GLUT-1 Expression in Pancreatic Neoplasia

Basturk, Olca; Singh, Vikram; Kaygusuz, Ecmel; Balcı, Serdar; Dursun, Nevra; Çulhacı, Nil; Adsay, Volkan

doi:10.1097/mpa.0b013e318201c935

Cited by 72 publications

(47 citation statements)

References 33 publications

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“…Increased GLUT-1 expression is also associated with pancreatic cancer invasiveness, where forced overexpression of GLUT-1 induced increased matrix metalloproteinase-2 (MMP-2) expression and activity, along with cellular invasiveness, while GLUT-1 silencing created reductions in MMP-2 expression and activity, cellular invasiveness, and metastatic potential in vivo [6]. GLUT-1 expression has also been found to be related to histological grade and tumor size of ductal adenocarcinomas, with progressive increases in GLUT-1 expression from low- to high-grade adenocarcinomas; however, these results did not reach statistical significance with regard to overall survival [7]. All stages of tumors were evaluated as well, with significant GLUT-1 expression in all stages but stage IV (autopsy cases, 0/2), likely due to the limited stage IV cases available in this study.…”

Section: Discussionmentioning

confidence: 99%

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Increased Expression of the Glucose Transporter Type 1 Gene Is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma

et al. 2016

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Objectives There is currently no reliable method to predict the risk of relapse after curative resection of early-stage pancreatic adenocarcinoma. Increased glucose metabolism observed on 18F-fluorodeoxyglucose positron emission tomography (PET) by malignant cells, the Warburg effect, is a well-known characteristic of the malignant phenotype. We investigated the role of glucose transporter type 1 (GLUT-1) gene expression, a glucose cell plasma membrane transporter, in early-stage pancreatic cancer. Methods Associations between GLUT-1 gene expression with PET maximum standardized uptake values (SUVmax) and histologic grade were investigated in early-stage pancreatic adenocarcinoma patients. Multivariate analysis was conducted to determine predictors of prognosis. Cox proportional hazards model was used for survival analysis. Results Sixty-three patients had GLUT-1 gene analysis performed, and 50 patients had both GLUT-1 analysis and PET scan. Patients with high GLUT-1 gene expression had a decreased overall survival by univariate analysis using Cox proportional hazards model (HR=2.82, p=0.001) and remained significant on multivariate analysis (HR=2.54, p=0.03). There was no correlation of GLUT-1 gene expression with histologic grade or PET SUVmax. Conclusion Increased GLUT-1 gene expression was associated with a decreased overall survival in pancreatic adenocarcinoma. This supports increased GLUT-1 gene expression as a potential prognostic marker in resected pancreatic adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

“…GLUT-1 expression has been demonstrated to be associated with pancreatic cancer invasiveness and increasing histologic grade. However, only a few prognostic studies on GLUT-1 expression with pancreatic cancer have been performed to date and were conducted using just immunohistochemistry [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Increased Expression of the Glucose Transporter Type 1 Gene Is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma

et al. 2016

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“…Specificity of the anti-CHD7 antibody was validated by western blot analysis following siRNA silencing (Fig 2B). An expression score was calculated using a previously defined scoring system (23, 27). Overall score was dichotomized into low (<3.1) and high (>3.1) expression groups for this analysis (Supplemental Fig S1).…”

Section: Methodsmentioning

confidence: 99%

CHD7 Expression Predicts Survival Outcomes in Patients with Resected Pancreatic Cancer

et al. 2014

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Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to utilize a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes including 55 genes linked to DNA damage responses (DDR) that demonstrated gemcitabine sensitization when silenced, including CHD7 which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 resected PDAC patients receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment.

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“…The glycolytic shift in cancer cells is regulated by aberrant cell signaling that is itself driven by signaling via growth factor receptors, activation of oncogenes, and environmental factors. The observed overexpression of glucose transporters (Glut) and 18 F-fluorodeoxyglucose accumulation on nuclear imaging studies provide evidence for preferential glucose utilization in pancreatic ductal adenocarcinoma (PDAC) (17–19). No studies to date, however, have linked exposure of PDAC cells to extracellular lumican with intracellular regulation of glycolysis.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Lumican Inhibits Pancreatic Cancer Cell Growth and Is Associated with Prolonged Survival after Surgery

Truty

Kang

et al. 2014

Clinical Cancer Research

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Purpose To evaluate the relevance between lumican expression patterns and the clinical course of PDAC patients, and to investigate the role of lumican in PDAC progression. Experimental Design 131 patient tumors were chosen for tissue microarray staining and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and HIF-1α and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. Results Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and three-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF-1α expression and activity via Akt. PDAC cells with enhanced HIF-1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. Conclusions There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.

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GLUT-1 Expression in Pancreatic Neoplasia

Cited by 72 publications

References 33 publications

Increased Expression of the Glucose Transporter Type 1 Gene Is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma

Increased Expression of the Glucose Transporter Type 1 Gene Is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma

CHD7 Expression Predicts Survival Outcomes in Patients with Resected Pancreatic Cancer

Extracellular Lumican Inhibits Pancreatic Cancer Cell Growth and Is Associated with Prolonged Survival after Surgery

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