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)

We provided evidence previously that bikunin, a Kunitz-type protease inhibitor, can disrupt dimerization of CD44 proteins, which may result in suppression of receptor-mediated MAP kinase signaling. However, to what extent dimerization may alter ligand-induced signaling has not been documented. Given the recent recognition that some growth factor receptors can form heterodimers with CD44, the present study was undertaken to determine whether the CD44 and growth factor receptors (e.g., EGFR, FGFR, HGFR, VEGFR, TGF-betaRI, or TGF-betaRII) can form heterodimers in cancer cells and, if so, to investigate the potential functional consequences of such heterodimerization. We also examined whether bikunin can abrogate these heterodimerizations and inhibit CD44/growth factor-dependent signaling. Here, we show direct evidence for heterodimerization of CD44-FGFR and CD44-TGF-betaRI in human chondrosarcoma HCS-2/8 cells, CD44-EGFR complex in human glioma U87MG cells, and CD44-TGF-betaRI heterodimer in human ovarian cancer HRA cells. Coupling of CD44 and growth factor receptor may be selective, depending on a cell type. Bikunin does not alter the ligand binding, whereas functionally reduces heterodimerization between CD44 and growth factor receptors. The disruption of heterodimerization substantially reduces receptor-induced tyrosine phosphorylation and ERK1/2 activation. Taken together, our data suggest that bikunin-mediated suppression of heterodimerization between CD44 and growth factors may inhibit the agonist-promoted activation of the signaling pathway.
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PMID:Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling. 1559 42

The development of novel therapeutic strategies is imperative for the treatment of advanced cancers like ovarian cancer and glioma, which are resistant to most traditional treatment modalities. In this regard, adenoviral (Ad) cancer gene therapy is a promising approach. However, the gene delivery efficiency of human serotype 5 recombinant adenoviruses (Ad5) in cancer gene therapy clinical trials to date has been limited, mainly due to the paucity of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human cancer cells. To circumvent CAR deficiency, Ad5 vectors have been retargeted by creating chimeric fibers possessing the knob domains of alternate human Ad serotypes. Recently, more radical modifications based on 'xenotype' knob switching with non-human adenovirus have been exploited. Herein, we present the characterization of a novel vector derived from a recombinant Ad5 vector containing the canine adenovirus serotype 1 (CAV-1) knob (Ad5Luc1-CK1), the tropism of which has not been previously described. We compared the function of this vector with our other chimeric viruses displaying the CAV-2 knob (Ad5Luc1-CK2) and Ad3 knob (Ad5/3Luc1). Our data demonstrate that the CAV-1 knob can alter Ad5 tropism through the use of a CAR-independent entry pathway distinct from that of both Ad5Luc1-CK2 and Ad5/3-Luc1. In fact, the gene transfer efficiency of this novel vector in ovarian cancer cell lines, and more importantly in patient ovarian cancer primary tissue slice samples, was superior relative to all other vectors applied in this study. Thus, CAV-1 knob xenotype gene transfer represents a viable means to achieve enhanced transduction of low-CAR tumors.
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PMID:A human adenoviral vector with a chimeric fiber from canine adenovirus type 1 results in novel expanded tropism for cancer gene therapy. 1603 51

Ependymoma is a glioma with differentiation toward ependymal cells that usually arises in the central nervous system. Ovarian ependymoma is extremely rare, and the treatment strategies for this disease have not been established. This is the first report of a patient with advanced ovarian ependymoma who received fertility-sparing surgery and is now alive without disease. A 23-year-old Japanese woman, gravida 0, presented with a chief complaint of lower abdominal distension and weight loss. She underwent left salpingo-oophorectomy for suspected ovarian cancer. Microscopic examination revealed a highly cellular tumor composed of small cells with hyperchromatic, round-to-oval nuclei and scanty cytoplasm. Perivascular pseudorosettes, ependymal rosettes, and extensive necrosis were observed. After thorough pathologic examination, she was diagnosed as having stage IIIC ovarian ependymoma. Postoperatively, she received adjuvant chemotherapy and underwent secondary cytoreductive surgery that preserved the uterus and right ovary. Her menstrual cycle has resumed, and she is alive without evidence of disease 16 months after the start of treatment. Although rare, primary ovarian ependymoma must be kept in mind in the differential diagnosis of ovarian tumors, especially in young women. Administration of etoposide-based chemotherapy along with cytoreductive surgery is a potential standard treatment for advanced ovarian ependymoma.
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PMID:Primary ependymoma of the ovary: a case report and literature review. 1634 97

Measles virus (MV) has shown promise as an oncolytic virus in the treatment of different tumor models for human B-cell lymphoma, multiple myeloma, ovarian cancer, and glioma. We have shown that, in a phase I clinical trial, MV vaccine induces tumor regression in cutaneous T-cell lymphoma (CTCL) patients. Here, we investigated in detail, the effect of recombinant MV (rMV) vaccine strain in CTCL cell cultures, and in vivo in established CTCL xenografts in nude mice. The susceptibility of three CTCL cell lines, originating from patients, to rMV was tested by determination of cell surface expression of MV receptors. All cell lines expressed the receptors CD150 and CD46 and were easily infected by rMV and induced complete cell lysis. The cytoreductive activity was apparent in cells forming aggregates, indicating a cell-to-cell spread of MV and cytolysis owing to virus infection. Intratumoral (i.t.) injection of rMV, expressing enhanced green fluorescent protein induced complete regression of large established human CTCL tumors in nude mice, whereas tumors with control treatment progressed exponentially. Immunohistochemical analysis of tumor biopsies, after i.t. treatment, for MV-NP protein complex demonstrated replication of MV within the tumors. The data demonstrate the potential of MV as a therapeutic agent against CTCL.
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PMID:Recombinant measles virus induces cytolysis of cutaneous T-cell lymphoma in vitro and in vivo. 1704 18

FBXW7 (F-box and WD40 domain protein 7) is an F-box protein with 7 tandem WDs (tryptophan-aspartic acid) that functions as a phosphoepitope-specific substrate recognition component of SCF (Skp1-Cul1-F-box protein) ubiquitin ligases and catalyzes the ubiquitination of proteins promoting cell proliferation, such as CCNE1, MYC, AURKA, NOTCH1, and JUN, which are frequently activated in a wide range of human cancers. FBXW7 is a candidate tumor suppressor, and mutations have been reported in some human tumors. In this study, we analyzed 84 human tumor cell lines in search for genetic alterations of FBXW7, as well as mRNA and protein expressional changes, and compared them with expression levels of the CCNE1, MYC, and AURKA proteins. We found a novel nonsense mutation in a colon cancer cell line SCC and confirmed the missense mutations in SKOV3, an ovarian cancer cell line, and LoVo, a colon cancer cell line. Moreover, suppressed expression of FBXW7 accompanied by activation of the target proteins were observed in ovarian, colon, endometrial, gastric, and prostate cancers. It is notable that highly suppressed mRNA expression of the FBXW7 beta-form was found in all the human glioma cell lines analyzed; enhanced expressions of CCNE1, MYC, and AURKA were observed in these cells. Our present results imply that FBXW7 plays a pivotal role in many tissues by controlling the amount of cell cycle promoter proteins and that dysfunction of this protein is one of the essential steps in carcinogenesis in multiple organs.
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PMID:The FBXW7 beta-form is suppressed in human glioma cells. 1727 47

A promising clinical application of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PP IX) is fluorescence detection and photodynamic treatment of residual tumour tissue during surgical resection of high grade malignant glioma. U373 MG human glioblastoma cells were used as a model system to study the relation between intracellular location and photodynamic efficacy of 5-ALA-induced PP IX in more detail. Therefore, ultra-sensitive fluorescence microscopy, using either optical excitation of whole cells or selective excitation of the plasma membrane by an evanescent electromagnetic field, was combined with quantitative measurements of intracellular porphyrin amount and phototoxicity. Glioblastoma cells accumulated PP IX to a moderate extent as compared to T47D breast cancer cells (high accumulation) or OV2774 ovarian cancer cells (low accumulation). Although photodynamic inactivation of the different cell lines (decreasing in the order T47D > U373 MG > OV2774) seemed to be directly related to PP IX accumulation, examination of the data in more detail revealed that photodynamic efficacy per photosensitizer molecule (PE) was about two times higher in glioblastoma and ovarian cancer cells as compared to breast cancer cells. The different photodynamic efficacy of PP IX was related to the different intracellular location. In contrast to breast cancer cells where PP IX fluorescence was localized in small granules, PP IX fluorescence in glioblastoma cells and ovarian cancer cells originated mainly from cellular membranes. Thus, the intracellular location of PP IX in a predominantly lipophilic environment, characterized by a comparably high photostability (probed by photobleaching and photoproduct formation) and a lower degree of porphyrin aggregation (probed previously by fluorescence decay kinetics), seems to be the key factor for high photodynamic efficacy of 5-ALA-induced PP IX. In the case of OV2774 ovarian cancer cells, however, a low PP IX accumulation limited cell inactivation upon irradiation, whereas the results obtained for glioblastoma cells are encouraging to develop PDT to an additional therapeutic option for the treatment of tumour margins in patients who underwent fluorescence-guided resection of high grade malignant glioma after 5-ALA administration.
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PMID:Relation between intracellular location and photodynamic efficacy of 5-aminolevulinic acid-induced protoporphyrin IX in vitro. Comparison between human glioblastoma cells and other cancer cell lines. 1727 37

In 1999, Maniotis reported that blood vessels of highly aggressive uveal melanomas are formed by tumor cells instead of endothelial cells. He termed this novel concept in tumor vascularization vasculogenic mimicry (VM). Since then, VM has been seen in several malignant tumor types such as breast cancer, liver cancer, glioma, ovarian cancer, melanoma, prostate cancer, and bidirectional differentiated malignant tumors. Laser scanning confocal angiography, electron microscopy, and three-dimensional cell culture have confirmed the existence of VM. The molecular mechanisms that underlie VM are not fully clear, but metalloproteinases via their cleavage of laminin, VE-cadherin by promoting adherence of the VM channel wall to tumor cells, tumor cell dedifferentiation, and tumor microenvironment have been shown to play a role in VM. Zhang and co-workers have proposed a three-stage phenomenon among VM channels, mosaic blood vessels, and endothelium-dependent blood vessels, wherein all three patterns participate in tumor blood supply. Therapeutic strategies that target endothelial cells have no effect on tumor cells that engage in VM. VM-targeting strategies include suppressing tyrosine kinase activity and using a knockout EphA2 gene, downregulating VE-cadherin, using antibodies against human MMPs and the laminin 5gamma2 chain, and using anti-PI3K therapy. We review here the current status of research on VM; discuss molecular mechanisms of VM, factors affecting VM formation, and its clinical significance; and explore the development of novel tumor-targeted treatments that are based on the biochemical and molecular events that regulate VM.
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PMID:Vasculogenic mimicry: current status and future prospects. 1730 54

p53 is known to prevent tumour formation by restricting the proliferation of damaged or oncogene-expressing cells. In contrast, how the p53 family member p73 suppresses tumour formation remains elusive. Using a step-wise transformation protocol for human cells, we show that, in premalignant stages, expression of the transactivation-competent p73 isoform TAp73 is triggered in response to pRB pathway alterations. TAp73 expression at this stage of transformation results in increased sensitivity to chemotherapeutic drugs and oxidative stress and inhibits proliferation and survival at high cell density. Importantly, TAp73 triggers a transcriptional programme to prevent anchorage-independent growth, which is considered a crucial hallmark of fully transformed cells. An essential suppressor of anchorage-independent growth is KCNK1, which is directly transactivated by TAp73 and commonly downregulated in glioma, melanoma and ovarian cancer. Oncogenic Ras switches p73 expression from TAp73 to the oncogenic deltaNp73 isoform in a phosphatidyl-inositol 3-kinase-dependent manner. Our results implicate TAp73 as a barrier to anchorage-independent growth and indicate that downregulation of TAp73 is a key transforming activity of oncogenic Ras mutants.
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PMID:p73 poses a barrier to malignant transformation by limiting anchorage-independent growth. 1823 87

Radioimmunotherapy (RIT) potentially is an attractive treatment for radiosensitive early-stage solid tumors and as an adjuvant to cytoreductive surgery. Topical administration of RIT may improve the efficacy because higher local concentrations are achieved. We reviewed the results of locally applied radiolabeled monoclonal antibodies for the treatment of solid tumors. Intracavitary RIT in patients with ovarian cancer and glioma showed improved targeting after local administration, as compared to the intravenous administration. In addition, various studies showed the feasibility of locally applied RIT in these patients. In studies that included patients with small-volume disease, adjuvant RIT in ovarian cancer and glioma showed to be at least as effective as standard therapy. The information about RIT for peritoneal carcinomatosis of colorectal origin is scarce, while results from preclinical data are promising. RIT may be applied for other, relatively unexplored indications. Studies on the application of radiolabeled antibodies in early urothelial cell cancer have been performed, showing that intracavitary RIT may hold a promise. Moreover, in patients with malignant pleural mesothelioma or malignant pleural effusion, RIT may play a role in the palliative treatment. Intracavitary RIT limits toxicity and improves tumor targeting. RIT is more effective in patients with small-volume disease of solid cancers. RIT may have potential for palliation in patients with malignant pleural mesothelioma or malignant pleural effusion. The future of RIT may, therefore, not only be in the inclusion in contemporary multimodality treatment, but also in the expansion to palliative treatment.
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PMID:Intracavitary radioimmunotherapy to treat solid tumors. 1829 33

Deregulated signaling through the epidermal growth factor receptor (EGFR) is involved in chemoresistance. To identify the molecular determinants of sensitivity to the EGFR inhibitor gefitinib (Iressa, ZD1839) in chemoresistance, we compared the response of matched chemosensitive and chemoresistant glioma and ovarian cancer cell lines. We found that chemoresistant cell lines were 2- to 3-fold more sensitive to gefitinib growth-inhibitory effects, because of decreased proliferation rather than survival. Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3, but not EGFR, altered HER ligand expression, and enhanced activation of EGF-triggered EGFR pathway. No activating mutations were found in EGFR. Gefitinib fully inhibited EGF-induced and constitutive Akt activation only in chemoresistant cells. In parallel, gefitinib downregulated constitutively phosphorylated HER2 and HER3, and activated GSK3beta with a concomitant degradation of cyclin D1. Ectopically overexpressed HER2 on its own was insufficient to sensitize chemonaive cells to gefitinib. pHER3 coimmunoprecipitated with p85-PI3K in chemoresistant cells and gefitinib dissociated these complexes. siRNA-mediated inhibition of HER3 decreased constitutive activation of Akt and sensitivity to gefitinib in chemoresistant cells. Our study indicates that in chemoresistant cells gefitinib inhibits both an enhanced EGF-triggered pathway and a constitutive HER3-mediated Akt activation, indicating that inhibition of HER3 together with that of EGFR could be relevant in chemorefractory tumors. Furthermore, in combination experiments gefitinib enhanced the effects of coadministered drugs more in chemoresistant than chemosensitive ovarian cancer cells. Combined treatment might be therapeutically beneficial in chemoresistant tumors from ovary and likely from other tissues.
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PMID:Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinib. 1880 87


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