Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

Brantley, Emily C.; Benveniste, Etty N.

doi:10.1158/1541-7786.mcr-07-2180

Cited by 205 publications

(167 citation statements)

References 101 publications

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“…Interestingly, accumulation of phosphorylated STAT3 and STAT3 hyperactivation are frequent events in solid tumors like GBM, yet the genetic basis of aberrant STAT3 activation is poorly understood. p-STAT3 has been implicated in a number of tumor-promoting processes, including blocking differentiation, maintaining the stem cell pool, promoting growth and angiogenesis, and regulating the immune response and tumor microenvironment (12)(13)(14). In this study, we show that allelic loss of Ptprd results in p-Stat3 accumulation and Stat3 hyperactivation, elucidating one genetic root cause for aberrant STAT3 activation in GBM.…”

mentioning

confidence: 61%

“…Using in vitro methods, we previously identified p-STAT3 as a candidate substrate of PTPRD (5). It is well-known that p-STAT3 functions as a transcription factor for genes involved in the tumorigenic process (12,14). We performed p-Stat3 immunohistochemistry (IHC) on glioma tumors from Ptprd +/+ p16 −/− , Ptprd +/− p16 −/− , and Ptprd −/− p16 −/− mice.…”

Section: Heterozygous Loss Of Ptprd Results In P-stat3 Accumulation Andmentioning

confidence: 99%

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Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16 INK4A tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16 INK4A deletion, as a driver of glioma progression.G lioblastoma multiforme (GBM) is a devastating disease. It is the most common and aggressive type of glioma and outcomes remain poor despite current treatments (1). To increase our understanding of the genetic basis of this malignancy, several mutational survey studies examining GBM have been completed and provide a detailed view of the molecular changes underlying this cancer (2-4). Because GBM is a highly heterogeneous tumor, a challenge remains to determine which molecular alterations drive tumorigenesis and to understand the underlying mechanisms of action. Recent work by our group and others have identified inactivation of protein tyrosine phosphatase receptor-δ (PTPRD) as a frequent alteration in GBM and other tumors, and showed that PTPRD copy number loss correlates with poor prognosis (5-10). Despite the high prevalence of PTPRD inactivation in human tumors, it is not known whether loss of PTPRD can promote tumorigenesis. Furthermore, the mechanisms of action and the oncogenic context in which PTPRD acts remain obscure.PTPRD belongs to a family of protein-tyrosine phosphatases that collectively have been implicated in functions, including the regulation of receptor tyrosine kinases, growth, cell migration, and angiogenesis (11). Previously, we demonstrated that phosphorylated STAT3 (p-STAT3) is a substrate of PTPRD and that cancer-specific mutations in PTPRD abrogate the ability of the phosphatase to dephosphorylate STAT3 (5). Interestingly, accumulation of phosphorylated STAT3 and STAT3 hyper...

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mentioning

confidence: 61%

Section: Heterozygous Loss Of Ptprd Results In P-stat3 Accumulation Andmentioning

confidence: 99%

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…STAT3 activation in TAM is induced by different cytokines of the tumour microenvironment such as IL-10, IL-6, epidermal growth factor (EGF) and fibroblast growth factor. Activated STAT3 is known to reduce the expression of surface molecules necessary for antigen presentation such as MHC-II, CD80, and CD86 [79], as well as to increase the expression of many M2-specific immunomodulatory mediators including IL-10, EGF, VEGF, and various matrix metalloproteinsases (MMPs) [18]. It is currently unclear whether a single dominant molecule or a complex network of molecules is responsible for the immunosuppressive phenotype of glioma TAM, but STAT3 activation appears to play a key role in generating and perpetuating the M2-shifted TAM in gliomas.…”

Section: Adaptive Immune Functions In Gliomasmentioning

confidence: 99%

CNS macrophages and peripheral myeloid cells in brain tumours

2014

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However, it is also becoming evident that some myeloid-directed glioma therapies may only be beneficial for distinct subclasses of gliomas and that a more cell-type specific manipulation of either microglia or macrophages may improve therapeutic outcome. 2 Neuropathological features of gliomasGlial tumours constitute approximately 50% of all newly diagnosed primary brain tumours, with low-grade gliomas accounting for roughly 15% of all brain tumours in adults [106]. The morphology and the cellular markers for gliomas share some similarities with the main macroglial cell-types (i.e. astrocytes, oligodendrocytes) [75].Histopathologically, gliomas are divided into four different grades (according to the classification scheme by the world health organization, WHO), in which low-grade tumours are defined as grade-I/-II and high-grade gliomas as grade-III and-IV [87]. The presence of mitotic activity is a key feature for distinguishing low-grade from high-grade gliomas [75]. Statistically, low-grade astrocytomas arise roughly in proportion to the relative mass of the different lobes with most common location within the frontal lobes, followed by temporal and parietal lobe lesions [107]. Overall, 5-and 10-year survival rates of ~70% and 50% for grade-I and grade-II gliomas, respectively, have been reported in the literature [25]. The tumour tissue has no obvious signs of neoangiogenesis, infiltrative invasion or inflammation [75]. On the contrary, the outlook for patients with high-grade gliomas is grim. The majority of individuals diagnosed with a grade-IV glioma, which are very heterogeneous tumours and therefore also named glioblastoma multiforme (GBM), have a median progression-free survival of just over half a year and median overall survival of 15-18 months [17], only some subpopulations of patients show median survivals of almost 2 years [54]. GBM is a fast growing, highly angiogenic and invasive tumour and the diffuse growth is a major obstacle for GBM therapy. Other hallmarks of malignant gliomas are break-down of the blood-brain barrier (BBB), many hypoxic areas and necrotic centres [75]. Gliomas are usually diagnosed by neurorimaging (i.e. magnetic resonance imaging) and visualisation of the uptake of a contrast-enhancing agent within the tissue indicates BBB-leakage/breakdown [159]. GBM typically presents as a ragged contrast-enhanced and complex multi-cystic structure. GBM may be diagnosed de novo, i.e. in patients without a clinical history for brain tumours (then named primary GBM) or may evolve from lower grade gliomas (secondary GBM) [103].3 Multi-modal glioma therapyGlioma therapy comprises very different strategies. For patients with deep-seated lesions or lesions located in eloquent regions which are clinically and radiographically indicated as low-grade glioma a conservative management including regular neuroimaging (after obtaining a histological diagnosis) [165], see also [130,150]. Individuals with high-grade gliomas undergo multi-modal treatment combining cytoreductive surgery, radiation-and ch...

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“…These diverse signals converge at specific transcription factors, including STAT3 (17). STAT3 was initially identified as a signal mediator for IFN stimulation with various gene targets controlling cell growth, and subsequently, STAT3 has been shown to play an important role for cellular transformation (18).…”

Section: Introductionmentioning

confidence: 99%

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

Wang

Yachi

Mahabir

et al. 2012

Molecular Cancer Therapeutics

162

134

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Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r ¼ 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM.

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Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

Abstract: Glioblastoma is the most common and severe primary brain tumor in adults.

Cited by 205 publications

References 101 publications

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

CNS macrophages and peripheral myeloid cells in brain tumours

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

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