Gli Activity Correlates with Tumor Grade in Platelet-Derived Growth Factor–Induced Gliomas

Becher, Oren J.; Hambardzumyan, Dolores; Fomchenko, Elena I.; Momota, Hiroyuki; Mainwaring, Lori; Bleau, Anne Marie; Katz, Amanda; Edgar, Mark A.; Kenney, Anna Marie; Cordon‐Cardo, Carlos; Blasberg, Ron G.; Holland, Eric C.

doi:10.1158/0008-5472.can-07-6350

Cited by 166 publications

(157 citation statements)

References 48 publications

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“…Standard PCR procedures were performed with the following reaction buffer: 1 M (NH 4 )2SO 4 tions into neonatal mice were used to introduce DF-1 cells expressing RCAS virus as described previously (44). RCAS-PDGF-HA and RCAS-PDGF-GFP viral expression plasmids were a gift from Eric Holland (Memorial Sloan-Kettering Cancer Center, New York, NY) and have been previously described (20,45). Mice were monitored daily and killed upon demonstration of brain tumor symptoms (hydrocephalus, hunched, or seizure) or at 16 wk of age.…”

Section: Methodsmentioning

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: Methodsmentioning

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.

Self Cite

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“…Such factors could be, for example, short range acting members of the Sonic Hedgehog family or membranebound receptors and ligands of the notch-family, both of which have already been shown to stimulate the growth of braintumors. 5,23 The in vitro system presented here can complement in vivo systems by providing easy experimental access to many parameters of the interaction. Currently, we use our model system to further examine the intricate interactions between endothelial cells and glioma cells that promote growth and therapy resistance of this tumor.…”

Section: Resultsmentioning

confidence: 99%

“…4 One of the major factors that plays an important role in tumor support and that contributes to its therapy resistance is the tumor microenvironment. 5 Thus, it has been speculated that the microenvironment plays a crucial role in sustaining CSCs in tumors. 6,7 A subpopulation of CSCs has also been identified in gliomas and transplanting as little as 100 CD133 1 cells into immune-deficient mice gave rise to tumors that mirrored the original patients' tumors.…”

mentioning

confidence: 99%

Tumor microvasculature supports proliferation and expansion of glioma‐propagating cells

Borovski

Verhoeff

Cate

et al. 2009

Intl Journal of Cancer

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The identification of 'cancer stem cellsÕ (CSC) has shed new light on the potential mechanism of therapy resistance of these tumors. Because these cells appear to be more resistant to conventional treatments, they are thought to drive tumor regrowth after therapy. Therefore, novel therapeutic approaches that target these cells are needed. Tumor cells interact with their microenvironment. It has been reported that close contact between CSCs and tumor microvascular endothelium in GBM is important for CSCs to preserve their undifferentiated state and self-renewal ability. However, our understanding of this interaction is still rudimentary. This is in part due to a lack of suitable in vitro models that accurately represent the in vivo situation. Therefore, we set up a co-culture system consisting of primary brain tumor microvascular endothelial cells (tMVECs) and glioma propagating cells (GPCs) derived from biopsies of GBM patients. We found that tMVECs support the growth of GPCs resulting in higher proliferation rates comparing to GPCs cultured alone. This effect was dependent on direct contact between the 2 cell types. In contrast to GPCs, the FCS-cultured cell line U87 was stimulated by culturing on tMVEC-derived ECM alone, suggesting that both cell types interact different with their microenvironment. Together, these results demonstrate the feasibility and utility of our system to model the interaction of GPCs with their microenvironment. Identification of molecules that mediate this interaction could provide novel targets for directed therapy for GBM. ' 2009 UICC

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“…В эксперименте по культивированию клеток мышиной PDGF-индуцированной глиомы на ростовой среде с сывороткой, работу GLI1 и GLI2 анализировали по репортерной активности люциферазы [57]. При инкубации клеток с Shh люциферазная активность не повышалась, что было расценено авторами как инактивированное состояние сигнального пути HH.…”

Section: изменения сигнального пути Hedgehog при глиомахunclassified

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

et al. 2015

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The review summarizes current knowledge on the Hedgehog signaling pathway, its role in normal embryogenesis and/or initiation and progression of neuro-oncological diseases, especially of high-grade gliomas, the most malignant neuroepithelial tumors. The main proteins forming the Hedgehog signaling pathway include Shh, PTCH1, SMO, HHIP, SUFU and GLI1 isoforms. Effects of other signaling pathways on the family of transcription factors GLI and other proteins are described. The review summarizes modern data about the impact of the Hedgehog signaling pathway on proliferation, migration activity and invasiveness, and also on tumor neoangiogenesis and tumor cell chemoresistance. The role of the Hedgehog signaling pathway in origin of cancer stem cells and epithelial-mesenchymal transition is also analyzed. Some prospects for new anticancer drugs acting on components of the Hedgehog signaling pathway inhibitors are demonstrated.

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Gli Activity Correlates with Tumor Grade in Platelet-Derived Growth Factor–Induced Gliomas

Cited by 166 publications

References 48 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

Tumor microvasculature supports proliferation and expansion of glioma‐propagating cells

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

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