Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The cellular receptor for urokinase-type plasminogen activator receptor (uPAR) is a member of the glycosylphosphatidylinositol (GPI) anchored protein family. It is a specific cell surface receptor for its ligand, urokinase-type plasminogen activator, which catalyzes the formation of plasmin from plasminogen to generate the proteolytic cascade and leads to the breakdown of the extracellular matrix. uPAR has been shown to correlate with a propensity to tumor invasion and metastasis in several types of non-central nervous system tumors. In this study, the authors examined the immunohistochemical expression of uPAR in 65 primary brain tumors (5 pilocytic astrocytomas, 5 diffuse astrocytomas, 6 anaplastic astrocytomas, 8 glioblastomas, 5 oligodendrogliomas, 4 oligoastrocytomas, 6 anaplastic oligoastrocytomas, 4 gangliogliomas, 4 ependymomas, 5 medulloblastomas, 6 schwannomas, 5 meningiomas, 2 atypical meningiomas). The specimens were evaluated for intensity of immunostaining (0-3 scale), cellular localization of staining, and specific or unique patterns of staining. Some degree of uPAR expression was observed in all tumors. A significant positive correlation (P = 0.0006) between tumor grade and staining intensity was identified within the astrocytoma/glioblastoma subgroup, suggesting a possible correlation with anaplastic change and propensity to tumor invasion. Expression of uPAR in nonmalignant, noninvasive tumors such as schwannoma and meningioma suggests that uPAR may have other biologic functions in addition to promotion of tumor invasion.
Appl Immunohistochem Mol Morphol 2005 Jun
PMID:Expression of urokinase-type plasminogen activator receptor (uPAR) in primary central nervous system neoplasms. 1589 33

As prerequisite for development and maintenance of many diseases angiogenesis is of particular interest in medicine. Pathologic angiogenesis takes place in chronic arthritis, collagen diseases, arteriosclerosis, retinopathy associated with diabetes, and particularly in cancers. However, angiogenesis as a physiological process regularly occurs in the ovary. After ovulation the corpus luteum is formed by rapid vascularization of initially avascular granulosa lutein cell tissue. This process is regulated by gonadotropic hormones. In order to gain further insights in the regulatory mechanisms of angiogenesis in the ovary, we investigated these mechanisms in cell culture of human granulosa lutein cells. In particular, we determined the expression and production of several angiogenic factors including tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), Leptin, connective tissue growth factor (CTGF), meningioma-associated complimentary DNA (Mac25), basic fibroblast growth factor (bFGF), and Midkine. In addition, we showed that human chorionic gonadotropin (hCG) has distinct effects on their expression and production. hCG enhances the expression and production of TIMP-1, whereas it downregulates the expression of CTGF and Mac25. Furthermore it decreases the expression of Leptin. Our results provide evidence that hCG determines growth and development of the corpus luteum by mediating angiogenic pathways in human granulosa lutein cells. Hence we describe a further approach to understand the regulation of angiogenesis in the ovary.
Mol Reprod Dev 2006 Jul
PMID:hCG-dependent regulation of angiogenic factors in human granulosa lutein cells. 1659 38

Aims/background-CD44 is a widely distributed cell surface molecule which has numerous isoforms generated by alternative splicing. The diverse functions related to the CD44 variants (CD44v) have been reported in various physiological and pathological conditions. The pattern of expression of CD44v among meningioma subtypes was investigated to ascertain whether CD44 variants play a role in a variety of biological processes, such as epithelial differentiation and extracranial metastasis.Methods-Twenty three meningiomas were studied immunohistochemically using novel antibodies directed against CD44 isoforms. Six of the 23 samples were analysed by reverse transcription polymerase chain reaction (RT-PCR), followed by Southern blotting with CD44v specific probes.Results-In meningothelial, fibrous and anaplastic meningiomas, a standard form of CD44 was detected by RT-PCR and was homogeneously expressed in tumour cells when studied immunohistochemically. CD44v was not detected in these subtypes. In secretory meningiomas, however, CD44v isoforms were strongly expressed in the cell clusters that produce secretory granules and also accumulated in the granules. The population of tumour cells immunopositive for CD44v was similar to that which stained with antibodies directed against carcinoembryonic antigen, epithelial membrane antigen and ezrin. On RT-PCR with Southern blotting, only the secretory type showed high level expression of CD44v.Conclusions-CD44v in meningiomas is expressed in relation to tumour cell differentiation towards the epithelial type.
Clin Mol Pathol 1996 Jun
PMID:Differential expression of CD44 variants among meningioma subtypes. 1669 62

The NF2 tumor suppressor gene, located in chromosome 22q12, is involved in the development of sporadic meningiomas of the nervous system. In order to evaluate the role of the NF2 gene in sporadic meningiomas, we analyzed the entire coding regions of the NF2 gene in a group of 42 sporadic meningiomas: 17 meningothelial, 11 transitional, 11 fibrous, one secretory, one atypical, and one malignant subtype, using denaturing high-performance liquid chromatography (DHPLC) and sequence analysis. Twenty-one mutations were identified in 20 patients with an overall mutation detection rate of 47.6%. The mutations included nine deletions (exons 1, 2, 5, 10, and 12), resulting in a frameshift, four non-sense mutations (exons 1, 2, and 7), four splice errors (exons 4, 5, 7, and 12), two missense mutations (exon 5) and two silent mutations (exon 11). Among these, 14 novel mutations were also identified in the present study. All mutations were noted in the first 12 exons, the region of homology with the ezrin-moesin-radixin protein. Furthermore, an association between NF2 mutations and histologic subtypes were observed; NF2 mutations were more frequent in fibrous meningiomas (8/11, 73%) and transitional meningiomas (6/11, 55%), than in meningothelial variant (5/17, 29%). These results provide evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas as well as indicating a different tumorigenesis of these meningioma variants.
Int J Mol Med 2006 Jul
PMID:Mutational analysis of the NF2 gene in sporadic meningiomas by denaturing high-performance liquid chromatography. 1678 52

Cyclooxygenase-2 (COX-2) is the inducible form of the enzyme involved in the first steps of the prostaglandins and thromboxane synthesis. COX-2 up-regulation is demonstrated in tumors where it can modulate tumoral progression, metastasis, multidrug resistance, and angiogenesis. Experimental data suggest a possible therapeutic use of the COX-inhibitors nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs can block tumor growth through many mechanisms, especially through antiangiogenic and proapoptotic effects. Moreover, NSAIDs can also improve the efficacy of radiotherapy, chemotherapy, and hormonal therapy. This study reviews the COX-2 expression as evaluated through immunohistochemistry and real time polymerase chain reaction (RT-PCR) in 23 meningiomas [14 World Health Organization (WHO) grade I; 5 WHO grade II; 3 WHO grade III; 1 oncocytic meningioma]. At immunohistochemistry all the lesions but 4 (83%) were COX-2 positive. At RT-PCR 9 meningiomas, 8 WHO grade I and 1 WHO grade II, showed a COX-2 expression greater than the reference value (average expression of all meningiomas that we studied). The association between tumor grade and immunohistochemical or RT-PCR COX-2 expression was not significant (P=0.427 and P=0.251, respectively). In conclusion, even if further studies on larger series are necessary, the common COX-2 overexpression in meningiomas may suggest considering the COX-2 inhibitors, alone or in combination with radiotherapy, a potential area of therapeutic intervention in some selected meningiomas.
Appl Immunohistochem Mol Morphol 2007 Jun
PMID:Cyclooxygenase-2 (COX-2) overexpression in meningiomas: real time PCR and immunohistochemistry. 1752 32

One of the most common chromosomal regions implicated in the meningiomas tumorigenesis is 22q12 where the neurofibromatosis 2 (NF2) gene resides. The NF2 tumor-suppressor gene encodes for the merlin/schwannomin protein, which is responsible for the inherited disease neurofibromatosis 2. NF2 gene mutations predominantly occur in transitional and fibroblastic meningiomas, whereas the meningothelial variant is less affected. Secretory meningioma is an infrequent meningioma subtype. Its most typical morphologic feature is the presence of intracytoplasmic or extracytoplasmic round hyaline, eosinophilic, and periodic acid Shiff-positive bodies in a lesion frequently otherwise classifiable as meningothelial meningioma. This study reviews the immunohistochemical merlin expression in 14 consecutive secretory meningiomas. Our purpose was to investigate if secretory meningiomas, analogous to meningothelial meningiomas, follow a molecular route of pathogenesis independent of the neurorofibromatosis 2 gene-associated pathway. All meningiomas showed positive immunocoloration involving the majority of the hyaline inclusions and secretory cells; in 12 (86%) meningiomas, a positive immunoreaction was also documented in nonsecretory tumoral cells. Our results may indicate a molecular, besides morphologic, similarity between secretory and meningothelial meningiomas: the almost constant merlin immunohistochemical expression in our series gives evidence for a possible NF2 gene-independent pathogenesis in secretory meningiomas.
Appl Immunohistochem Mol Morphol 2007 Sep
PMID:Merlin expression in secretory meningiomas: evidence of an NF2-independent pathogenesis? Immunohistochemical study. 1772 Dec 84

Limitations of conventional light microscopy in pathological diagnosis of brain tumors include subjective bias in interpretation and discordance of nomenclature. A study using mid-infrared (IR) spectromicroscopy was undertaken to determine whether meningiomas, a group of brain tumors prone to recurrence, could be identified by the unique spectral 'fingerprints' of their chemical composition. Paired, thin (5-microm) cryosections of snap-frozen human meningioma tumor samples removed at elective surgery were mounted on glass (hematoxylin and eosin-stained tissue section) and infrared (unstained tissue section) reflectance slides, respectively. Concordance of the tumor-bearing areas identified in the stained section by a pathologist with the unstained IR tissue section was ensured using a novel digital grid and tumor-mapping system developed in our laboratory. Compared with the normal control, tumor samples from four meningioma patients revealed a marked decrease in bands associated with unsaturated fatty acids, particularly in the bands at 3010, 2920, 2850, and 1735 cm(-1). Spectral datasets were subjected to hierarchical cluster analyses (HCA) using Ward's algorithm for comparison and grouping of similar data groups, and were converted into color-coded digital maps for matching spectra with their respective clusters. False color images of 5 and 6 clusters obtained by HCA identified dominant clusters corresponding to tumor tissue. Corroboration of these findings in a larger number of meningiomas may allow for more precise identification of these and other types of brain tumors.
Int J Mol Med 2008 Mar
PMID:Fourier transform infrared spectromicroscopy and hierarchical cluster analysis of human meningiomas. 1828 76

Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.
Mol Cell Biol 2009 Aug
PMID:NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. 1945 Dec 25

Chordoma originates from embryonic notochordal remnants in the midline along the spinal axis and is characterized by cords and lobules of neoplastic cells arranged within myxoid matrix. Because of histologic similarities with myxoid matrix and overlapping immunohistochemical profile, chondrosarcoma, myxopapillary ependymoma, and chordoid meningioma enter in the histologic differential diagnosis at this site. Therefore, the judicious use of a panel of selected immunostains is unquestionably helpful in diagnostically challenging cases. To find useful immunohistochemical markers for assisting in differential diagnosis between chordoma and other tumors with chordoid morphology, an immunohistochemical study using D2-40, epithelial membrane antigen (EMA), pan-cytokeratin (panCK), glial fibrillary acidic protein (GFAP), S-100 protein, galectin-3, neural cell adhesion molecule (NCAM), beta-catenin, E-cadherin, and carcinoembryonic antigen was performed on 14 chordomas, 7 chondrosarcomas, 9 myxopapillary ependymomas, and 4 chordoid meningiomas. Chordoma typically showed positive for EMA and panCK and negative for D2-40 and GFAP; whereas chondrosarcoma revealed positive for D2-40, and negative for EMA, panCK, and GFAP; myxopapillary ependymoma positive for GFAP and negative for EMA; and chordoid meningioma positive for EMA, and negative for panCK and GFAP. On the basis of our immunohistochemical study, a panel of D2-40, EMA, panCK, and GFAP allowed the correct recognition of all tumors examined. Other immunohistochemical markers including S-100 protein, galectin-3, NCAM, beta-catenin, E-cadherin, and carcinoembryonic antigen were of little value in differential diagnosis. In summary, the best immunohistochemical markers useful for the evaluation of tumors with chordoid morphology were D2-40, EMA, cytokeratin, and GFAP. D2-40 was a true chondroid marker to be useful for the differential diagnosis with chordoma.
Appl Immunohistochem Mol Morphol 2009 Mar
PMID:Immunohistochemical comparison of chordoma with chondrosarcoma, myxopapillary ependymoma, and chordoid meningioma. 1952 Dec 76

Despite advances in biomedical sciences, the prognosis of patients with brain tumors remains poor. Effective treatment is lacking for these central nervous system (CNS) cancers. Targeted immunotoxins are a new class of therapeutic approaches that have emerged for the treatment of human cancers. In this approach, tumor antigen or cell surface receptor is targeted by a chimeric fusion protein consisting of an antibody or a ligand and a suicidal gene or toxin to kill tumor cells. In that regard, receptors for interleukin (IL)-4 (IL-4R) have been identified to be overexpressed on a variety of human CNS tumor cell lines and tissue samples including meningioma. In various studies, high grade brain tumor specimens and malignant brain tumor cell lines have been shown to overexpress high-affinity IL-4R, while normal brain samples or cell lines expressed lower levels of these receptors. The structures of IL-4R on CNS tumors have been studied, which demonstrate that these cells express predominantly type II IL-4R. These receptors are functional as IL-4 can cause signal transduction, inhibit growth of some tumor cell lines and increase expression of major histocompatibility antigens and intracellular adhesion molecular-1 (ICAM-1) on some tumor cells lines. To target IL-4R, a chimeric fusion protein composed of IL-4 and truncated Pseudomonas exotoxin has been developed. This cytotoxin is highly cytotoxic to IL-4R positive tumors in vitro and has been reported to be highly effective in pre-clinical animal model of human brain cancer. Several Phase I/II clinical trials for treatment of IL-4R positive cancers have been completed. This review article will summarize pre-clinical and clinical development of IL-4PE cytotoxin.
Curr Mol Med 2009 Aug
PMID:A review of studies on targeting interleukin 4 receptor for central nervous system malignancy. 1968


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