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1.  The p75 Neurotrophin Receptor Is a Central Regulator of Glioma Invasion  
PLoS Biology  2007;5(8):e212.
The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75NTR) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75NTR dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75NTR-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75NTR as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target.
Author Summary
Gliomas are highly malignant and invasive tumors with tendrils that extend far from the primary tumor site, rendering conventional therapies ineffective and leading to an invariably poor prognosis. To understand the molecular mechanisms underlying this invasive behavior, we injected immunocompromised mice with human gliomas and compared invasive cells, which left the primary tumor site, to noninvasive cells, which remained at the site of injection. We identified the neurotrophin receptor p75NTR—which normally functions during development to induce neurite outgrowth and promote neuronal cell death—as an important regulator of glioma invasion. We present the first evidence that this neurotrophin receptor can also be a potent mediator of glioma invasion, and we show that the expression of this receptor is sufficient to impart a dramatic invasive behavior on genetically distinct tumors. These data highlight a previously unknown function of this receptor and suggest it may be a novel therapeutic target in the treatment of this devastating cancer.
By in vivo selection of a human glioma, the authors identify the p75NTR neuotrophin receptor as a critical molecule regulating increased invasiveness.
doi:10.1371/journal.pbio.0050212
PMCID: PMC1939884  PMID: 17696644
2.  Mithramycin downregulates proinflammatory cytokine-induced matrix metalloproteinase gene expression in articular chondrocytes 
Arthritis Research & Therapy  2005;7(4):R777-R783.
Interleukin-1 (IL-1), IL-17 and tumor necrosis factor alpha (TNF-α) are the main proinflammatory cytokines implicated in cartilage breakdown by matrix metalloproteinase (MMPs) in arthritic joints. We studied the impact of an anti-neoplastic antibiotic, mithramycin, on the induction of MMPs in chondrocytes. MMP-3 and MMP-13 gene expression induced by IL-1β, TNF-α and IL-17 was downregulated by mithramycin in human chondrosarcoma SW1353 cells and in primary human and bovine femoral head chondrocytes. Constitutive and IL-1-stimulated MMP-13 levels in bovine and human cartilage explants were also suppressed. Mithramycin did not significantly affect the phosphorylation of the mitogen-activated protein kinases, extracellular signal-regulated kinase, p38 and c-Jun N-terminal kinase. Despite effective inhibition of MMP expression by mithramycin and its potential to reduce cartilage degeneration, the agent might work through multiple unidentified mechanisms.
doi:10.1186/ar1735
PMCID: PMC1175029  PMID: 15987479

Results 1-2 (2)