Article

Effect of brain- and tumor-derived connective tissue growth factor on glioma invasion.

Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1002, USA.
CancerSpectrum Knowledge Environment (Impact Factor: 14.07). 08/2011; 103(15):1162-78. DOI: 10.1093/jnci/djr224
Source: PubMed

ABSTRACT Tumor cell invasion is the principal cause of treatment failure and death among patients with malignant gliomas. Connective tissue growth factor (CTGF) has been previously implicated in cancer metastasis and invasion in various tumors. We explored the mechanism of CTGF-mediated glioma cell infiltration and examined potential therapeutic targets.
Highly infiltrative patient-derived glioma tumor-initiating or tumor stem cells (TIC/TSCs) were harvested and used to explore a CTGF-induced signal transduction pathway via luciferase reporter assays, chromatin immunoprecipitation (ChIP), real-time polymerase chain reaction, and immunoblotting. Treatment of TIC/TSCs with small-molecule inhibitors targeting integrin β1 (ITGB1) and the tyrosine kinase receptor type A (TrkA), and short hairpin RNAs targeting CTGF directly were used to reduce the levels of key protein components of CTGF-induced cancer infiltration. TIC/TSC infiltration was examined in real-time cell migration and invasion assays in vitro and by immunohistochemistry and in situ hybridization in TIC/TSC orthotopic xenograft mouse models (n = 30; six mice per group). All statistical tests were two-sided.
Treatment of TIC/TSCs with CTGF resulted in CTGF binding to ITGB1-TrkA receptor complexes and nuclear factor kappa B (NF-κB) transcriptional activation as measured by luciferase reporter assays (mean relative luciferase activity, untreated vs CTGF(200 ng/mL): 0.53 vs 1.87, difference = 1.34, 95% confidence interval [CI] = 0.69 to 2, P < .001). NF-κB activation resulted in binding of ZEB-1 to the E-cadherin promoter as demonstrated by ChIP analysis with subsequent E-cadherin suppression (fold increase in ZEB-1 binding to the E-cadherin promoter region: untreated + ZEB-1 antibody vs CTGF(200 ng/mL) + ZEB-1 antibody: 1.5 vs 6.4, difference = 4.9, 95% CI = 4.8 to 5.0, P < .001). Immunohistochemistry and in situ hybridization revealed that TrkA is selectively expressed in the most infiltrative glioma cells in situ and that the surrounding reactive astrocytes secrete CTGF.
A CTGF-rich microenvironment facilitates CTGF-ITGB1-TrkA complex activation in TIC/TSCs, thereby increasing the invasiveness of malignant gliomas.

1 Bookmark
 · 
125 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion. In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC) xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs) compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT) processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.
    PLoS ONE 11/2014; 9(11):e111783. DOI:10.1371/journal.pone.0111783 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The recognition that the progression of many tumors may be driven by specific subpopulations of cells with stem/progenitor-like properties (tumor-initiating cells or TICs, a.k.a. cancer stem cells) represents an important recent paradigm shift in cancer biology and therapeutics. TICs in solid tissues are expected to interface with the extracellular matrix (ECM), which can strongly influence cell behavior through a variety of biochemical and biophysical mechanisms. Understanding ECM regulation of TIC behavior is important for developing strategies to isolate, expand, and characterize TICs in a laboratory setting and for understanding the roles ECM-based inputs may play in disease progression and therapy. In this chapter, we discuss how the ECM regulates TICs, starting with a brief overview of TIC biology, isolation, and characterization, molecular mechanisms through which TICs may be regulated by ECM-based signals, and the potential importance of these signals to TIC-driven tumor progression and metastasis.
    Progress in molecular biology and translational science 01/2014; 126:243-56. DOI:10.1016/B978-0-12-394624-9.00010-5 · 3.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Downregulation of E-cadherin in solid tumors with regional migration and systematic metastasis is well recognized. In view of its significance in tumorigenesis and solid cancer progression, studies on the regulatory mechanisms are important for the development of target treatment and prediction of clinical behavior for cancer patients. The vertebrate zinc finger E-box binding homeobox (ZEB) protein family comprises 2 major members: ZEB1 and ZEB2. Both contain the motif for specific binding to multiple enhancer boxes (E-boxes) located within the short-range transcription regulatory regions of the E-cadherin gene. Binding of ZEB1 and ZEB2 to the spaced E-cadherin E-boxes has been implicated in the regulation of E-cadherin expression in multiple human cancers. The widespread functions of ZEB proteins in human malignancies indicate their significance. Given the significance of E-cadherin in the solid tumors, a deeper understanding of the functional role of ZEB proteins in solid tumors could provide insights in the design of target therapy against the migratory nature of solid cancers.
    BioMed Research International 08/2014; 2014:921564. DOI:10.1155/2014/921564 · 2.71 Impact Factor
    This article is viewable in ResearchGate's enriched format

Preview

Download
2 Downloads
Available from