Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth

Daginakatte, Girish; Gutmann, David H.

doi:10.1093/hmg/ddm059

Cited by 171 publications

(173 citation statements)

References 62 publications

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“…More specifically, Ptprd +/− p16 −/− tumors had activated genes involved in up-regulation of several chemokines, all of which promote M2 polarization (23)(24)(25)(26). Macrophages can enhance tumor cell survival by promoting tumor growth, invasion, or immunosuppression (27)(28)(29)(38)(39)(40). 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).…”

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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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: 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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“…Results from in vitro studies support the idea that microglia can promote tumor invasion and growth (Bettinger et al, 2002;Markovic et al, 2005). Perhaps the most convincing evidence of the importance of microglia to glioma formation is from in vivo studies that have shown that tumor cell growth is inhibited in microglia-deficient glioma mouse models (Daginakatte and Gutmann, 2007;Markovic et al, 2009). These findings suggest that therapies that target glioma-associated microglia may be promising antitumor agents.…”

Section: Microgliamentioning

confidence: 85%

“…There are several cell types that make up the tumor stroma and can contribute to the biology of glioma to include astrocytes, endothelial cells, pericytes and cells involved in the immune response (that is, microglia and T-lymphocytes; Daginakatte and Gutmann, 2007;Charles et al, 2011). The tumor microenvironment is enriched with soluble factors secreted by these cells.…”

Section: Glioblastomas Are Molecularly Heterogeneous Tumorsmentioning

confidence: 99%

Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

Jones

Holland

2011

Oncogene

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“…The cells that mainly contribute to the supportive effect of the glioma microenvironment on glioma progression are tumor-associated microglia/macrophages (TMMs) [5][6][7][8] .…”

Section: Research Highlightmentioning

confidence: 99%

“…It is now well established that the tumor microenvironment supports glioma progression [6][7][8][9][10][11] . Thus the ineffectiveness of the current treatments may result, at least in part, from their inability to suppress the tumor microenvironment's supportive effect.…”

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confidence: 99%

Targeting CD38 in the tumor microenvironment; a novel approach to treat glioma

Blacher¹,

Levy²,

Baruch³

et al. 2015

Can Cell Microenviron

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Glioblastoma multiforme (GBM) is one of the most lethal human cancers, accounting for about 15% of all primary brain tumors in adults. Tumor-associated microglia/macrophages (TMMs) are a major constituent of the tumor mass and the tumor microenvironment where they support tumor progression. We previously demonstrated that the NAD + utilizing ectoenzyme CD38 regulates microglia activation and that loss of CD38 inhibits glioma progression and extends the survival of glioma-bearing mice. These results indicated that targeting CD38 in the tumor microenvironment may serve as a novel therapeutic approach to treat glioma. To test this hypothesis, we identified small molecules that inhibit CD38 enzymatic activity (NAD + glycohydrolase): the natural anthranoid rhein, its water-soluble tri-potassium salt (K-rhein), and the polyphenol tannic acid (TA). Microglial properties regulated by CD38 (e.g., NO secretion and LPS/IFN activation induced cell death) were inhibited in primary microglia treated with rhein in a CD38-dependent manner. Furthermore, wild-type mice intracranially injected with GL261 mouse glioma cells and intranasally treated with K-rhein or TA, exhibited significant reduction in tumor volume and prolonged life-span compared to vehicle treated mice. On the other hand, these inhibitors had only a modest effect on tumor-bearing Cd38 / mice. Taken together, our results demonstrate that small molecule CD38 inhibitors such as K-rhein and TA can target CD38 in the tumor microenvironment and offer a novel and useful strategy for glioma treatment.

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Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth

Cited by 171 publications

References 62 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

Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

Targeting CD38 in the tumor microenvironment; a novel approach to treat glioma

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