_:b28707720 "Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [>>16<<,17,18,19]." . _:b28707728 "by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,20,21,22,>>23<<]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24]." . _:b28707784 "In comparison, only 27%, 29%, and 57% of Grade I, II, and III gliomas, respectively, were found to have similar activation [>>41<<]. These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [57,58,59]. In contrast, Wang et al. reported STAT3" . . . _:b28707859 . _:b28707720 . _:b28707775 "point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,22,>>29<<,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases." . _:b544538179 . _:b544538163 . _:b28707875 . . _:b28707724 . . _:b28707880 "Conversely, Gordziel and colleagues found that strong STAT3 expression in colorectal carcinoma biopsies is associated with an improvement in median survival of about 30 months compared to STAT3 negative biopsies [>>126<<]. Such discrepancies in study results may reflect the dependence of STAT3 tumorigenic versus tumor suppressor function on the tumor genetic background, potentially confounding the results." . _:b544538134 . _:b28707864 . _:b28707727 "activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,20,21,>>22<<,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24]." . _:b28707721 "Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,>>17<<,18,19]. STAT3 can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family" . . . _:b28707878 . _:b28707885 . _:b544538142 . _:b28707779 "This mechanism has been described in multiple myeloma, where IL-6 overexpression led to increased JAK/STAT3 activity [>>52<<], as well as in squamous cell carcinoma of the head and neck, where elevated levels of transforming growth factor-\u03B1 (TGF-\u03B1) and subsequent STAT3 activation abrogated apoptosis of epithelial cells [53]." . . _:b28707710 . . _:b28707829 . _:b28707901 "Other drug targets include STAT3 associated genes that inhibit tumor cell migration or invasion [>>135<<]. AG490 inhibits JAK2, the upstream activator of STAT3, which results in decreased expression of the STAT3 regulated genes MMP-2 and MMP-9 [84]." . . _:b544538177 . . . _:b28707907 "responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,>>134<<,137,138,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134]." . _:b544538180 . _:b28707891 "of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific cis elements [>>36<<]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream decreased expression of MMP-2 and MMP-9 and inhibition of tumor cell invasiveness" . . _:b28707895 "Moreover, treatment with LLL3 increased survival in GBM-bearing mice by 12.5 days [>>26<<,131]. Others have targeted the JAK2/STAT3 pathway in glioma stem-like cells (GSCs). WP1193 is a small molecule inhibitor of JAK2/STAT3, which promotes in vivo glioma inhibition in a dose-dependent manner and is partially associated with" . . _:b28707841 . _:b544538192 . _:b28707800 . _:b28707858 "STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of tumor-infiltrating Treg cells, as well as enhanced activity of DCs, natural killer (NK) cells, T cells, and neutrophils [>>107<<]. These findings further implicate STAT3 as a negative regulator of the host immune system." . . _:b28707765 "dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [>>45<<,46,47]3. Constitutive" . _:b28707819 . . _:b28707822 "Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [>>42<<,84,85]. Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [40]. Further studies of the underlying signaling pathways are needed to more clearly" . _:b28707897 "WP1193 is a small molecule inhibitor of JAK2/STAT3, which promotes in vivo glioma inhibition in a dose-dependent manner and is partially associated with G1 arrest in GSCs [>>132<<]. STAT3 knockdown with interfering RNA, delivered by a lentivirus vector, resulted in down-regulation of cyclin D1 and inhibition of glioma cell proliferation [133]. Oligodeoxynucleotides may also serve as future therapeutic options as" . _:b28707776 . . . _:b28707805 "Under normal physiologic conditions, STAT3 activity is tightly regulated via ligand-dependent receptor and non-receptor tyrosine phosphorylation [>>72<<]. Coordinated interactions with protein tyrosine phosphatases, direct protein inhibitor, and SOCS proteins allow for multiple checkpoints and feedback inhibition [16]." . _:b28707843 . . _:b544538165 . _:b28707826 "VEGF-mediated angiogenesis is critical for the survival of most tumors, providing the requisite nutrients for accelerated growth and progression [>>24<<]. Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [86,87], and IL-6 receptor associated kinases in myeloma [88]." . . . _:b28707900 "role in Th17 T cell differentiation and cytokine production renders it an attractive target for immunotherapy in autoimmune pathways, as ablation of STAT3 in CD4 cells results in increased Th1 responses rather than Th17 responses [>>134<<]." . _:b544538136 . _:b544538175 . _:b28707741 "Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [23,>>31<<,32,33]. STAT3 signaling is tightly regulated by several upstream and downstream checkpoints to ensure an appropriate growth response to activation. Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and" . _:b28707909 . . _:b28707884 "found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent prognostic indicator of decreased survival [56,>>129<<]. Recent studies demonstrate that STAT3 could be a useful tumor marker of poor prognosis; however, given the tumor suppressive role of STAT3 in PTEN deficient tumors, it is important that future studies stratify GBM samples based on" . . . _:b28707719 . . . _:b28707785 . _:b544538232 . . _:b28707706 "Glioblastoma multiforme (GBM) is the most common primary malignancy of the central nervous system (CNS), with an incidence of 3.19 per 100,000 and a five-year survival rate of less than 5% [1,>>2<<]. GBM\u2019s molecular heterogeneity, genomic instability, radio- and chemo-resistance, infiltrative capacity, and immune evasion are important contributing factors in GBM pathogenesis." . _:b28707835 "VEGF is often overexpressed in GBM [10,92,>>93<<], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [11]." . . _:b28707754 "of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,>>21<<,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3" . _:b28707843 "Secreted factors include IL-10 (an inhibitor of Th1 activity), VEGF, and TGF-beta, which inhibit T cell, B cell, natural killer (NK) cell, and monocyte functions [49,>>95<<,96]. VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [97]. STAT3 hyperactivity can lead to abnormal DC differentiation" . . _:b28707818 "Increased expression of Y705-phosphorylated STAT3 in GBM samples correlated with significantly shorter overall survival [>>82<<]. Together, there is consistent evidence that STAT3 is a key contributor to GBM pathogenesis by mediating cell survival, growth, and proliferation." . . _:b544538122 . . . _:b544538211 . _:b28707804 _:b28707805 . _:b28707804 _:b28707806 . _:b28707804 _:b28707807 . _:b28707801 . _:b28707813 . . . _:b544538249 . _:b28707851 . _:b28707804 _:b28707828 . _:b28707804 _:b28707829 . _:b28707804 _:b28707830 . _:b28707804 _:b28707831 . _:b28707804 _:b28707824 . _:b28707804 _:b28707825 . _:b28707804 _:b28707826 . _:b28707804 _:b28707827 . _:b28707804 _:b28707836 . _:b28707804 _:b28707837 . _:b28707750 "Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [>>5<<,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators" . _:b28707804 _:b28707838 . _:b28707804 _:b28707839 . _:b28707835 . _:b28707804 _:b28707832 . _:b28707859 "stat3 as a tumor suppressor" . _:b28707804 _:b28707833 . _:b28707804 _:b28707834 . . _:b28707804 _:b28707835 . _:b28707804 _:b28707812 . _:b28707804 _:b28707813 . _:b28707804 _:b28707814 . _:b28707804 _:b28707815 . . _:b28707804 _:b28707808 . _:b28707804 _:b28707809 . _:b28707804 _:b28707810 . _:b28707804 _:b28707811 . _:b28707838 . _:b544538187 . _:b28707804 _:b28707820 . _:b28707804 _:b28707821 . . _:b28707804 _:b28707822 . . _:b544538252 . _:b28707804 _:b28707823 . _:b28707804 _:b28707816 . _:b28707828 . _:b28707804 _:b28707817 . _:b544538154 . . _:b28707804 _:b28707818 . _:b28707804 _:b28707819 . _:b28707748 . . _:b28707911 . . . _:b28707903 . . _:b28707914 . _:b28707718 "[7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [>>14<<] have been described as possible bases of molecular therapies for both primary and secondary GBMs." . _:b28707757 "antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,>>37<<,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of" . . . . _:b28707752 . _:b28707871 "GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [118,>>119<<]." . _:b28707778 "For example, aberrant methylation silencing of SOCS-3 has been associated with constitutive JAK/STAT activity and higher levels of pSTATs in non-small cell lung cancer [>>51<<]." . . . _:b28707785 "These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [>>57<<,58,59]. In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [60]. However differing methods in protein detection is a possible explanation for inconsistent" . . _:b28707844 . _:b28707709 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,>>5<<,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme" . _:b28707845 . . . . _:b28707846 . _:b28707826 . _:b28707847 . _:b28707840 . _:b28707841 . _:b28707853 . _:b544538243 . _:b28707842 . _:b28707820 "STAT3 inhibitors have been shown to decrease GBM invasion in human glioma cell line U251 [>>74<<]. Using a JAK2 inhibitor and monolayer wound-healing assays, Senft et al. demonstrated decreased STAT3 activation and migratory behaviors across five different GBM cell lines in vitro [84]. Though the precise mechanisms remain unknown," . _:b28707843 . _:b28707788 . _:b28707852 . . . _:b28707853 . _:b28707854 . _:b544538228 . _:b28707855 . _:b28707819 "tumor cell migration preferentially occurs along white matter tracts, accounting for the characteristic \u201Cbutterfly lesions\u201D frequently observed crossing the corpus callosum, perineuronal satellitosis, and perivascular or subpial spread [>>83<<]. STAT3 inhibitors have been shown to decrease GBM invasion in human glioma cell line U251 [74]." . _:b28707848 . _:b28707836 . . _:b28707849 . _:b28707850 . _:b544538223 . _:b28707851 . . _:b28707860 . _:b28707861 . _:b28707771 . _:b28707811 . _:b28707862 . _:b28707816 "Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC\u2019s) [>>80<<]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal capacities in GBM stem cells [81]. STAT3 tyrosine (Y) phosphorylation has also been associated with more" . . _:b28707872 . _:b28707753 "Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,>>20<<,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3" . _:b28707863 . "PMC0" . . _:b28707790 . _:b28707856 . _:b28707901 . _:b544538234 . _:b28707857 . _:b544538245 . _:b28707736 _:b28707740 . . _:b28707736 _:b28707741 . _:b28707736 _:b28707742 . _:b28707736 _:b28707743 . _:b28707879 . _:b28707858 . _:b28707736 _:b28707737 . _:b28707736 _:b28707738 . _:b28707736 _:b28707739 . _:b28707859 . _:b28707736 _:b28707748 . _:b28707736 _:b28707749 . _:b28707736 _:b28707750 . _:b28707736 _:b28707751 . _:b28707868 . . _:b544538191 . _:b28707736 _:b28707744 . _:b28707736 _:b28707745 . _:b28707736 _:b28707746 . _:b28707736 _:b28707747 . _:b28707869 . _:b28707736 _:b28707756 . _:b28707736 _:b28707757 . . _:b544538170 . _:b28707736 _:b28707758 . _:b28707736 _:b28707759 . _:b28707870 . _:b28707736 _:b28707752 . _:b28707736 _:b28707753 . _:b28707736 _:b28707754 . _:b28707736 _:b28707755 . _:b28707871 . _:b28707736 _:b28707764 . _:b28707736 _:b28707765 . _:b28707865 . _:b28707736 _:b28707766 . _:b28707736 _:b28707767 . _:b28707864 . _:b28707736 _:b28707760 . . _:b28707736 _:b28707761 . _:b28707736 _:b28707762 . _:b28707736 _:b28707763 . _:b28707865 . _:b28707883 "found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent prognostic indicator of decreased survival [>>56<<,129]. Recent studies demonstrate that STAT3 could be a useful tumor marker of poor prognosis; however, given the tumor suppressive role of STAT3 in PTEN deficient tumors, it is important that future studies stratify GBM samples based on" . _:b28707707 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [>>3<<,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme" . _:b28707866 . _:b28707793 . _:b28707868 "differentiation involves STAT3 activation and its association with p27kip1 accumulation, while hepatocyte epithelial tubule differentiation relies on hepatocyte growth factor-mediated STAT3 activation and translocation to the nucleus [>>116<<,117]. GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [118,119]." . _:b28707760 . _:b28707867 . _:b28707876 . _:b28707877 . _:b28707878 . . _:b544538218 . _:b28707879 . _:b28707872 . _:b544538212 . _:b28707873 . _:b28707786 "These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [57,>>58<<,59]. In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [60]. However differing methods in protein detection is a possible explanation for inconsistent" . _:b28707874 . _:b28707742 . _:b28707849 "However, relatively recent evidence suggests that exposure to glioma-derived chemokines induce constitutive STAT3 activation in MG, with consequent suppression of antitumor mechanisms or even tolerance to tumor antigens [>>99<<,100,101]. In contrast, a study by Komohara et al. demonstrated that direct interaction with glioma cells led to STAT3 activation in tumor infiltrating macrophages. In return, MG/macrophage-derived factors were shown to activate STAT3" . _:b28707875 . _:b28707765 . _:b28707884 . _:b544538123 . _:b28707885 . _:b28707886 . _:b28707887 . _:b544538247 . _:b28707868 . _:b28707880 . . _:b28707833 "VEGF is often overexpressed in GBM [>>10<<,92,93], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [11]." . _:b28707815 "Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [77,78,>>79<<]. Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC\u2019s) [80]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal" . _:b28707881 . . _:b28707882 . _:b28707883 . _:b28707892 . . . _:b28707893 . _:b544538141 . _:b28707894 . . _:b28707895 . . _:b28707888 . _:b28707863 "STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [>>111<<,112,113]." . _:b28707889 . _:b28707890 . _:b544538178 . _:b28707891 . . _:b28707900 . _:b544538241 . _:b28707901 . . _:b544538173 . _:b28707903 "Resveratrol, a grape polyphenol, has been shown to enhance glioma radiosensitivity by inhibiting STAT3 signaling, rendering future promise for more effective radiotherapy [>>136<<]. Resistance to temozolomide has been shown to be associated with STAT3 activation and upregulation of the DNA repair enzyme MGMT [14]. Thus, STAT3 knockdown prior to temozolomide therapy may reduce the incidence of tumor resistance to" . _:b28707902 . . _:b28707910 . _:b28707732 . _:b28707903 . _:b544538138 . . _:b28707896 . _:b28707780 "led to increased JAK/STAT3 activity [52], as well as in squamous cell carcinoma of the head and neck, where elevated levels of transforming growth factor-\u03B1 (TGF-\u03B1) and subsequent STAT3 activation abrogated apoptosis of epithelial cells [>>53<<]." . _:b28707892 "cycle arrest and apoptosis by mimicking STAT3 specific cis elements [36]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream decreased expression of MMP-2 and MMP-9 and inhibition of tumor cell invasiveness [>>84<<" . _:b28707897 . _:b28707768 _:b28707772 . _:b28707812 . _:b28707768 _:b28707773 . _:b28707768 _:b28707774 . _:b28707768 _:b28707775 . _:b28707898 . _:b28707786 . _:b28707880 . _:b28707768 _:b28707769 . _:b28707768 _:b28707770 . _:b28707768 _:b28707771 . _:b28707899 . _:b28707768 _:b28707780 . _:b28707768 _:b28707781 . _:b28707768 _:b28707782 . _:b28707792 . _:b28707768 _:b28707783 . _:b28707908 . _:b28707725 . _:b544538186 . _:b28707768 _:b28707776 . _:b28707768 _:b28707777 . _:b28707768 _:b28707778 . _:b28707768 _:b28707779 . _:b28707909 . _:b28707768 _:b28707788 . _:b28707767 "[43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,>>47<<]3. Constitutive" . _:b28707768 _:b28707789 . _:b28707768 _:b28707790 . _:b544538159 . . _:b28707768 _:b28707791 . _:b28707910 . _:b28707768 _:b28707784 . _:b28707768 _:b28707785 . _:b28707768 _:b28707786 . _:b28707768 _:b28707787 . _:b28707911 . . _:b28707768 _:b28707796 . _:b28707768 _:b28707797 . _:b28707873 "The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,>>121<<,122,123,124]." . _:b28707768 _:b28707798 . _:b28707787 . _:b28707726 "be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,20,>>21<<,22,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24]." . _:b28707768 _:b28707799 . _:b28707904 . _:b28707768 _:b28707792 . . _:b28707768 _:b28707793 . _:b28707768 _:b28707794 . _:b28707768 _:b28707795 . _:b28707905 . _:b544538128 . _:b544538185 . _:b28707712 . _:b544538208 . _:b28707906 . _:b544538203 . _:b28707768 _:b28707800 . _:b28707768 _:b28707801 . _:b28707768 _:b28707802 . _:b28707768 _:b28707803 . _:b28707907 . . _:b28707739 . _:b28707802 "Focal deletions, missense, and nonsense mutations of the PTPRD gene have been identified in up to 41% of GBM samples [70,>>71<<]. Furthermore, Veeriah et al. observed a greater frequency of PTPRD expression loss in GBM versus lower grade gliomas. Decreased PTPRD expression was also predictive of poorer prognosis in GBM patients [71]." . _:b28707846 "STAT3 hyperactivity can lead to abnormal DC differentiation via constitutive JAK2/STAT3 activation [>>18<<] and decreased expression of major histocompatibility complex (MHC) class II, costimulatory CD40, and IL-12 molecules [98]." . _:b544538244 . _:b28707912 . _:b28707877 . _:b28707913 . _:b28707837 . _:b28707710 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,>>6<<], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme" . _:b28707914 . _:b28707740 . . . _:b28707813 "Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [>>77<<,78,79]. Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC\u2019s) [80]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of" . _:b28707830 . _:b28707853 "STAT3 also recruits and promotes the proliferation of T regulatory cells (Tregs), which suppress effector lymphocyte activity within the tumor microenvironment [>>103<<,104]. Tregs are preferentially recruited to high-grade gliomas following tumor secretion of CCL2/22 chemokines [105]." . . _:b28707728 . _:b28707860 . . . _:b28707854 . _:b28707779 . _:b28707769 . . _:b28707770 . _:b28707794 "Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,63,64,>>65<<]. Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [65]." . . . . . _:b28707807 "Constitutive STAT3 activation may confer resistance to apoptosis and promote cell cycle progression through its interactions with the IL-6 signal transducer, gp130 [>>73<<]. STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,74,75,76]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of" . _:b544538233 . _:b28707753 . _:b28707829 "Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [86,87], and IL-6 receptor associated kinases in myeloma [>>88<<]. Niu et al. noted that VEGF expression in several cancer cell lines correlated with constitutive STAT3 activity, and that STAT3 inhibition led to reduced Src-induced VEGF expression [89]. Results from promoter mutagenesis and chromatin" . _:b544538126 . . . _:b28707867 . _:b28707815 . . _:b544538240 . _:b544538125 . _:b544538124 . . _:b544538132 . _:b544538224 . . _:b544538127 . _:b544538199 . _:b544538190 . . _:b544538126 . _:b28707887 "DrugMechanism of ActionOleanolic acidSuppresses IL-10 secretion which suppresses M2 polarization of tumor-associated macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [>>26<<,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3" . _:b28707862 "Similarly, IL-6 mediated growth arrest in melanoma is STAT3-dependent [>>110<<]. STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [111,112,113]." . _:b28707730 . _:b544538121 . _:b544538200 . _:b544538120 . _:b544538123 . _:b28707759 . . _:b544538122 . _:b28707745 . _:b544538133 . _:b28707869 "involves STAT3 activation and its association with p27kip1 accumulation, while hepatocyte epithelial tubule differentiation relies on hepatocyte growth factor-mediated STAT3 activation and translocation to the nucleus [116,>>117<<]. GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [118,119]." . . _:b544538132 . _:b544538135 . _:b28707811 "STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,74,75,>>76<<]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [61]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3" . _:b544538134 . . _:b544538129 . _:b28707732 "Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,>>25<<,26,27,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM." . _:b544538128 . . _:b28707747 "In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block STAT protein\u2019s DNA-binding activity, thereby inhibiting gene transcription [>>37<<]. Furthermore, STAT3 interacting protein (StIP1) may block STAT3 activation, translocation, and reporter gene induction via overexpression of its STAT3-binding domain [38]." . _:b544538131 . _:b28707772 "as the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [>>16<<,21,22,29,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases." . _:b28707742 "Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [23,31,>>32<<,33]. STAT3 signaling is tightly regulated by several upstream and downstream checkpoints to ensure an appropriate growth response to activation. Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and" . _:b544538130 . _:b544538222 . _:b544538141 . _:b28707908 . _:b544538140 . _:b28707886 . . . _:b544538143 . _:b544538250 . _:b28707733 "Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,25,>>26<<,27,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM." . _:b544538142 . _:b544538137 . _:b544538140 . _:b28707777 . _:b544538136 . _:b28707861 "For example, the IL-6 growth-inhibitory and terminal differentiation signal has been correlated with STAT3 transcriptional activity in prostate cancer [108,>>109<<]. Similarly, IL-6 mediated growth arrest in melanoma is STAT3-dependent [110]. STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation" . . _:b544538139 . _:b28707715 . . _:b28707808 . _:b28707844 . _:b544538138 . . _:b544538220 . _:b544538149 . _:b28707855 . . _:b544538148 . . _:b544538151 . _:b544538215 . . _:b28707771 "Constitutive STAT3 activation has been reported in 50%\u201390% of human cancers [48,>>49<<]. This prevalence can be attributed to STAT3\u2019s position as the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met," . _:b544538150 . _:b544538148 . _:b544538145 . _:b28707893 . _:b28707892 . _:b544538144 . _:b28707831 "More specifically, in vitro overexpression of the viral chemokine receptor US28 has been shown to activate several downstream transcription factors such as hypoxia inducible factor-1 and STAT3, resulting in VEGF promoter activation [>>90<<,91]." . _:b544538147 . _:b544538146 . . _:b544538157 . _:b544538156 . _:b544538159 . _:b28707821 "Using a JAK2 inhibitor and monolayer wound-healing assays, Senft et al. demonstrated decreased STAT3 activation and migratory behaviors across five different GBM cell lines in vitro [>>84<<]. Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [42,84,85]. Increased STAT3 and focal adhesion kinase" . _:b28707902 . _:b544538158 . _:b544538153 . _:b28707869 . _:b544538152 . . _:b544538155 . _:b28707870 . _:b544538154 . . _:b28707816 . _:b544538231 . _:b544538165 . _:b28707764 . _:b28707719 "STAT3 has emerged as a key initiator and master regulator of mesenchymal transformation in malignant gliomas [>>15<<]. Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,17,18,19]. STAT3 can be activated by growth factor receptors including EGFR and" . _:b544538120 . _:b544538164 . _:b544538217 . . _:b544538167 . . _:b544538166 . _:b544538161 . _:b28707881 . _:b544538160 . _:b544538163 . _:b544538207 . _:b544538162 . _:b28707908 "responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,>>137<<,138,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134]." . _:b28707748 "Furthermore, STAT3 interacting protein (StIP1) may block STAT3 activation, translocation, and reporter gene induction via overexpression of its STAT3-binding domain [>>38<<]." . _:b544538173 . . _:b544538172 . _:b28707899 . _:b28707833 . _:b544538175 . _:b28707746 "Suppressor of cytokine signaling (SOCS) proteins negatively feedback on the JAK/STAT signaling pathway by disrupting or degrading JAKs [>>36<<]. In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block STAT protein\u2019s DNA-binding activity, thereby inhibiting gene transcription [37]. Furthermore, STAT3 interacting protein (StIP1) may block STAT3" . _:b544538174 . _:b544538169 . _:b28707864 "STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [111,>>112<<,113]." . _:b544538168 . _:b544538171 . _:b544538170 . . _:b544538181 . _:b28707714 . _:b544538180 . _:b28707891 . . . _:b544538183 . _:b28707792 "Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,>>63<<,64,65]. Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [65]." . _:b28707890 "macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [>>133<<]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific cis elements [36]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream decreased expression of MMP-2 and MMP-9 and inhibition" . _:b28707782 "In 2006, Mizoguchi et al. demonstrated similar rates of STAT3 activation in anaplastic astrocytomas (AA) and GBMs (55.6% and 56.4%, respectively) [>>55<<]. Abou-Ghazal reported similar results in 2008, with 50% of AA and 51% of GBM samples staining positively for pSTAT3 [56]. Lo et al. expanded on these findings by describing a positive correlation between glioma grade and extent of STAT3" . _:b544538182 . _:b28707749 "These molecules play a significant role in regulating the STAT3 signaling cascade, and under normal physiologic conditions, represent important checkpoints in the activation and deactivation of cell proliferation [>>39<<]. However, under pathologic or experimental conditions, these regulatory molecules serve as natural targets for STAT3 signal disruption or even constitutive activation." . _:b544538177 . _:b28707808 "STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [>>52<<,74,75,76]." . _:b544538176 . _:b544538179 . . _:b544538161 . _:b544538178 . . . _:b544538189 . . _:b544538188 . . _:b544538191 . _:b28707834 "VEGF is often overexpressed in GBM [10,>>92<<,93], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [11]." . _:b544538190 . _:b544538185 . _:b28707894 "Small molecule inhibitors are also candidates for suppressing STAT3 activity, as they produce a similar anti-tumor inflammatory microenvironment as siRNA-mediated knockdown of STAT3 [>>17<<]. Other small molecule inhibitors, including LLL12 and LLL3, suppress phosphorylation of STAT3 and inhibit STAT3 DNA binding, resulting in decreased viability of tumor cells and resultant apoptosis. Moreover, treatment with LLL3 increased" . . _:b544538184 . _:b28707822 . _:b28707836 "VEGF is often overexpressed in GBM [10,92,93], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [>>11<<]. Constitutively activated STAT3 and VEGF receptors can be coexpressed in glioma [58]." . _:b544538187 . _:b28707770 "Constitutive STAT3 activation has been reported in 50%\u201390% of human cancers [>>48<<,49]. This prevalence can be attributed to STAT3\u2019s position as the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met," . _:b544538186 . . _:b544538197 . . _:b28707890 . _:b544538196 . _:b28707729 "It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [>>17<<,24]." . _:b544538199 . . _:b28707782 . _:b544538198 . _:b28707705 "Glioblastoma multiforme (GBM) is the most common primary malignancy of the central nervous system (CNS), with an incidence of 3.19 per 100,000 and a five-year survival rate of less than 5% [>>1<<,2]. GBM\u2019s molecular heterogeneity, genomic instability, radio- and chemo-resistance, infiltrative capacity, and immune evasion are important contributing factors in GBM pathogenesis." . _:b544538193 . . _:b544538192 . _:b544538160 . _:b544538195 . . . _:b28707809 "STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,>>74<<,75,76]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [61]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3" . _:b544538194 . . _:b544538205 . . _:b28707898 . _:b28707798 . _:b544538204 . _:b28707735 "Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,25,26,27,>>28<<]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM." . _:b28707823 . _:b544538206 . _:b544538207 . _:b544538206 . _:b28707821 . _:b28707886 "DrugMechanism of ActionOleanolic acidSuppresses IL-10 secretion which suppresses M2 polarization of tumor-associated macrophages [>>130<<]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells" . _:b544538201 . . _:b28707741 . _:b544538200 . _:b28707799 "Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [>>69<<]." . . _:b28707775 . _:b544538203 . . _:b544538202 . . _:b544538213 . _:b544538212 . _:b544538215 . _:b544538137 . _:b544538214 . . _:b28707806 "Coordinated interactions with protein tyrosine phosphatases, direct protein inhibitor, and SOCS proteins allow for multiple checkpoints and feedback inhibition [>>16<<]. However, loss of any counter-regulatory mechanisms can lead to uninhibited proliferation and survival. Constitutive STAT3 activation may confer resistance to apoptosis and promote cell cycle progression through its interactions with the" . _:b544538209 . . _:b544538208 . _:b28707817 . _:b544538211 . _:b544538210 . _:b544538221 . _:b544538220 . _:b544538223 . _:b28707847 "STAT3 hyperactivity can lead to abnormal DC differentiation via constitutive JAK2/STAT3 activation [18] and decreased expression of major histocompatibility complex (MHC) class II, costimulatory CD40, and IL-12 molecules [>>98<<]. Conversely, STAT3 blockade in human GBM cell lines has been shown to alter pro-inflammatory cytokine and immune cell profiles. A study by See et al. demonstrated that siRNA-mediated STAT3 suppression triggered the release of soluble" . _:b544538222 . _:b544538217 . _:b28707807 . _:b544538216 . _:b544538237 . _:b28707754 . _:b544538155 . _:b544538219 . _:b544538218 . _:b544538229 . _:b544538196 . _:b544538228 . _:b28707896 "Moreover, treatment with LLL3 increased survival in GBM-bearing mice by 12.5 days [26,>>131<<]. Others have targeted the JAK2/STAT3 pathway in glioma stem-like cells (GSCs). WP1193 is a small molecule inhibitor of JAK2/STAT3, which promotes in vivo glioma inhibition in a dose-dependent manner and is partially associated with G1" . _:b544538231 . . _:b544538230 . _:b544538209 . _:b544538225 . _:b28707791 "Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [>>62<<,63,64,65]." . _:b544538224 . _:b28707827 . . _:b544538176 . _:b544538227 . _:b28707912 . . _:b544538226 . _:b28707906 "anti-tumor responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [>>16<<,134,137,138,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134]." . . . _:b544538237 . _:b28707854 "STAT3 also recruits and promotes the proliferation of T regulatory cells (Tregs), which suppress effector lymphocyte activity within the tumor microenvironment [103,>>104<<]. Tregs are preferentially recruited to high-grade gliomas following tumor secretion of CCL2/22 chemokines [105]." . . _:b544538236 . _:b544538239 . _:b544538153 . _:b544538238 . _:b544538233 . _:b28707877 "De la Iglesia et al. have shown that in PTEN-deficient GBM, endogenous STAT3 inhibition prevents STAT3-mediated transcriptional IL-8 repression, resulting in increased tumor proliferation and invasiveness [>>118<<]. Furthermore, they found that reactivation of STAT3 in PTEN-deficient GBM suppresses the invasive phenotype and GBM proliferation along myelin in white matter tracts. Thus, whether STAT3 behaves as a tumor suppressor or oncogene relies" . . _:b544538232 . _:b544538235 . _:b28707873 . _:b544538234 . _:b28707737 . _:b544538245 . . _:b544538238 . . _:b28707780 . _:b544538244 . . _:b544538247 . _:b28707716 . _:b544538246 . . _:b544538241 . _:b28707773 . . _:b544538240 . . _:b544538243 . _:b544538242 . _:b28707882 "In GBM, survivin positivity has been suggested as a strong prognostic indicator of significantly poorer survival and higher malignant grade, owing to its anti-apoptotic activity [127,>>128<<]. Regarding STAT3, Abou-Ghazal and colleagues found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent" . . _:b28707722 "Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,17,>>18<<,19]. STAT3 can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family" . . . _:b28707839 . _:b544538252 . . _:b28707790 "The majority of STAT3 activity in U251 cells was catalyzed by gp130-associated JAKs secondary to IL-6, a cytokine secreted by GBM cells both in vivo and in vitro [>>61<<]. Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,63,64,65]. Furthermore, IL-6 gene amplification has been associated with a" . _:b28707898 "STAT3 knockdown with interfering RNA, delivered by a lentivirus vector, resulted in down-regulation of cyclin D1 and inhibition of glioma cell proliferation [>>133<<]. Oligodeoxynucleotides may also serve as future therapeutic options as they induce cell-cycle arrest and apoptosis by mimicking STAT3 specific cis-elements [36]. Furthermore, STAT3\u2019s role in Th17 T cell differentiation and cytokine" . . _:b544538249 . _:b28707707 . . _:b544538248 . . . . _:b544538251 . _:b28707789 "However differing methods in protein detection is a possible explanation for inconsistent results between studies [>>54<<]." . _:b28707810 . _:b28707740 "Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [>>23<<,31,32,33]." . _:b28707913 "Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [>>134<<]. Thus, multi-modality therapy involving cancer vaccines may be the key to the role of STAT3 inhibition in curative immunotherapy by promoting CD4 and CD8 T cell mediated tumor-specific killing [140]." . _:b28707848 "such as interferon (IFN) gamma-inducible protein 10 (IP-10), Rantes, IL-8, IL-6, tumor necrosis factor (TNF)-\u03B1 and interferon (IFN)-\u03B2; furthermore, exposure to these paracrine signaling molecules induced DC maturation and activation [>>17<<]." . _:b544538250 . _:b28707910 "over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,138,>>139<<,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134]." . _:b544538164 . _:b28707726 . . _:b544538235 . _:b28707709 . _:b28707839 "De Groot et al. demonstrated that anti-VEGF therapy in glioma patients results in markedly elevated levels of STAT3 expression, and that STAT3 inhibitors could enhance the efficacy of antiangiogenic treatment strategies [>>94<<]. Further study of the VEGF and STAT3 interactions will be required to better understand tumor escape and resistance patterns." . _:b28707904 . _:b28707739 "These tyrosine kinases include growth factor receptors, such as EGFR and PDGFR, and cytoplasmic enzymes, specifically the JAK and Src kinase families [>>23<<]. Phosphorylated STAT proteins dimerize via reciprocal phosphotyrosine-SH2 interactions and undergo nuclear translocation. There, they bind consensus STAT binding proteins, or DNA-response elements of the targeted sequences to regulate" . . _:b28707766 . . . _:b28707846 . _:b28707867 "Moreover, STAT3 activation is implicated in epithelial cell apoptosis in the mammary gland, and STAT3 knockout in mammary gland tissue results in delayed involution suggesting an early role for STAT3 in initiation of apoptosis [>>115<<]. Keratinocyte differentiation involves STAT3 activation and its association with p27kip1 accumulation, while hepatocyte epithelial tubule differentiation relies on hepatocyte growth factor-mediated STAT3 activation and translocation to" . . . _:b544538248 . _:b28707842 . _:b544538131 . . . _:b28707851 "However, relatively recent evidence suggests that exposure to glioma-derived chemokines induce constitutive STAT3 activation in MG, with consequent suppression of antitumor mechanisms or even tolerance to tumor antigens [99,100,>>101<<]. In contrast, a study by Komohara et al. demonstrated that direct interaction with glioma cells led to STAT3 activation in tumor infiltrating macrophages." . _:b544538156 . _:b28707717 . _:b544538182 . . . _:b28707818 . . . _:b28707704 "introduction" . _:b28707876 "The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,121,122,123,>>124<<]. While STAT3 activation has been associated with GBM evasion of immunosurveillance and enhancement of cell survival and proliferation, it is not surprising that STAT3 activation suppresses malignant transformation in certain GBM" . . _:b28707824 "Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [42,84,>>85<<]. Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [40]. Further studies of the underlying signaling pathways are needed to more clearly define" . _:b28707711 . . _:b28707713 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [>>9<<,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular" . _:b28707905 . _:b28707906 . . _:b544538214 . _:b544538143 . . _:b544538246 . . . . _:b28707749 . _:b544538129 . _:b28707872 "The role of the JAK-STAT pathway is well established in astrocyte differentiation [>>120<<,121,122,123,124]." . _:b28707778 . . _:b28707743 . _:b28707883 . _:b28707738 . _:b544538219 . _:b28707717 "growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [>>13<<] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies for both primary and secondary GBMs." . . _:b544538133 . _:b28707856 "Following direct interaction with local dendritic cells, Tregs secrete TGFb to inhibit activation of cytotoxic T cells [>>19<<,106]. STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of tumor-infiltrating Treg cells, as well as enhanced activity of DCs, natural killer (NK) cells, T cells, and neutrophils [107]. These" . _:b28707865 "STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [111,112,>>113<<]." . _:b28707763 "of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [>>43<<,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,47]3." . _:b28707858 . _:b28707860 "For example, the IL-6 growth-inhibitory and terminal differentiation signal has been correlated with STAT3 transcriptional activity in prostate cancer [>>108<<,109]. Similarly, IL-6 mediated growth arrest in melanoma is STAT3-dependent [110]. STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation" . _:b544538135 . _:b28707766 "[43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,>>46<<,47]3. Constitutive" . . _:b28707852 . _:b28707889 "which suppresses M2 polarization of tumor-associated macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [>>132<<]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific cis elements [36]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream" . . _:b544538125 . . _:b544538226 . _:b544538145 . _:b28707831 . _:b28707827 "Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [>>86<<,87], and IL-6 receptor associated kinases in myeloma [88]." . . _:b28707862 . . _:b28707838 "recombinant humanized monoclonal anti-VEGF antibody, Keunen et al. found that vascular remodeling and the creation of a more hypoxic tumor microenvironment paradoxically resulted in a more invasive, glycolysis-dependent tumor phenotype [>>93<<]. De Groot et al. demonstrated that anti-VEGF therapy in glioma patients results in markedly elevated levels of STAT3 expression, and that STAT3 inhibitors could enhance the efficacy of antiangiogenic treatment strategies [94]." . _:b28707847 . _:b28707804 _:b28707856 . _:b28707804 _:b28707857 . _:b28707804 _:b28707858 . _:b544538202 . _:b28707841 "T cell anergy, lymphodepletion, lymphosuppression, and impaired antibody synthesis are just some of the ways in which GBMs avoid antigen recognition and targeted destruction [>>39<<]." . _:b28707881 "In GBM, survivin positivity has been suggested as a strong prognostic indicator of significantly poorer survival and higher malignant grade, owing to its anti-apoptotic activity [>>127<<,128]. Regarding STAT3, Abou-Ghazal and colleagues found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent" . _:b28707804 _:b28707844 . _:b28707870 "GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [>>118<<,119]." . _:b28707804 _:b28707845 . _:b28707804 _:b28707846 . _:b28707804 _:b28707847 . _:b544538146 . _:b28707804 _:b28707840 . _:b28707804 _:b28707841 . . _:b28707876 . _:b28707804 _:b28707842 . _:b28707804 _:b28707843 . _:b28707804 _:b28707852 . _:b28707804 _:b28707853 . _:b28707774 "convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,>>22<<,29,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases." . _:b28707804 _:b28707854 . _:b28707804 _:b28707855 . . _:b28707804 _:b28707848 . _:b28707804 _:b28707849 . _:b28707804 _:b28707850 . _:b28707804 _:b28707851 . . _:b544538149 . . _:b544538162 . . _:b28707828 "Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [86,>>87<<], and IL-6 receptor associated kinases in myeloma [88]." . _:b544538197 . _:b28707708 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,>>4<<,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme" . _:b28707761 . _:b28707716 "epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [>>12<<], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies for both primary and secondary GBMs." . _:b28707845 . _:b28707762 . _:b28707763 . . . _:b28707810 "STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,74,>>75<<,76]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [61]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3" . _:b28707747 . . _:b28707797 "In particular, missense mutations of EGFR genes may lead to constitutive downstream activation, and have been implicated in de novo GBMs in older patients [66,>>67<<,68]. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [69]." . . . _:b28707723 "Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,17,18,>>19<<]. STAT3 can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family" . _:b28707823 "Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [42,>>84<<,85]. Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [40]. Further studies of the underlying signaling pathways are needed to more clearly" . . . . . _:b28707774 . _:b544538125 "5"^^ . _:b544538124 "5"^^ . _:b544538130 . _:b544538121 . _:b544538127 "4"^^ . _:b28707705 . _:b28707757 . . _:b544538126 "4"^^ . _:b28707783 . _:b28707834 . _:b544538124 . . _:b28707773 "the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,>>21<<,22,29,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases." . _:b544538120 "7"^^ . _:b28707756 "antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [>>36<<,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of" . _:b544538123 "5"^^ . _:b544538121 "6"^^ . _:b544538122 "5"^^ . _:b544538133 "4"^^ . _:b28707850 . _:b544538132 "4"^^ . _:b28707743 "Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [23,31,32,>>33<<]. STAT3 signaling is tightly regulated by several upstream and downstream checkpoints to ensure an appropriate growth response to activation. Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and" . _:b28707896 . . _:b544538135 "4"^^ . _:b28707708 . _:b544538134 "4"^^ . _:b28707814 . _:b544538129 "4"^^ . _:b544538128 "4"^^ . _:b544538131 "4"^^ . . _:b544538130 "4"^^ . _:b544538141 "3"^^ . _:b28707799 . _:b544538140 "3"^^ . . _:b28707888 . _:b544538143 "3"^^ . _:b28707712 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,>>8<<], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have" . _:b28707768 "constitutive activation" . _:b28707879 "Jin et al. report that STAT3 expression in colorectal carcinoma is correlated with higher-grade tumors and poorer survival [>>125<<]. Conversely, Gordziel and colleagues found that strong STAT3 expression in colorectal carcinoma biopsies is associated with an improvement in median survival of about 30 months compared to STAT3 negative biopsies [126]. Such" . _:b544538142 "3"^^ . . _:b544538137 "3"^^ . _:b544538230 . _:b544538136 "3"^^ . _:b544538139 "3"^^ . _:b28707736 "stat3 signaling pathways" . _:b544538138 "3"^^ . _:b544538127 . _:b544538149 "3"^^ . _:b544538210 . _:b544538148 "3"^^ . _:b28707744 . . _:b544538151 "3"^^ . _:b544538150 "3"^^ . _:b544538145 "3"^^ . . _:b544538144 "3"^^ . _:b28707852 "In return, MG/macrophage-derived factors were shown to activate STAT3 signals in tumor cells, perpetuating glioma pathogenesis and progression [>>102<<]." . . _:b544538147 "3"^^ . _:b544538146 "3"^^ . _:b544538157 "3"^^ . _:b544538156 "3"^^ . _:b544538159 "3"^^ . . _:b544538158 "3"^^ . _:b28707803 . _:b544538153 "3"^^ . _:b28707884 . _:b28707802 . _:b544538152 "3"^^ . _:b544538155 "3"^^ . _:b28707744 "Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and inactivate ligand-receptor complexes and phosphorylated-STAT (pSTAT) dimers [>>34<<,35]. Suppressor of cytokine signaling (SOCS) proteins negatively feedback on the JAK/STAT signaling pathway by disrupting or degrading JAKs [36]. In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block" . _:b544538204 . _:b28707755 "disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,>>28<<]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3" . _:b544538154 "3"^^ . . . _:b544538169 . _:b544538165 "2"^^ . . _:b28707842 "Secreted factors include IL-10 (an inhibitor of Th1 activity), VEGF, and TGF-beta, which inhibit T cell, B cell, natural killer (NK) cell, and monocyte functions [>>49<<,95,96]. VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [97]. STAT3 hyperactivity can lead to abnormal DC" . _:b544538164 "2"^^ . _:b544538167 "2"^^ . _:b544538166 "2"^^ . _:b544538161 "2"^^ . _:b28707787 "These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [57,58,>>59<<]. In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [60]. However differing methods in protein detection is a possible explanation for inconsistent results" . _:b544538150 . _:b544538160 "3"^^ . _:b544538163 "2"^^ . . . _:b544538198 . . . _:b544538162 "2"^^ . _:b544538173 "2"^^ . _:b544538251 . _:b544538172 "2"^^ . _:b28707798 "In particular, missense mutations of EGFR genes may lead to constitutive downstream activation, and have been implicated in de novo GBMs in older patients [66,67,>>68<<]. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [69]." . _:b544538188 . . _:b28707727 . _:b544538175 "2"^^ . _:b28707718 . _:b544538174 "2"^^ . _:b544538236 . _:b544538169 "2"^^ . . _:b544538168 "2"^^ . _:b544538171 "2"^^ . _:b544538170 "2"^^ . . _:b544538181 "2"^^ . _:b28707894 . _:b28707764 "of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,>>44<<]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,47]3." . _:b544538180 "2"^^ . . _:b544538183 "2"^^ . . _:b544538182 "2"^^ . _:b28707760 "inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [>>25<<,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy" . _:b544538177 "2"^^ . _:b28707801 "Focal deletions, missense, and nonsense mutations of the PTPRD gene have been identified in up to 41% of GBM samples [>>70<<,71]. Furthermore, Veeriah et al. observed a greater frequency of PTPRD expression loss in GBM versus lower grade gliomas. Decreased PTPRD expression was also predictive of poorer prognosis in GBM patients [71]." . _:b544538176 "2"^^ . . _:b28707804 "role of stat3 in tumorigenesis" . _:b544538179 "2"^^ . _:b28707812 "STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [>>61<<]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [77,78,79]. Furthermore, STAT3 may be required for the maintenance" . . _:b544538178 "2"^^ . . _:b544538216 . _:b544538189 "2"^^ . . _:b544538188 "2"^^ . . . _:b544538191 "2"^^ . _:b28707848 . _:b544538190 "2"^^ . . _:b28707730 "It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,>>24<<]." . . _:b544538185 "2"^^ . _:b28707737 "STAT proteins are a family of cytoplasmic transcription factors that are activated by tyrosine kinases and mediate cellular response to inflammatory and proliferative signals [>>29<<,30]. These tyrosine kinases include growth factor receptors, such as EGFR and PDGFR, and cytoplasmic enzymes, specifically the JAK and Src kinase families [23]." . _:b544538184 "2"^^ . _:b28707805 . _:b544538187 "2"^^ . _:b28707897 . _:b28707861 . _:b28707796 "In particular, missense mutations of EGFR genes may lead to constitutive downstream activation, and have been implicated in de novo GBMs in older patients [>>66<<,67,68]. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [69]." . _:b28707708 . _:b544538186 "2"^^ . _:b28707709 . _:b544538197 "2"^^ . _:b28707710 . _:b544538196 "2"^^ . _:b28707711 . _:b544538199 "2"^^ . . _:b28707840 . . _:b28707825 "Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [>>40<<]. Further studies of the underlying signaling pathways are needed to more clearly define the relationship between STAT3 activation and GBM invasiveness." . . _:b544538198 "2"^^ . _:b28707704 . _:b28707705 . _:b544538193 "2"^^ . _:b28707706 . _:b28707767 . _:b544538192 "2"^^ . . . _:b28707707 . _:b28707889 . _:b544538195 "2"^^ . _:b28707716 . _:b544538194 "2"^^ . _:b28707717 . _:b544538205 "2"^^ . _:b28707718 . _:b544538204 "2"^^ . . . _:b28707719 . _:b544538207 "2"^^ . _:b28707793 "Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,63,>>64<<,65]. Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [65]." . _:b28707849 . _:b28707712 . _:b544538206 "2"^^ . _:b28707713 . _:b544538201 "2"^^ . . _:b28707714 . _:b544538200 "2"^^ . _:b544538167 . . _:b28707715 . _:b544538203 "2"^^ . _:b28707776 "point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,22,29,>>49<<,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases." . _:b28707713 . _:b28707724 . _:b544538202 "2"^^ . _:b28707734 . _:b28707725 . _:b544538213 "2"^^ . _:b28707837 "Constitutively activated STAT3 and VEGF receptors can be coexpressed in glioma [>>58<<]. In a study of the phenotypic, physiologic, and molecular tumor response to bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, Keunen et al. found that vascular remodeling and the creation of a more hypoxic tumor" . . _:b28707726 . _:b544538212 "2"^^ . _:b28707912 "vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,138,139,140,>>141<<]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134]." . _:b28707727 . _:b544538215 "2"^^ . _:b28707720 . _:b544538214 "2"^^ . _:b28707721 . _:b544538209 "2"^^ . . _:b28707797 . _:b28707722 . _:b544538208 "2"^^ . _:b28707751 . _:b28707723 . _:b544538211 "2"^^ . . _:b28707732 . _:b544538210 "2"^^ . _:b28707733 . _:b544538221 "2"^^ . _:b28707734 . _:b544538220 "2"^^ . _:b544538193 . _:b28707735 . _:b28707874 "The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,121,>>122<<,123,124]. While STAT3 activation has been associated with GBM evasion of immunosurveillance and enhancement of cell survival and proliferation, it is not surprising that STAT3 activation suppresses malignant transformation in certain GBM" . _:b544538223 "2"^^ . _:b544538213 . _:b28707728 . _:b544538222 "2"^^ . _:b28707817 "Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal capacities in GBM stem cells [>>81<<]. STAT3 tyrosine (Y) phosphorylation has also been associated with more aggressive tumors. Increased expression of Y705-phosphorylated STAT3 in GBM samples correlated with significantly shorter overall survival [82]. Together, there is" . _:b28707729 . _:b544538217 "2"^^ . _:b28707832 "More specifically, in vitro overexpression of the viral chemokine receptor US28 has been shown to activate several downstream transcription factors such as hypoxia inducible factor-1 and STAT3, resulting in VEGF promoter activation [90,>>91<<]." . _:b28707730 . _:b544538216 "2"^^ . _:b28707824 . _:b28707731 . _:b544538219 "2"^^ . _:b28707740 . _:b544538218 "2"^^ . _:b28707711 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [>>7<<,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have" . _:b544538242 . . _:b544538229 "2"^^ . _:b28707741 . _:b28707791 . _:b544538168 . . _:b28707742 . _:b544538228 "2"^^ . . _:b28707743 . _:b544538231 "2"^^ . _:b544538181 . _:b544538230 "2"^^ . _:b28707736 . _:b28707737 . _:b544538225 "2"^^ . _:b28707866 . _:b28707761 "[15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,>>43<<]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy" . _:b28707738 . _:b544538224 "2"^^ . _:b28707893 "Potential drugs that directly inhibit STAT3 activation include the naturally occurring triterpenoid oleanolic acid, which also suppresses the M2 polarization of tumor-associated macrophages by suppressing IL-10 secretion [>>130<<]. Small molecule inhibitors are also candidates for suppressing STAT3 activity, as they produce a similar anti-tumor inflammatory microenvironment as siRNA-mediated knockdown of STAT3 [17]." . _:b28707739 . _:b544538227 "2"^^ . _:b28707748 . _:b544538226 "2"^^ . _:b544538152 . _:b28707749 . _:b544538237 "2"^^ . _:b28707750 . _:b544538236 "2"^^ . _:b28707714 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,>>10<<,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies" . _:b28707751 . _:b544538239 "2"^^ . _:b28707734 "Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,25,26,>>27<<,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM." . _:b28707738 "STAT proteins are a family of cytoplasmic transcription factors that are activated by tyrosine kinases and mediate cellular response to inflammatory and proliferative signals [29,>>30<<]. These tyrosine kinases include growth factor receptors, such as EGFR and PDGFR, and cytoplasmic enzymes, specifically the JAK and Src kinase families [23]." . _:b28707725 "can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,>>20<<,21,22,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24]." . _:b544538238 "2"^^ . _:b28707744 . . _:b28707814 "Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [77,>>78<<,79]. Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC\u2019s) [80]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal" . _:b544538233 "2"^^ . _:b28707745 . _:b28707746 . _:b544538232 "2"^^ . _:b28707758 . _:b28707747 . _:b544538235 "2"^^ . _:b544538184 . . . . _:b28707855 "Tregs are preferentially recruited to high-grade gliomas following tumor secretion of CCL2/22 chemokines [>>105<<]. Following direct interaction with local dendritic cells, Tregs secrete TGFb to inhibit activation of cytotoxic T cells [19,106]. STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of" . _:b28707756 . _:b544538234 "2"^^ . _:b28707885 "stat3 as a therapeutic target" . _:b28707757 . _:b544538245 "2"^^ . _:b544538147 . _:b28707758 . _:b28707874 . _:b544538244 "2"^^ . . _:b544538244 . _:b28707759 . _:b544538247 "2"^^ . _:b544538245 . _:b544538246 . _:b28707723 . _:b544538247 . _:b544538240 . . _:b28707752 . _:b544538246 "2"^^ . _:b544538241 . _:b544538242 . _:b544538243 . _:b28707905 "is clearly an integral pathway to tumor growth and invasion, lifting the \u201Cbrakes\u201D on immune function through STAT3 checkpoint blockade combined with tumor-specific vaccine therapy may show promise for more robust anti-tumor responses [>>16<<]. Such checkpoint blockade combined with vaccine based immune activation has shown enhanced anti-tumor responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4)" . _:b544538252 . _:b28707753 . _:b544538241 "2"^^ . _:b28707796 . _:b544538248 . _:b28707754 . _:b544538240 "2"^^ . _:b544538249 . _:b544538250 . _:b544538251 . _:b28707750 . _:b28707755 . _:b544538243 "2"^^ . _:b28707887 . . _:b28707764 . _:b544538242 "2"^^ . _:b28707765 . _:b28707766 . _:b544538252 "2"^^ . _:b544538195 . . _:b28707767 . . _:b28707760 . . . . _:b544538249 "2"^^ . _:b28707761 . _:b544538151 . _:b28707762 . _:b544538248 "2"^^ . _:b28707763 . _:b544538251 "2"^^ . _:b28707772 . _:b544538250 "2"^^ . _:b28707756 . . _:b28707773 . _:b28707774 . _:b544538172 . _:b28707775 . _:b28707882 . _:b28707768 . . . _:b544538144 . _:b28707769 . _:b28707840 "Tumor-mediated immune suppression at both the local and systemic levels has been well described in GBM patients [>>17<<]. T cell anergy, lymphodepletion, lymphosuppression, and impaired antibody synthesis are just some of the ways in which GBMs avoid antigen recognition and targeted destruction [39]." . _:b28707755 . _:b28707770 . _:b28707771 . _:b28707914 "Thus, multi-modality therapy involving cancer vaccines may be the key to the role of STAT3 inhibition in curative immunotherapy by promoting CD4 and CD8 T cell mediated tumor-specific killing [>>140<<]." . _:b28707780 . _:b28707781 . . _:b28707782 . _:b28707746 . _:b28707857 . _:b544538171 . _:b28707783 . _:b544538158 . _:b28707781 "The presence of STAT3 activation in GBMs varies considerably, with detection rates of most retrospective, immunohistochemistry-based studies ranging from 9%\u201383% [>>54<<]. These discrepant data could be attributed to the varying tumor grades of the brain tissue sampled in each study." . _:b28707776 . _:b28707777 . _:b28707731 "Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [>>17<<,25,26,27,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM." . _:b544538229 . _:b28707751 "Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,>>40<<]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators" . _:b28707778 . _:b28707779 . _:b28707895 . _:b28707788 . . _:b28707789 . _:b28707878 "stat3 as a prognostic indicator" . . _:b28707790 . _:b28707791 . _:b28707904 "Resistance to temozolomide has been shown to be associated with STAT3 activation and upregulation of the DNA repair enzyme MGMT [>>14<<]. Thus, STAT3 knockdown prior to temozolomide therapy may reduce the incidence of tumor resistance to chemotherapy." . _:b28707784 . _:b544538124 . _:b28707785 . _:b544538125 . _:b544538126 . _:b544538127 . _:b28707900 . _:b28707850 "However, relatively recent evidence suggests that exposure to glioma-derived chemokines induce constitutive STAT3 activation in MG, with consequent suppression of antitumor mechanisms or even tolerance to tumor antigens [99,>>100<<,101]. In contrast, a study by Komohara et al. demonstrated that direct interaction with glioma cells led to STAT3 activation in tumor infiltrating macrophages. In return, MG/macrophage-derived factors were shown to activate STAT3 signals" . _:b544538120 . _:b28707786 . . _:b544538121 . _:b544538122 . _:b28707704 . _:b544538123 . _:b544538132 . . _:b544538133 . _:b28707787 . _:b544538183 . _:b544538134 . _:b544538135 . . _:b544538128 . _:b28707796 . _:b544538129 . _:b544538130 . _:b544538131 . _:b28707788 "In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [>>60<<]. However differing methods in protein detection is a possible explanation for inconsistent results between studies [54]." . _:b544538140 . _:b28707797 . _:b544538141 . _:b544538142 . _:b544538143 . _:b544538136 . _:b28707798 . _:b544538137 . _:b28707800 "Brantley et al. demonstrated a negative correlation between transcription inhibitor PIAS3 and phospho-STAT3 expression, with subsequent PIAS3 overexpression leading to decreased STAT3 transcriptional activity and cell proliferation [>>57<<]. Protein tyrosine phosphatase receptor delta (PTPRD), a STAT3 phosphatase, has been implicated as a suppressor of neuroectoderm-derived tumors." . _:b544538239 . _:b544538138 . _:b544538139 . _:b544538148 . _:b28707799 . _:b544538149 . _:b28707885 _:b28707904 . _:b544538150 . _:b28707885 _:b28707905 . _:b544538189 . _:b544538151 . _:b28707885 _:b28707906 . _:b544538144 . _:b28707752 "Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [>>15<<,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3" . _:b28707704 _:b28707708 . _:b28707777 "point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,22,29,49,>>50<<]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases." . _:b544538145 . _:b28707792 . _:b28707885 _:b28707907 . _:b28707704 _:b28707709 . _:b544538146 . . _:b28707885 _:b28707908 . _:b28707704 _:b28707710 . . _:b544538147 . _:b28707885 _:b28707909 . _:b28707704 _:b28707711 . _:b28707724 "can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [>>16<<,20,21,22,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24]." . _:b544538156 . _:b28707885 _:b28707910 . _:b28707885 _:b28707911 . _:b544538157 . _:b28707793 . _:b28707704 _:b28707705 . _:b28707863 . _:b544538158 . _:b28707885 _:b28707912 . _:b28707704 _:b28707706 . _:b544538159 . _:b28707885 _:b28707913 . _:b28707704 _:b28707707 . _:b544538152 . _:b28707885 _:b28707914 . _:b28707704 _:b28707716 . _:b544538153 . _:b28707794 . _:b28707704 _:b28707717 . _:b544538154 . _:b28707704 _:b28707718 . _:b544538155 . _:b28707715 "Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,>>11<<] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies for" . _:b544538164 . _:b28707704 _:b28707719 . _:b28707704 _:b28707712 . _:b544538165 . _:b28707795 . _:b28707704 _:b28707713 . _:b544538166 . _:b28707704 _:b28707714 . _:b544538167 . _:b28707704 _:b28707715 . _:b28707809 . _:b544538160 . _:b28707704 _:b28707724 . _:b544538161 . _:b28707704 _:b28707725 . _:b544538162 . _:b28707804 . _:b28707704 _:b28707726 . _:b544538163 . _:b28707704 _:b28707727 . _:b544538172 . _:b28707704 _:b28707720 . _:b544538173 . _:b28707805 . _:b28707704 _:b28707721 . _:b544538174 . _:b28707704 _:b28707722 . _:b544538175 . _:b28707704 _:b28707723 . _:b544538168 . _:b28707704 _:b28707732 . _:b544538169 . _:b28707806 . _:b28707704 _:b28707733 . _:b544538170 . "10.3390%2Fcancers6010376" . _:b544538171 . _:b28707704 _:b28707734 . _:b28707704 _:b28707735 . _:b544538180 . _:b28707704 _:b28707728 . _:b544538139 . _:b544538181 . _:b28707807 . _:b28707704 _:b28707729 . _:b544538182 . _:b544538225 . _:b544538183 . _:b28707704 _:b28707730 . _:b28707704 _:b28707731 . _:b544538176 . _:b28707800 . _:b544538177 . _:b544538178 . _:b544538227 . _:b544538179 . _:b28707783 "Abou-Ghazal reported similar results in 2008, with 50% of AA and 51% of GBM samples staining positively for pSTAT3 [>>56<<]. Lo et al. expanded on these findings by describing a positive correlation between glioma grade and extent of STAT3 activation. Constitutive activation was detected in 60% of primary high grade/malignant gliomas, secondary to JAK2, EGFR" . _:b544538188 . _:b28707801 . _:b544538189 . _:b544538190 . _:b544538191 . . _:b28707844 "Secreted factors include IL-10 (an inhibitor of Th1 activity), VEGF, and TGF-beta, which inhibit T cell, B cell, natural killer (NK) cell, and monocyte functions [49,95,>>96<<]. VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [97]. STAT3 hyperactivity can lead to abnormal DC differentiation via" . _:b544538184 . _:b28707802 . _:b544538185 . _:b544538186 . _:b544538187 . _:b544538196 . _:b28707803 . _:b544538197 . _:b544538198 . _:b544538199 . _:b544538192 . _:b28707812 . _:b544538193 . _:b544538194 . _:b28707825 . _:b28707706 . _:b544538195 . _:b544538204 . _:b28707813 . _:b544538205 . _:b544538206 . _:b544538207 . _:b28707832 . _:b544538200 . _:b28707814 . _:b544538201 . _:b544538202 . _:b544538203 . _:b544538212 . _:b28707820 . _:b28707815 . _:b544538213 . _:b28707878 _:b28707884 . _:b544538214 . _:b544538215 . . _:b544538208 . _:b28707808 . _:b544538209 . _:b28707878 _:b28707880 . _:b28707875 "The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,121,122,>>123<<,124]. While STAT3 activation has been associated with GBM evasion of immunosurveillance and enhancement of cell survival and proliferation, it is not surprising that STAT3 activation suppresses malignant transformation in certain GBM" . _:b544538210 . _:b544538174 . _:b28707878 _:b28707881 . _:b544538211 . _:b28707878 _:b28707882 . _:b544538220 . . _:b544538221 . _:b28707809 . _:b28707878 _:b28707883 . _:b544538222 . _:b28707804 . _:b544538223 . _:b544538216 . _:b28707888 "DrugMechanism of ActionOleanolic acidSuppresses IL-10 secretion which suppresses M2 polarization of tumor-associated macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,>>131<<]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific" . _:b28707878 _:b28707879 . _:b544538217 . _:b28707810 . _:b544538218 . . _:b544538219 . _:b544538228 . _:b28707811 . _:b544538229 . _:b28707885 _:b28707888 . _:b544538230 . _:b28707885 _:b28707889 . _:b544538231 . _:b28707885 _:b28707890 . _:b544538224 . _:b28707885 _:b28707891 . _:b544538225 . _:b28707820 . _:b28707885 _:b28707892 . _:b544538226 . _:b28707885 _:b28707893 . _:b544538227 . _:b28707885 _:b28707894 . _:b28707911 "over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,138,139,>>140<<,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134]." . . _:b544538236 . _:b28707885 _:b28707895 . _:b544538237 . _:b28707821 . _:b28707885 _:b28707896 . _:b544538238 . _:b28707735 . _:b544538239 . _:b28707885 _:b28707897 . _:b28707885 _:b28707898 . _:b28707902 "AG490 inhibits JAK2, the upstream activator of STAT3, which results in decreased expression of the STAT3 regulated genes MMP-2 and MMP-9 [>>84<<]." . _:b544538232 . _:b28707885 _:b28707899 . _:b544538233 . _:b28707822 . _:b28707885 _:b28707900 . _:b544538234 . _:b28707885 _:b28707901 . _:b544538235 . _:b28707885 _:b28707902 . _:b28707885 _:b28707903 . _:b28707871 . _:b28707823 . . _:b28707816 . . . _:b28707817 . . . . _:b28707818 . _:b28707885 _:b28707886 . _:b544538205 . _:b28707806 . _:b28707819 . _:b28707885 _:b28707887 . _:b544538201 . . . _:b28707828 . _:b28707829 . _:b28707859 _:b28707872 . _:b28707859 _:b28707873 . _:b28707859 _:b28707874 . _:b28707859 _:b28707875 . _:b28707830 . _:b28707859 _:b28707876 . _:b28707721 . _:b28707759 "[5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,>>42<<]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear" . _:b28707899 "Oligodeoxynucleotides may also serve as future therapeutic options as they induce cell-cycle arrest and apoptosis by mimicking STAT3 specific cis-elements [>>36<<]. Furthermore, STAT3\u2019s role in Th17 T cell differentiation and cytokine production renders it an attractive target for immunotherapy in autoimmune pathways, as ablation of STAT3 in CD4 cells results in increased Th1 responses rather than" . _:b28707859 _:b28707877 . _:b28707831 . _:b28707824 . _:b28707825 . _:b28707826 . _:b28707736 . _:b28707733 . . _:b28707827 . _:b28707836 . _:b28707837 . _:b28707866 "Inhibition of STAT3 via overexpression of the tumor suppressor PTEN promotes proliferation and tumorigenesis [>>114<<]. Moreover, STAT3 activation is implicated in epithelial cell apoptosis in the mammary gland, and STAT3 knockout in mammary gland tissue results in delayed involution suggesting an early role for STAT3 in initiation of apoptosis [115]." . _:b28707909 "responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,>>138<<,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134]." . _:b28707857 "Following direct interaction with local dendritic cells, Tregs secrete TGFb to inhibit activation of cytotoxic T cells [19,>>106<<]. STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of tumor-infiltrating Treg cells, as well as enhanced activity of DCs, natural killer (NK) cells, T cells, and neutrophils [107]. These findings" . _:b544538221 . _:b28707838 . _:b28707907 . _:b28707830 "Niu et al. noted that VEGF expression in several cancer cell lines correlated with constitutive STAT3 activity, and that STAT3 inhibition led to reduced Src-induced VEGF expression [>>89<<]. Results from promoter mutagenesis and chromatin immunoprecipitation assays further indicated that the VEGF gene is directly regulated by STAT3, thereby suggesting that STAT3-targeted therapy could play a significant role in disrupting" . _:b28707839 . _:b28707745 "Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and inactivate ligand-receptor complexes and phosphorylated-STAT (pSTAT) dimers [34,>>35<<]. Suppressor of cytokine signaling (SOCS) proteins negatively feedback on the JAK/STAT signaling pathway by disrupting or degrading JAKs [36]. In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block" . _:b28707859 _:b28707864 . _:b28707769 "Persistent STAT3 activation\u2014secondary to intrinsic hyperactivity, aberrant upstream signaling, or defective negative regulation\u2014can lead to abnormal survival and tumorigenesis [>>48<<]. Constitutive STAT3 activation has been reported in 50%\u201390% of human cancers [48,49]." . _:b28707859 _:b28707865 . _:b28707859 _:b28707866 . _:b28707859 _:b28707867 . _:b28707832 . _:b28707859 _:b28707868 . _:b28707856 . _:b28707859 _:b28707869 . _:b28707859 _:b28707870 . _:b28707859 _:b28707871 . _:b28707833 . _:b28707758 "[5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,>>41<<,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of" . _:b28707834 . _:b28707859 _:b28707860 . _:b28707859 _:b28707861 . _:b28707768 . _:b28707859 _:b28707862 . _:b544538194 . _:b28707794 . _:b28707835 . _:b28707859 _:b28707863 . _:b28707795 . _:b544538166 . _:b28707913 . . _:b544538157 . _:b28707784 . _:b28707781 . _:b28707803 "Decreased PTPRD expression was also predictive of poorer prognosis in GBM patients [>>71<<]." . _:b28707762 "protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [>>43<<]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,47]3." . _:b28707845 "VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [>>97<<]. STAT3 hyperactivity can lead to abnormal DC differentiation via constitutive JAK2/STAT3 activation [18] and decreased expression of major histocompatibility complex (MHC) class II, costimulatory CD40, and IL-12 molecules [98]." . _:b28707795 "Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [>>65<<]." . . . _:b28707729 . _:b28707722 . _:b28707789 . _:b28707731 . _:b28707772 . .