Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: Spatial distribution and prognostic value of GLUT1 and MCT4

Meijer, T.; Schuurbiers, Olga C.J.; Kaanders, Johannes H.A.M.; Looijen-Salamon, Monika; Geus-Oei, Lioe-Fee de; Verhagen, Ad F. T. M.; Lok, Jasper; Heijden, Erik H F M van der; Rademakers, Saskia E.; Span, Paul N.; Bussink, Johan

doi:10.1016/j.lungcan.2011.11.006

Cited by 100 publications

(115 citation statements)

References 39 publications

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“…Previous results from adenocarcinomas of the lung showed that high MCT4 expression is associated with aggressive tumor behavior (21). In addition, in mouse xenograft models of human colorectal and breast cancer, release of lactate from tumor cells through MCT4 (and not the isoform MCT1) is sufficient to increase tumor growth (22).…”

Section: Discussionmentioning

confidence: 98%

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

Fisel

Kruck

Winter

et al. 2013

Clinical Cancer Research

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Purpose: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts.Experimental Design: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n ¼ 482) and DNA methylation (n ¼ 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n ¼ 64). Promoter activity assays were conducted in four RCC cell lines.Results: MCT4 protein expression was upregulated (P < 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (P < 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR ¼ 0.39; 95% confidence interval (CI), 0. Conclusion:We identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC with first evidence of a biological rationale for prognosis and clinical outcome.

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Section: Discussionmentioning

confidence: 98%

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

Fisel

Kruck

Winter

et al. 2013

Clinical Cancer Research

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“…Because radiation requires oxygen for its cytotoxic effects, cellular metabolism is changed under hypoxic conditions. Via upregulation of hypoxia-inducible factor 1a, change in cellular metabolism under hypoxic conditions leads to increased glycolysis, with subsequent increased demand of glucose leading to upregulation of glucose transporters and eventually increased 18 F-FDG uptake (24)(25)(26). Because a high hypoxia-inducible factor 1a expression in NSCLC is associated with an earlier disease progression (27), we suspect resistance mechanisms to be correlated with less decrease in DTLG.…”

Section: Discussionmentioning

confidence: 99%

¹⁸F-FDG PET Early Response Evaluation of Locally Advanced Non–Small Cell Lung Cancer Treated with Concomitant Chemoradiotherapy

et al. 2013

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The potential of 18 F-FDG PET changes was evaluated for prediction of response to concomitant chemoradiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). Methods: For 28 patients, 18 F-FDG PET was performed before treatment, at the end of the second week of treatment, and at 2 wk and 3 mo after the completion of treatment. Standardized uptake value (SUV), maximum SUV, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained. Early metabolic changes were defined as fractional change (DTLG) when 18 F-FDG PET at the end of the second week was compared with pretreatment 18 F-FDG PET. In-treatment metabolic changes, as measured by serial 18 F-FDG PET, were correlated with standard criteria of response evaluation of solid tumors by means of CT imaging (Response Evaluation Criteria In Solid Tumors 1.1). Parameters were analyzed for stratification in progression-free survival (PFS). Results: When compared with early metabolic nonresponders, a DTLG decrease of 38% or more was associated with a significantly longer PFS (1-y PFS 80% vs. 36%, P 5 0.02). Pretreatment TLG was found to be a prognostic factor for PFS. Conclusion: The degree of change in TLG was predictive for response to concomitant chemoradiotherapy as early as the end of the second week into treatment for patients with locally advanced NSCLC. Pretreatment TLG was prognostic for PFS.

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“…Lactate produced by glycolytic hypoxic tumor cells can be taken up through MCT1 and used as a fuel for mitochondrial oxidation by aerobic tumor cells (89)(90)(91)(92). The use of lactate instead of glucose by oxygenated cells saves glucose for the hypoxic cells to support glycolysis.…”

Section: Tumor Glucose Metabolism and Radioresistancementioning

confidence: 99%

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

Meijer

Kaanders

Span

et al. 2012

Clinical Cancer Research

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Radiotherapy, an important treatment modality in oncology, kills cells through induction of oxidative stress. However, malignant tumors vary in their response to irradiation as a consequence of resistance mechanisms taking place at the molecular level. It is important to understand these mechanisms of radioresistance, as counteracting them may improve the efficacy of radiotherapy. In this review, we describe how the hypoxia-inducible factor 1 (HIF-1) pathway has a profound effect on the response to radiotherapy. The main focus will be on HIF-1-controlled protection of the vasculature postirradiation and on HIF-1 regulation of glycolysis and the pentose phosphate pathway. This aberrant cellular metabolism increases the antioxidant capacity of tumors, thereby countering the oxidative stress caused by irradiation. From the results of translational studies and the first clinical phase I/II trials, it can be concluded that targeting HIF-1 and tumor glucose metabolism at several levels reduces the antioxidant capacity of tumors, affects the tumor microenvironment, and sensitizes various solid tumors to irradiation. Clin Cancer Res; 18(20); 5585-94. Ó2012 AACR.

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Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: Spatial distribution and prognostic value of GLUT1 and MCT4

Cited by 100 publications

References 39 publications

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

¹⁸F-FDG PET Early Response Evaluation of Locally Advanced Non–Small Cell Lung Cancer Treated with Concomitant Chemoradiotherapy

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

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Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: Spatial distribution and prognostic value of GLUT1 and MCT4

Cited by 100 publications

References 39 publications

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

18F-FDG PET Early Response Evaluation of Locally Advanced Non–Small Cell Lung Cancer Treated with Concomitant Chemoradiotherapy

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

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Product

Resources

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¹⁸F-FDG PET Early Response Evaluation of Locally Advanced Non–Small Cell Lung Cancer Treated with Concomitant Chemoradiotherapy