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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2011, Vol.478(7368), p.197
    Description: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Cancer Research, 04/15/2011, Vol.71(8 Supplement), pp.LB-382-LB-382
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: The Journal of clinical investigation, April 2011, Vol.121(4), pp.1344-8
    Description: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
    Keywords: Astrocytoma -- Etiology ; Brain Neoplasms -- Etiology ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 5
    In: Nature, 2008, Vol.453(7193), p.410
    Description: The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.
    Keywords: Neovascularization, Pathologic -- Prevention & Control ; Pancreatic Neoplasms -- Blood Supply ; Rgs Proteins -- Deficiency;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 6
  • 7
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.4736-4736
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 8
    Language: English
    In: Cancer Research, 04/15/2011, Vol.71(8 Supplement), pp.3458-3458
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 9
    In: Brain, 2012, Vol. 135(4), pp.1027-1041
    Description: In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797 . In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name ‘focadhesin’. Since KIAA1797 genetic variation has been implicated in Alzheimer’s disease, our data are also relevant for neurodegeneration.
    Keywords: Tumour Relevant Gene ; Functional Characterization ; Focal Adhesion Complex ; Cell Motility ; Glioma
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 10
    Language: English
    In: Tissue engineering. Part A, May 2015, Vol.21(9-10), pp.1565-78
    Description: QUESTION/AIM: Cell-based therapy by cultivated stem cells (mesenchymal stem cells [MSC] and endothelial progenitor cells [EPC]) in a large-sized bone defect has already shown improved vascularization and new bone formation. However, these methods are clinically afflicted with disadvantages. Another heterogeneous bone marrow cell population, the so-called human bone marrow-derived mononuclear cells (BMC), has nevertheless been used clinically and showed improved vascularization in ischemic limbs or in the myocardium. For clinical use, a certified process has been established; thus, BMC were isolated from bone marrow aspirate by density gradient centrifugation, washed, cleaned, and given back to patients within several hours. This investigation tested the ability of human BMC seeded on beta-tricalcium phosphate (β-TCP) and placed into a large bone defect in rats to improve the bone healing process in vivo. Human EPC were isolated from buffy coat, and MSC or BMC, respectively, were isolated from bone marrow aspirate by density gradient centrifugation. 1.0×10(6) cells were loaded onto 750 μL β-TCP (0.7-1.4 mm). Large femoral defects (6 mm) in athymic rats were created surgically and stabilized with an internal fixateur. The remaining defects were filled with β-TCP granules alone (group 1), β-TCP+EPC/MSC (group 2), or β-TCP+BMC (group 3). After 8 weeks, histomorphometric analysis (new bone formation), radiological microcomputer tomography analysis (bony bridging), and biomechanical testing (three-point bending) were achieved. Moreover, a tumorigenicity study was performed to evaluate the safety of BMC implantation after 26 weeks. For statistical analysis, the Kruskal-Wallis test was used. Eight weeks after implantation of EPC/MSC or BMC, respectively, we detected a more significant new bone formation compared to control. In group 2 and 3, bony bridging of the defect was seen. In the control group, more chondrocytes and osteoid were detected. In the BMC and EPC/MSC group, respectively, less chondrocytes and a significantly more advanced bone formation were observed. The biomechanical stability of the bone regenerate was significantly enhanced if BMC and EPC/MSC, respectively, were implanted compared to control. Moreover, no tumor formation was detected either macroscopically or histologically after 26 weeks of BMC implantation. Implanted BMC suggest that a heterogeneous cell population may provide a powerful cellular therapeutic strategy for bone healing in a large bone defect in humans.
    Keywords: Implants, Experimental ; Stem Cell Transplantation ; Wound Healing ; Bone Marrow Cells -- Cytology ; Femur -- Pathology ; Mesenchymal Stem Cells -- Cytology
    ISSN: 19373341
    E-ISSN: 1937-335X
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