Article

STAT3 regulation of glioblastoma pathogenesis

Department of Pathology, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA 02115, USA.
Current Molecular Medicine (Impact Factor: 3.61). 08/2009; 9(5):580-90. DOI: 10.2174/156652409788488739
Source: PubMed

ABSTRACT Malignant gliomas are the most common primary brain tumors. Despite efforts to find effective treatments, these tumors remain incurable. The failure of malignant gliomas to respond to conventional cancer therapies may reflect the unique biology of these tumors, underscoring the need for new approaches in their investigation. Recently, progress has been made in characterization of the molecular pathogenesis of glioblastoma using a developmental neurobiological perspective, by exploring the role of signaling pathways that control the differentiation of neural stem cells along the glial lineage. The transcription factor STAT3, which has an established function in neural stem cell and astrocyte development, has been found to play dual tumor suppressive and oncogenic roles in glial malignancy depending on the mutational profile of the tumor. These findings establish a novel developmental paradigm in the study of glioblastoma pathogenesis and provide the rationale for patient-tailored therapy in the treatment of this devastating disease.

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Available from: Nuria de la Iglesia, Mar 18, 2014
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    • "STAT3 activation coexisted with EGFR (epidermal growth factor receptor) expression in 27.2% of primary high-grade gliomas, and coexpression with EGFR and its constitutively active variant EGFRvIII in glioblastoma cell lines have been detected [24]. STAT3 can play tumor suppressive or oncogenic roles in gliomas depending on the tumor genetic background [6] [7] [8], but its target genes are largely unknown. A recent ChIP-seq study has provided information regarding putative STAT3 targets in sub types of glioblastoma and its cooperation with the TCF4 transcription factor [25]. "
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    ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 08/2014; 1839(11). DOI:10.1016/j.bbagrm.2014.07.010 · 5.44 Impact Factor
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    • "needed moving forward , SHP2 inhibitors might eventually offer an attractive alternative in the treatment of GBM where resistance to other inhibitors arises . Of course , our data support the potential usefulness of STAT3 inhibitors in treating GBM . STAT3 has previously been identified as a key regulator of GBM cell survival ( Lo et al . , 2008 ; de la Iglesia et al . , 2009 ) and at least one clinical trial ( ClinicalTrials . gov NCT01904123 ) is scheduled to begin recruiting patients later this year to test the efficacy of STAT3 inhibition in cancers including GBM ."
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    ABSTRACT: Information from multiple signaling axes is integrated in the determination of cellular phenotypes. Here, we demonstrate this aspect of cellular decision making in glioblastoma multiforme (GBM) cells by investigating the multivariate signaling regulatory functions of the protein tyrosine phosphatase SHP2. Specifically, we demonstrate that SHP2's ability to simultaneously drive ERK and antagonize STAT3 pathway activities produces qualitatively different effects on the phenotypes of proliferation and resistance to EGFR and c-MET co-inhibition. While the ERK and STAT3 pathways independently promote proliferation and resistance to EGFR and c-MET co-inhibition, SHP2-driven ERK activity is dominant in driving cellular proliferation, and SHP2's antagonism of STAT3 phosphorylation prevails in promoting GBM cell death in response to EGFR and c-MET co-inhibition. Interestingly, the extent of these SHP2 signaling regulatory functions is diminished in glioblastoma cells expressing sufficiently high levels of the EGFR variant III (EGFRvIII) mutant, which is commonly expressed in GBM. In cells and tumors expressing EGFRvIII, SHP2 also antagonizes EGFRvIII and c-MET phosphorylation and drives expression of HIF-1/2α, adding complexity to the evolving understanding of SHP2's regulatory functions in GBM.
    Journal of Cell Science 06/2014; 127(16). DOI:10.1242/jcs.150862 · 5.33 Impact Factor
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    • "Consequently STAT1 and STAT3 are recruited to the receptor which leads to their phosphorylation by JAK on Tyr 701 and Tyr 705, respectively. The phosphorylated STAT transcription factors dimerize and translocate to the nucleus to bind to promoters or growth factors associated with that cytokine [8]. Another common transcription factor that is abnormally regulated in GBM is nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB). "
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    ABSTRACT: Cytokines play a significant role in cancer diagnosis, prognosis and therapy. The immune system's failure to recognize the malignant tumor cells and mount an effective response may be the result of tumor-associated cytokine deregulation. Glioblastoma Multiforme (GBM) has a characteristic cytokine expression pattern, and abnormalities in cytokine expression have been implicated in gliomagenesis. Within the heterogeneous GBM microenvironment, the tumor cells, normal brain cells, immune cells, and stem cells interact with each other through the complex cytokine network. This review summarizes the current understanding of the functions of key cytokines on GBM, and highlights potential therapeutic applications targeting these cytokines.
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