell lines investigated whereas CXCR4 was only scarcely transcribed on one of eight lines. In contrast, a tumor stem-like cell line preferentially expressed CXCR4 which diminished upon differentiation, whereas CXCR7 increased drastically. Stimulation of CXCR7-positive glioma cells (CXCR4- and CXCR3-negative) by CXCL12 induced transient phosphorylation of extracellular signal-regulated kinases Erk1/2, indicating that the receptor is functionally active. The phosphoinositide-specific phospholipase C inhibitor U73122 effectively inhibited Erk activation and suggests that the mitogen-activated protein kinase pathway is activated indirectly. Whereas proliferation and migration were little influenced, chemokine stimulation prevented camptothecin- and temozolomide-induced apoptosis. The selective CXCR7 antagonist CCX733 reduced the antiapoptotic effects of CXCL12 as shown by nuclear (Nicoletti) staining, caspase-3/7 activity assays, and cleavage of poly(ADP-ribose) polymerase-1. Thus, CXCR7 is a functional receptor for CXCL12 in astrocytomas/glioblastomas and mediates resistance to drug-induced apoptosis. Whereas CXCR7 is found on "differentiated" glioma cells, the alternate receptor CXCR4 is also localized on glioma stem-like cells.
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PMID:The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. 2038 3

Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, alpha(v)beta(3) integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs) likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4) results in a nonfunctioning vasculature and could be another important target distinct from VEGF.
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PMID:Molecular therapeutic targets for glioma angiogenesis. 2041 63


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