Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The interaction of Neisseria meningitidis with the meninges that surround and protect the brain is a pivotal event in the progression of bacterial meningitis. Two models of the human meninges were established in vitro, using (i) sections of fresh human brain and (ii) cultures of viable cells grown from human meningiomas. Neisseria meningitidis showed a specific predilection for binding to the leptomeninges and meningeal blood vessels in human brain and not to the cerebral cortex. There was a close correlation between the adherence of different Neisseria species to leptomeninges and cultured cells. The major ligand that mediated adherence was the pilus, and pilin variation modulated the interactions. The presence of Opa protein increased the association of Cap+ meningococci that expressed low-adhesive pili, but did not influence the association of high-adhesive pili. In contrast, Opc did not influence the adherence of Cap+ meningococci, whereas loss of capsule was associated with a more intimate interaction between the bacteria and the meningioma cell that was not apparent with Cap+ meningococci. There was no evidence of internalization of meningococci by meningioma cells in vitro, an observation that is consistent with the barrier properties of the leptomeninges to N. meningitidis observed in vivo.
Mol Microbiol 2000 May
PMID:Interactions of Neisseria meningitidis with cells of the human meninges. 1084 70

Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor gene on 22q12, which is inactivated in 40% of sporadic meningiomas. The NF2 gene product, merlin (or schwannomin), is a member of the protein 4.1 family of membrane-associated proteins, which also includes ezrin, radixin and moesin. Recently, we identified another protein 4.1 gene, DAL-1 (differentially expressed in adenocarcinoma of the lung) located on chromosome 18p11.3, which is lost in approximately 60% of non-small cell lung carcinomas, and exhibits growth-suppressing properties in lung cancer cell lines. Given the homology between DAL-1 and NF2 and the identification of significant LOH in the region of DAL-1 in lung, breast and brain tumors, we investigated the possibility that loss of expression of DAL-1 was important for meningioma development. In this report, we demonstrate DAL-1 loss in 60% of sporadic meningiomas using LOH, RT-PCR, western blot and immunohistochemistry analyses. Analogous to merlin, we show that DAL-1 loss is an early event in meningioma tumorigenesis, suggesting that these two protein 4.1 family members are critical growth regulators in the pathogenesis of meningiomas. Furthermore, our work supports the emerging notion that membrane-associated alterations are important in the early stages of neoplastic transformation and the study of such alterations may elucidate the mechanism of tumorigenesis shared by other tumor types.
Hum Mol Genet 2000 Jun 12
PMID:Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas. 1088

Meningiomas, commonly benign tumors, rarely display aggressive behavior by recurrences and invasion. In addition to surgery, irradiation is beneficial for recurrent, atypical, and malignant meningiomas. The role of chemotherapy, however, remains controversial, although there is evidence that meningiomas respond well to adjuvant chemotherapy. A major obstacle in chemotherapy remains drug resistance with reduced cellular drug accumulation through membrane efflux pumps, drug detoxification, and alterations in drug target specificity. In 84 classic, atypical, and malignant meningiomas, the immunohistochemical expression profile of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase IIalpha were studied. All types of meningiomas showed constant expression of P-gp, LRP, MRP, and topoisomerase IIalpha; metallothionein was found in 67% of the tumors, especially in atypical and malignant meningiomas. Furthermore, metallothionein. P-gp, LRP, and topoisomerase IIalpha were strongly expressed by normal and neoplastic vessels, which may confer to impaired penetration of therapeutic agents through the blood-brain and blood-tumor barrier. Neither recurrent nor previously irradiated meningiomas revealed any significant difference to primary tumors. These intrinsic drug resistances indicate that successful chemotherapy may require additional inhibition of these factors to be a promising approach in the management of meningiomas.
Appl Immunohistochem Mol Morphol 2001 Sep
PMID:Intrinsic expression of drug resistance-associated factors in meningiomas. 1155 52

We have constructed a three-dimensional stereotaxic ROI template (3DSRT) on anatomically standardised cerebral blood flow (CBF) single-photon emission tomography (SPET) images to objectively estimate regional CBF (rCBF). The 3DSRT is composed of 259 regions of interest (ROIs) in 11 segments (1, superior frontal; 2, middle and inferior frontal; 3, primary sensorimotor; 4, parietal; 5, angular; 6, temporal; 7, occipital; 8, pericallosal; 9, lenticular nucleus; 10, thalamus; 11, hippocampus) on each side. We measured the rCBF values of the 518 ROIs and calculated the area-weighted average (segmental CBF; sCBF) of the 22 segments based on the rCBF in each ROI. We compared vascular reserve before and after revascularisation surgery using sCBF on anatomically standardised resting and acetazolamide (Acz)-challenged CBF SPET images, which were obtained using an equal-volume-split dual-injection single-day protocol [resting and vascular reserve (RVR) method] in 13 patients who had not suffered any major stroke but did have significant cerebrovascular stenosis. Prior to the evaluation, we examined the sCBF values of 16 subjects with various cerebrovascular conditions (8, normal; 3, lacunar infarction; 2, chronic infarction; 2, meningioma; 1, aneurysm) using physiological saline instead of Acz (placebo study) in order to confirm the reproducibility of the RVR method. In the placebo study we observed excellent linearity (y=1.444+0.964x) between the 352 pairs of baseline (x) and post-placebo (y) sCBF values in the 16 subjects, irrespective of the segment location. In all of the 13 patients, estimation of sCBF demonstrated impaired vascular reserve pre-operatively and improved vascular reserve postoperatively. We conclude that the 3DSRT, which could be identically set on the anatomically standardised images obtained at baseline and after Acz injection, allowed objective assessment of the pre- and postoperative vascular reserve, which was not easy with conventional ROI settings. While 3DSRT appeared useful for the evaluation of regional vascular reserve as well as rCBF, further study is necessary to clarify its general clinical value.
Eur J Nucl Med Mol Imaging 2002 Mar
PMID:Usefulness of a three-dimensional stereotaxic ROI template on anatomically standardised 99mTc-ECD SPET. 1200 7

Telomere length maintenance is essential for tumorigenesis; most human tumors stabilize their chromosome ends via the activity of a specialized reverse transcriptase, telomerase, that uses the template region of the RNA moiety complementary to the TTAGGG repeat to synthesize one strand of telomeric DNA. Meningiomas are estimated to constitute between 13% and 26% of primary intracranial tumors. The aim of this study was to evaluate telomerase activity and its messenger expression in meningiomas in relation to their different histologic pattern and grade of cytonuclear atypies, which are associated with relapse, and consequently represent the most important parameter for the evaluation of the clinical behavior of this tumor. Telomerase activity was examined by the telomeric repeat amplification protocol (TRAP) assay in 32 meningiomas (26 typical and 6 atypical/anaplastic). Telomerase messenger expression (hTERT mRNA) was evaluated by reverse transcription-PCR analysis in the same group of tumors. Telomerase activity ranged from undetectable to low levels in 19/26 (73%) of typical meningiomas, while all the atypical/anaplastic meningiomas showed medium-high levels of activity (>3 TPG units, median value), (chi(2) test; p=0.001). The levels of telomerase in terms of its messenger level expression overlapped the activity; a significant association between telomerase activity and hTERT mRNA expression was also found (chi(2) test; p=0.01). Moreover, 2 atypical/anaplastic meningiomas of our series relapsed; in these samples we found high levels of telomerase, both in terms of activity and mRNA expression. Telomerase activity and its hTERT mRNA expression tended to increase as the histologic grading of intracranial tumors increased, suggesting a role of telomerase reactivation in the progression of these tumors. Moreover, our results indicate RT-PCR assay as a rapid tool to identify and quantify telomerase RNA in intracranial meningiomas as in other human tumor models.
Int J Mol Med 2003 Dec
PMID:Telomerase in intracranial meningiomas. 1461 71

Matrix metalloproteinases (MMPs) belong to a super family of endopeptidases which have been implicated as crucial mediators of angiogenesis and tumour invasion in brain tumours. This study was undertaken in an attempt to establish the relationship between 2 specific MMPs and the main classical subtypes of meningioma. We examined the expression of MMP-2 and -9 (gelatinase-A and -B respectively), by gelatin zymography, in a series of 18 cell cultures derived from human meningiomas of a range of histological subtypes and grades of malignancy, including 7 meningothelial, 6 transitional, 2 fibroblastic and 3 atypical meningiomas. Our findings indicate that generally, the meningothelial subtype, had the weakest expression, the transitional subtype had an intermediate expression whereas the fibroblastic subtype had the strongest expression of both MMP-2 and -9. There was no correlation between other clinicopathological features (age, sex, site of tumour) and the level of MMP-2 and -9 expression. Although, the number of samples in this study is limited, these findings suggest that there may be a trend for association between the expression of these 2 MMPs and the main classical histological subtypes of meningioma.
Int J Mol Med 2003 Dec
PMID:Expression of MMP-2 and -9 in short-term cultures of meningioma: influence of histological subtype. 1461 77

Neurofibromatosis (NF) type I (NF1) is the most common familial cancer-predisposing syndrome in humans, while type 2 (NF2) accounts for an extremely small percentage of the total cases of NF. Tumors occurring in patients with NF1 are primarily peripheral neurofibromas, while NF2 patients present with central schwannomas. Malignant transformation has been described in NF1 patients; however, in NF2 the risk of malignant transformation is extremely rare. In this case report, the authors document a retroperitoneal neurogenic sarcoma occurring in a 20-year-old woman with NF2 (bilateral acoustic schwannomas, meningioma, and multiple intraspinal tumors).
Pediatr Pathol Mol Med
PMID:Retroperitoneal neurofibrosarcoma in a patient with neurofibromatosis. 2: A case report and review of the literature. 1469 88

Meningiomas are cytogenetically heterogeneous tumors in which chromosome gains and losses frequently occur. Based on the intertumoral cytogenetic heterogeneity of meningiomas, hypothetical models of clonal evolution have been proposed in these tumors which have never been confirmed at the intratumoral cell level. The aim of this study was to establish the intratumoral patterns of clonal evolution associated with chromosomal instability in individual patients as a way to establish tumor progression pathways in meningiomas and their relationship with tumor histopathology and behavior. A total of 125 meningioma patients were analyzed at diagnosis. In all cases, multicolor interphase fluorescence in situ hybridization (iFISH) studies were performed on fresh tumor samples for the detection of quantitative abnormalities for 11 different chromosomes. In addition, overall tumor cell DNA content was measured in parallel by flow cytometry. iFISH studies were also performed in parallel on tissue sections in a subset of 30 patients. FISH studies showed that 56 (45%) of the 125 cases analyzed had a single tumor cell clone, all these cases corresponding to histologically benign grade I tumors. In the remaining cases (55%) more than one tumor cell clone was identified: two in 45 cases (36%), three in 19 (15%), and four or more clones in five cases (4%). Overall, flow cytometric analysis of cell DNA contents showed the presence of DNA aneuploidy in 44 of these cases (35%), 30% corresponding to DNA hyperdiploid and 5% to hypodiploid cases; from the DNA aneuploid cases, 35 (28%) showed two clones and 9 (7%) had three or more clones. A high degree of correlation (r >/= 0.89; P < 0.001) was found between FISH and flow cytometry as regards the overall quantitative DNA changes detected with both techniques, the former being more sensitive. Among the cases with chromosome abnormalities, the earliest tumor cell clone observed was frequently characterized by the loss of one or more chromosomes (64% of all meningiomas); loss of either a single chromosome 22 or, less frequently, of a sex chromosome (X or Y) and del (1p) was commonly found as the single initial cytogenetic aberration (30%, 5%, and 5% of the cases, respectively). Interestingly, an isolated loss of chromosome 22 was only found as the initial abnormality in one out of 14 atypical/anaplastic meningiomas, while the same cytogenetic pattern was present in the ancestral tumor cell clone of 32% of the benign tumors. Cytogenetic patterns based on chromosome gains were found in the ancestral tumor cell clone in 4% of the patients, 2% corresponding to tetraploid tumors. Overall, cytogenetic evolution of the earliest tumor cell clones was frequently associated with tetraploidization (31%). Our results show that meningiomas are genetically heterogeneous tumors that display different patterns of numerical chromosome changes, with the presence of more than one tumor cell clone detected in almost half of the cases including all atypical/anaplastic cases. Interestingly, the pathways of intratumoral clonal evolution observed in the benign tumors were different from those observed in atypical/anaplastic meningiomas, suggesting that the latter tumors might not always represent a more advanced stage of histologically benign meningiomas.
J Mol Diagn 2004 Nov
PMID:Intratumoral patterns of clonal evolution in meningiomas as defined by multicolor interphase fluorescence in situ hybridization (FISH): is there a relationship between histopathologically benign and atypical/anaplastic lesions? 1550 70

We describe the clinical, radiologic, surgical, and pathologic findings of a 29-year-old Peruvian human immunodeficiency virus-infected man with a primary parasellar meningeal leiomyosarcoma involving the left lesser esphenoidal wing and the cavernous sinus. Over a period of 13 months, he developed headache, vomiting, insomnia, and diplopia. Magnetic resonance imaging revealed a left parasellar extra-axial mass that was isointense in T1, hypointense in T2, and gadolinium-enhanced. The patient underwent subtotal resection of the tumor. The neoplasm was composed of spindle cells with smooth-muscle features. It showed moderate atypia, inconspicuous nucleoli, and scanty mitosis. No tumor necrosis was detected. The immunohistochemistry revealed strong positivity for vimentin, desmin, and smooth-muscle alpha-actin. A low-grade leiomyosarcoma was diagnosed. The in situ hybridization showed positive nuclear reactivity for Epstein-Barr virus-encoded RNA. The immunohistochemistry was negative for Epstein-Barr virus latent membrane protein 1. The main differential diagnosis of primary meningeal smooth-muscle tumors includes meningioma and peripheral nerve sheath tumors. Epstein-Barr virus has been demonstrated in most smooth-muscle tumors associated with acquired immune deficiency syndrome (AIDS). Primary meningeal smooth-muscle tumors, exceedingly rare neoplasms, remarkably affect young adults with AIDS. Comparatively, most AIDS-related visceral (nonmeningeal) smooth-muscle tumors have been reported in children. The permissiveness and tumorigenesis associated with Epstein-Barr virus may depend on the age of human immunodeficiency virus infection.
Appl Immunohistochem Mol Morphol 2004 Dec
PMID:Primary meningeal Epstein-Barr virus-related leiomyosarcoma in a man infected with human immunodeficiency virus: review of literature, emphasizing the differential diagnosis and pathogenesis. 1553 43

Fusion of the MN1 gene to TEL (ETV6) results in myeloid leukemia. The fusion protein combines the transcription activating domain of MN1 and the DNA binding domain of TEL and is thought to act as a deranged transcription factor. In addition, disruption of the large first exon of the MN1 gene is thought to inactivate MN1 function in a meningioma. To further investigate the role of MN1 in cancer, we generated Mn1 knockout mice. Mn1(+/-) animals were followed for 30 months, but they had no higher incidence of tumor formation than wild-type littermates. Mn1 null mice, however, were found to die at birth or shortly thereafter as the result of a cleft palate. Investigation of newborn or embryonic day 15.5 (E15.5) to E17.5 null mice revealed that the development of several bones in the skull was abnormal. The affected bones are almost exclusively formed by intramembranous ossification. They are either completely agenic at birth (alisphenoid and squamosal bones and vomer), hypoplastic, deformed (basisphenoid, pterygoid, and presphenoid), or substantially thinner (frontal, parietal, and interparietal bones). In heterozygous mice hypoplastic membranous bones and incomplete penetrance of the cleft palate were observed. We conclude that Mn1 is an important factor in development of membranous bones.
Mol Cell Biol 2005 May
PMID:Targeted disruption of the Mn1 oncogene results in severe defects in development of membranous bones of the cranial skeleton. 1587 Feb 92


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