RNA Interference Targeting Transforming Growth Factor-β Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity<b><i>In vivo</i></b>

Friese, Manuel A.; Wischhusen, Jörg; Wick, Wolfgang; Weiler, Markus; Eisele, Günter; Steinle, Alexander; Weller, Michael

doi:10.1158/0008-5472.can-04-1627

Cited by 272 publications

(234 citation statements)

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“…The loss of invasiveness of LNT-229 cells stably expressing small interfering TGF-b 1/2 RNA has been linked to the loss of MMP activity. 23 Appropriate control experiments using antibodies against TGF-b and a MMP inhibitor confirmed that the proinvasive effect of BCL-x L entirely depended on these molecules (Figures 4a and 6b). These data do not differentiate between the necessity for TGF-b 2 in baseline and BCL-x L -induced invasiveness.…”

Section: Discussionmentioning

confidence: 68%

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

et al. 2005

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Conditionally BCL-x L -overexpressing LNT-229 Tet-On glioma cell clones were generated to investigate whether the 'antiapoptosis phenotype' and the 'motility phenotype' mediated by BCL-2 family proteins in glioma cells could be separated. BCL-x L induction led to an immediate and concentration-dependent protection of LNT-229 cells from apoptosis. BCL-x L induction for up to 3 days did not result in altered invasiveness. In contrast, long-term BCL-x L induction for 21 days resulted in increased transforming growth factorb 2 expression, and in metalloproteinase-2 and -14 dependent, but integrin independent, increased invasiveness. Withdrawal of doxycycline (Dox) abolished the protection from apoptosis whereas the 'invasion phenotype' remained stable. Dox stimulation of BCL-x L -inducible LNT-229 cells conferred infiltrative growth to BCL-x L -positive glioma cells in vivo and reduced the survival of tumor-bearing mice. These data allow to dissect a direct antiapoptotic action of BCL-x L from an indirect effect, presumably mediated by altered gene expression, which modifies tumor cell invasiveness in vitro and in vivo.

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Section: Discussionmentioning

confidence: 68%

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

et al. 2005

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“…Excessive proliferation, diffuse infiltration of surrounding brain tissue, and suppression of antitumor immune surveillance contribute to the malignant phenotype of gliomas (Weller and Fontana, 1995). Silencing of TGF-b expression by small interfering RNA (siRNA) technology has been reported to abrogate glioma cell tumorigenicity in vivo (Friese et al, 2004).…”

Section: Tgf-b and Neural Stem Cells (Nscs)mentioning

confidence: 99%

TGF-β, Neuronal Stem Cells and Glioblastoma

Golestaneh

Mishra

2005

Oncogene

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Transforming growth factor beta (TGF-b) signaling leads to a number of biological end points involving cell growth, differentiation, and morphogenesis. Typically, the cellular effect accompanies an induction of mesodermal cell fate and inhibition of neural cell differentiation. However, during pathological conditions, these defined effects of TGF-b can be reversed; for example, the growthinhibitory effect is replaced with its tumor promoting ability. A multitude of factors and cross-signaling pathways have been reported to be involved in modulating the dual effects of TGF-b. In this review, we focus on the potential role of TGF-b signal transduction during development of neural progenitor cells and its relation to glioblastoma development from neural stem cells.

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“…9 Recent NKG2D regulation studies showed that many cytokines influence NKG2D expression on CD8 C T and NK cells, including the NKG2D-promoting cytokines interleukin (IL)-2, IL-7, and IL-12 [10][11][12] ; the NKG2D-suppressing cytokines IL-4 and transforming growth factor-b; and interferon-g, at high levels. 13,14 However, the mechanisms of NKG2D regulation on CD8 C T cells remain poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Batth

Xia

et al. 2016

OncoImmunology

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The natural killer (NK) group 2D (NKG2D) receptor, which displays on mouse and human NK cells, activates CD8 C T cells and small subsets of other T cells. NKG2D C CD8 C T cells play critical roles in both innate and adaptive immunity upon engagement with NKG2D ligands to eliminate tumor and infected cells. Despite the important role of NKG2D C CD8 C T cells in immune surveillance, the mechanisms of how NKG2D expression on CD8 C T cells is regulated remain poorly defined. We treated mouse and human CD8 C T cells with CD80 recombinant protein, plus a pharmacologic model with small molecular inhibitors to determine which signaling pathway leads to NKG2D regulation on CD8 C T cells. This study revealed that CD28 activation gives rise to sustained NKG2D expression on both mouse and human CD8 C T cells in a signal transducer and activator of transcription 3 (STAT3) phosphorylation-dependent manner. Further, we found that CD28 activation stimulated sustained activation of the tyrosine kinase Lck, which recruits and triggers Janus kinase/STAT3 signaling to phosphorylate STAT3, and in turn increases NKG2D expression. Moreover, NKG2D induction on CD8 C T cells exerts cytolytic activity against target tumor cells in vitro, as well as significantly improves the antitumor therapeutic effects in vivo in an NKG2D-dependent manner. Taken together, these results elucidated a novel mechanism of NKG2D regulation by phosphorylated STAT3 (pSTAT3) on CD8 C T cells upon CD28 activation. This mechanism may shed light on the effectiveness of CD80-based, NKG2D-dependent antitumor immunotherapy.

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RNA Interference Targeting Transforming Growth Factor-β Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates TumorigenicityIn vivo

Abstract: ABSTRACT

Cited by 272 publications

References 43 publications

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

TGF-β, Neuronal Stem Cells and Glioblastoma

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

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RNA Interference Targeting Transforming Growth Factor-β Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates TumorigenicityIn vivo

Abstract: ABSTRACT

Cited by 272 publications

References 43 publications

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

TGF-β, Neuronal Stem Cells and Glioblastoma

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

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Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism