TGF-β Increases Glioma-Initiating Cell Self-Renewal through the Induction of LIF in Human Glioblastoma

Peñuelas, Silvia; Anido, Judit; Prieto-Sánchez, Rosa M.; Folch, Gerard; Barba, Ignasi; Cuartas, Isabel; Garcı́a-Dorado, David; Poca, María A.; Sahuquillo, Juan; Baselga, José; Seoane, Joan

doi:10.1016/j.ccr.2009.02.011

Cited by 491 publications

(457 citation statements)

References 51 publications

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“…As TGF-b suppressed the expression of ABCG2 in other types of cancer cells (Figure 4), it is possible that the percentages of CICs in other types of cancers are also decreased by TGF-b. However, contrary to the present findings for diffuse-type gastric carcinomas, TGF-b was reported to maintain the 'stemness' of glioblastoma-initiating cells (Ikushima et al, 2009;Pen˜uelas et al, 2009). TGF-b also maintains the stem-cell-like properties of leukemiainitiating cells in chronic myeloid leukemia through regulation of AKT activation and FOXO3a localization (Naka et al, 2010).…”

Section: Reduction Of Sp Cells In Gastric Cancer By Tgf-b S Ehata Et Alcontrasting

confidence: 99%

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

et al. 2010

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Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-b (TGF-b) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-b repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-b, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-b negatively contributes to maintain the CICs within the cancer.

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Section: Reduction Of Sp Cells In Gastric Cancer By Tgf-b S Ehata Et Alcontrasting

confidence: 99%

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

et al. 2010

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“…7C ). This is in agreement with our previous work in which we showed that TGFβ regulates the ability of neurospheres to initiate tumors ( 3,4 ) and, moreover, the two selected models respond to TGFβ receptor inhibitors (unpublished observations), indicating that in those two tumors the regulation of the TGFβ activity is relevant for cancer progression.…”

Section: Creb1 Regulates the Levels Of Tgfb2 In Patient-derived Xenogsupporting

confidence: 81%

“…A potent immune suppressor, TGFβ at high levels facilitates tumor growth through the inhibition of the anticancer immune response. On the other hand, TGFβ has been shown to promote proliferation, angiogenesis, and invasion through the induction of metalloproteases, to enhance the self-renewal of cancer-initiating cells (CIC), and to mediate metastasis due in part to the induction of an epithelial-to-mesenchymal transition (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

Rodón¹,

Gonzàlez-Juncà²,

Inda³

et al. 2014

Cancer Discovery

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In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identifi ed cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. SIGNIFICANCE:TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. Cancer Discov; 4(10); 1230-41.

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“…In addition, gp130 can be activated by ligands such as IL-6 or leukemia inhibitory factor (LIF), and is crucial for signal transductions in multiple stem cells, including ES and cancer stem cells. [37][38][39] In GSCs, gp130 is critical for the maintenance of the stem celllike phenotype of GSCs (Figures 2f and g). As our study demonstrated that CD9 stabilized gp130 expression, we speculate that CD9 could also affect LIF-stimulated gp130 downstream signal transduction, which warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

et al. 2016

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Glioblastoma (GBM) is the most malignant and lethal brain tumor harboring glioma stem cells (GSCs) that promote tumor propagation and therapeutic resistance. GSCs preferentially express several critical cell surface molecules that regulate the prosurvival signaling for maintaining the stem cell-like phenotype. Tetraspanin CD9 has recently been reported as a GSC biomarker that is relevant to the GSC maintenance. However, the underlying molecular mechanisms of CD9 in maintaining GSC property remain elusive. Herein, we report that CD9 stabilizes the IL-6 receptor glycoprotein 130 (gp130) by preventing its ubiquitindependent lysosomal degradation to facilitate the STAT3 activation in GSCs. CD9 is preferentially expressed in GSCs of human GBM tumors. Mass spectrometry analysis identified gp130 as an interacting protein of CD9 in GSCs, which was confirmed by immunoprecipitation and immunofluorescent analyses. Disrupting CD9 or gp130 by shRNA significantly inhibited the self-renewal and promoted the differentiation of GSCs. Moreover, CD9 disruption markedly reduced gp130 protein levels and STAT3 activating phosphorylation in GSCs. CD9 stabilized gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote the BMX-STAT3 signaling in GSCs. Importantly, targeting CD9 potently inhibited GSC tumor growth in vivo, while ectopic expression of the constitutively activated STAT3 (STAT3-C) restored the tumor growth impaired by CD9 disruption. Collectively, we uncovered a critical regulatory mechanism mediated by tetraspanin CD9 to maintain the stem cell-like property and tumorigenic potential of GSCs.

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TGF-β Increases Glioma-Initiating Cell Self-Renewal through the Induction of LIF in Human Glioblastoma

Cited by 491 publications

References 51 publications

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

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