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Yin, J.; Oh, Y.T.; Kim, J.-Y.; Kim, S.S.; Choi, E.; Kim, T.H.; Hong, J.H.; Chang, N.; Cho, H.J.; Sa, J.K.; Kim, J.C.; Kwon, H.J.; Park, S.; Lin, W.; Nakano, I.; Gwak, H.-S.; Yoo, H.; Lee, S.-H.; Lee, J.; Kim, J.H.; Kim, S.-Y.; Nam, D.-H.; Park, M.-J.; Park, J.B. |
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Title |
Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPbeta Signaling |
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Journal Article |
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Year |
2017 |
Publication |
Cancer Research |
Abbreviated Journal |
Cancer Res |
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Volume |
77 |
Issue |
18 |
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4973-4984 |
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Abstract |
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPbeta, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-kappaB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPbeta expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. (c)2017 AACR. |
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Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea |
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0008-5472 |
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PMID:28754668 |
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ref @ user @ |
Serial |
96575 |
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Author |
Voss, D.M.; Spina, R.; Carter, D.L.; Lim, K.S.; Jeffery, C.J.; Bar, E.E. |
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Title |
Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression |
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Journal Article |
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Year |
2017 |
Publication |
Scientific Reports |
Abbreviated Journal |
Sci Rep |
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Volume |
7 |
Issue |
1 |
Pages |
4292 |
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Abstract |
We have previously shown that glioblastoma stem cells (GSCs) are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter-4 (MCT4) is critical for mediating GSC signaling in hypoxia. Basigin is involved in many physiological functions during early stages of development and in cancer and is required for functional plasma membrane expression of MCT4. We sought to determine if disruption of the MCT-Basigin interaction may be achieved with a small molecule. Using a cell-based drug-screening assay, we identified Acriflavine (ACF), a small molecule that inhibits the binding between Basigin and MCT4. Surface plasmon resonance and cellular thermal-shift-assays confirmed ACF binding to basigin in vitro and in live glioblastoma cells, respectively. ACF significantly inhibited growth and self-renewal potential of several glioblastoma neurosphere lines in vitro, and this activity was further augmented by hypoxia. Finally, treatment of mice bearing GSC-derived xenografts resulted in significant inhibition of tumor progression in early and late-stage disease. ACF treatment inhibited intratumoral expression of VEGF and tumor vascularization. Our work serves as a proof-of-concept as it shows, for the first time, that disruption of MCT binding to their chaperon, Basigin, may be an effective approach to target GSC and to inhibit angiogenesis and tumor progression. |
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Department of Neurological Surgery, Case Western Reserve University School of Medicine and The Case Comprehensive Cancer Center, Cleveland, OH, USA. eli.bar@case.edu |
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2045-2322 |
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PMID:28655889 |
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ref @ user @ |
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96580 |
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Yan, H.; Romero-Lopez, M.; Benitez, L.I.; Di, K.; Frieboes, H.B.; Hughes, C.C.W.; Bota, D.A.; Lowengrub, J.S. |
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Title |
3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy |
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Journal Article |
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Year |
2017 |
Publication |
Cancer Research |
Abbreviated Journal |
Cancer Res |
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Volume |
77 |
Issue |
15 |
Pages |
4171-4184 |
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Keywords |
Brain Neoplasms/*pathology; Cell Transdifferentiation/physiology; Endothelial Cells/*pathology; Glioblastoma/*pathology; Humans; *Models, Theoretical; Neoplastic Stem Cells/*pathology |
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Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, cross-talk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Furthermore, GSC also transdifferentiate into bona fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional antiangiogenic therapies. Here we use three-dimensional mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSCs drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with antiangiogenic therapies reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSCs and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GECs maintain GSCs. Our study suggests that a combinatorial regimen targeting the vasculature, GSCs, and GECs, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. Cancer Res; 77(15); 4171-84. (c)2017 AACR. |
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Center for Complex Biological Systems, University of California, Irvine, California |
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0008-5472 |
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PMID:28536277 |
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ref @ user @ |
Serial |
96585 |
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Author |
Godin, K.M.; Chacon, V.; Barnoya, J.; Leatherdale, S.T. |
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Title |
The school environment and sugar-sweetened beverage consumption among Guatemalan adolescents |
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Journal Article |
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Year |
2017 |
Publication |
Public Health Nutrition |
Abbreviated Journal |
Public Health Nutr |
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20 |
Issue |
16 |
Pages |
2980-2987 |
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Keywords |
Latin America; Nutrition policy; School health; Sugar-sweetened beverages |
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Abstract |
OBJECTIVE: The current study sought to examine Guatemalan adolescents' consumption of sugar-sweetened beverages (SSB), identify which individual-level characteristics are associated with SSB consumption and describe school characteristics that may influence students' SSB consumption. DESIGN: Within this observational pilot study, a questionnaire was used to assess students' consumption of three varieties of SSB (soft drinks, energy drinks, sweetened coffees/teas), as well as a variety of sociodemographic and behavioural characteristics. We collected built environment data to examine aspects of the school food environment. We developed Poisson regression models for each SSB variety and used descriptive analyses to characterize the sample. SETTING: Guatemala City, Guatemala. SUBJECTS: Guatemalan adolescents (n 1042) from four (two public, two private) secondary schools. RESULTS: Built environment data revealed that students from the two public schools lacked access to water fountains/coolers. The SSB industry had a presence in the schools through advertisements, sponsored food kiosks and products available for sale. Common correlates of SSB consumption included school type, sedentary behaviour, frequency of purchasing lunch in the cafeteria, and frequency of purchasing snacks from vending machines in school and off school property. CONCLUSIONS: Guatemalan adolescents frequently consume SSB, which may be encouraged by aspects of the school environment. Schools represent a viable setting for equitable population health interventions designed to reduce SSB consumption, including increasing access to clean drinking-water, reducing access to SSB, restricting SSB marketing and greater enforcement of existing food policies. |
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1School of Public Health and Health Systems,University of Waterloo, 200 University Avenue West,Waterloo,ON,Canada,N2L 3G1 |
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1368-9800 |
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PMID:28803573 |
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ref @ user @ |
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97159 |
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Author |
Godin, K.M.; Chacon, V.; Barnoya, J.; Leatherdale, S.T. |
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Title |
The school environment and sugar-sweetened beverage consumption among Guatemalan adolescents |
Type |
Journal Article |
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Year |
2017 |
Publication |
Public Health Nutrition |
Abbreviated Journal |
Public Health Nutr |
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Volume |
20 |
Issue |
16 |
Pages |
2980-2987 |
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Keywords |
Latin America; Nutrition policy; School health; Sugar-sweetened beverages |
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Abstract |
OBJECTIVE: The current study sought to examine Guatemalan adolescents' consumption of sugar-sweetened beverages (SSB), identify which individual-level characteristics are associated with SSB consumption and describe school characteristics that may influence students' SSB consumption. DESIGN: Within this observational pilot study, a questionnaire was used to assess students' consumption of three varieties of SSB (soft drinks, energy drinks, sweetened coffees/teas), as well as a variety of sociodemographic and behavioural characteristics. We collected built environment data to examine aspects of the school food environment. We developed Poisson regression models for each SSB variety and used descriptive analyses to characterize the sample. SETTING: Guatemala City, Guatemala. SUBJECTS: Guatemalan adolescents (n 1042) from four (two public, two private) secondary schools. RESULTS: Built environment data revealed that students from the two public schools lacked access to water fountains/coolers. The SSB industry had a presence in the schools through advertisements, sponsored food kiosks and products available for sale. Common correlates of SSB consumption included school type, sedentary behaviour, frequency of purchasing lunch in the cafeteria, and frequency of purchasing snacks from vending machines in school and off school property. CONCLUSIONS: Guatemalan adolescents frequently consume SSB, which may be encouraged by aspects of the school environment. Schools represent a viable setting for equitable population health interventions designed to reduce SSB consumption, including increasing access to clean drinking-water, reducing access to SSB, restricting SSB marketing and greater enforcement of existing food policies. |
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1School of Public Health and Health Systems,University of Waterloo, 200 University Avenue West,Waterloo,ON,Canada,N2L 3G1 |
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1368-9800 |
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PMID:28803573 |
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ref @ user @ |
Serial |
97261 |
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