Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice

Zhang, Leying; Alizadeh, Darya; Handel, Michelle Van; Kortylewski, Marcin; Yu, Hua; Badie, Behnam

doi:10.1002/glia.20863

Cited by 174 publications

(142 citation statements)

References 57 publications

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“…5C); this was concentrated in the larger tumors. p-Stat3 is a marker of M2 protumor polarized macrophages (28,33). To determine whether macrophages in our tumors might be M2 polarized, we performed immunofluorescence for Iba1 and p-Stat3 and quantified the number of cells that were Iba1 + and p-Stat3 + .…”

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

confidence: 99%

“…In addition, recent work by Pyonteck et al showed that RCAS PDGFB gliomas have tumor-associated macrophages, and that inhibiting their polarization state can significantly improve survival (30). Several studies demonstrate that p-Stat3 within macrophages polarizes them to a M2 tumorpromoting state (28,33). We show that Ptprd +/− p16 −/− tumors had higher levels of p-Stat3 in macrophages, demonstrating that Ptprd loss can affect p-Stat3 accumulation in the macrophages and may alter the macrophage state.…”

Section: Discussionmentioning

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

confidence: 99%

Section: Discussionmentioning

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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“…В клетках опухолевого микроокружения активность STAT3 значительно повышена, что проявляется гиперэкс-прессией IL-6, IL-10 и снижением экспрессии IL-1 [53]. Блокирование функции STAT3 на мышиных моделях глиом приводило к активации микроглии и торможению опухо-левого роста, что сопровождалось снижением экспрессии IL-10 и СD163 (маркеров иммуносупрессивного М2-фе-нотипа [54]) и других мишеней STAT3 (c-myc, циклин D1, сурвивин, HIF-1 , VEGF).…”

Section: блокирование молекулярных мишеней иммуносупрессии и туморогеunclassified

Tumor microenvironment as a target of malignant gliomas treatment

Borisov¹,

Sakaeva²

2015

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“…In vitro studies on human monocyte-derived macrophages showed that this compound prevented M2 macrophage polarization, as measured by inhibition of CD163 expression and IL-10 secretion (M2 markers); it also augmented glioblastoma cell apoptosis (Fujiwara et al, 2010). In mouse models, a STAT3 inhibitor or small interfering RNA blocked "immunosuppressive polarization"(principally IL-10 and IL-6 secretion) of microglia stimulated by glioma cell supernatant (Zhang et al, 2009). Furthermore, in orthotopic GL261 murine glioma in vivo, intratumoural STAT3 siRNA injection augmented TNF mRNA expression, and prolonged survival (Zhang et al, 2009).…”

Section: Stat3 Inhibitionmentioning

confidence: 99%

“…In mouse models, a STAT3 inhibitor or small interfering RNA blocked "immunosuppressive polarization"(principally IL-10 and IL-6 secretion) of microglia stimulated by glioma cell supernatant (Zhang et al, 2009). Furthermore, in orthotopic GL261 murine glioma in vivo, intratumoural STAT3 siRNA injection augmented TNF mRNA expression, and prolonged survival (Zhang et al, 2009). …”

Section: Stat3 Inhibitionmentioning

confidence: 99%