Metabonomic profiling of renal cell carcinoma: High-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis

Gao, Hongchang; Dong, Baijun; Liu, Xia; Xuan, Hanqing; Huang, Yiran; Lin, Donghai

doi:10.1016/j.aca.2008.06.051

Cited by 119 publications

(114 citation statements)

References 38 publications

(42 reference statements)

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“…Accordingly, Gao and coauthors described elevated levels of LDH and lactate in the serum of RCC patients. 20 We have demonstrated that lactate, the end product of glycolysis, inhibits the maturation of human dendritic cells 22 and impairs the activation and proliferation of CD8 þ T cells. Furthermore, high lactate concentration leads to induction of apoptosis in CD8 þ T cells.…”

Section: Tumor Immunologymentioning

confidence: 98%

“…17 Proteomic analysis of tumor tissues 18,19 and metabolic profiling of serum samples revealed a ''Warburg phenotype'' in RCC with increased levels of glycolytic enzymes in tumor lesions and higher levels of the glycolysis end product lactate in the serum of RCC patients. 20 We have demonstrated that lactate can suppress effector functions of human cytotoxic T cells 21 as well as maturation of dendritic cells 22 in vitro. Since RCC represents a highly immunogenic tumor the glycolytic switch of RCC cells might influence the antitumor immune response in tumor patients and the high glucose turnover by tumor cells could alter T cell activation.…”

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confidence: 99%

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Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Singer

Kastenberger

Gottfried³

et al. 2011

Intl Journal of Cancer

137

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Many tumor cells are characterized by a dysregulated glucose metabolism associated with increased glycolysis in the presence of oxygen (''Warburg Effect''). Here, we analyzed for the first time a possible link between glucose metabolism and immune cell infiltration in renal cell carcinoma (RCC). RCC specimens revealed a highly significant increase in the expression of lactate dehydrogenase A (LDHA) and glucose-transporter 1 (GLUT-1) compared to the corresponding normal kidney tissue on mRNA level. Accordingly, tumor cell lines of different origin such as RCC, melanoma and hepatocellular carcinoma strongly expressed LDHA and GLUT-1 compared to their nonmalignant counterparts. In line with this finding, tumor cells secreted high amounts of lactate. High expression of GLUT-1 and LDH5, a tetramer of 4 LDHA subunits, was confirmed by tissue microarray analysis of 249 RCC specimens. Overall, 55/79 (69.6%) and 46/71 (64.7%) cases of clear cell carcinoma showed a constitutive, but heterogeneous expression of GLUT-1 and LDH5, respectively. The number of CD3 1 , CD8 1 and FOXP3 1 T cells was significantly elevated in RCC lesions compared to normal kidney epithelium, but effector molecules such as granzyme B and perforin were decreased in tumor infiltrating T cells. Of interest, further analysis revealed an inverse correlation between GLUT-1 expression and the number of CD8 1 T cells in RCC lesions. Together, our data suggest that an accelerated glucose metabolism in RCC tissue is associated with a low infiltration of CD8 1 effector T cells. Targeting the glucose metabolism may represent an interesting tool to improve the efficacy of specific immunotherapeutic approaches in RCC.Renal cell carcinoma (RCC) constitutes 2-3% of all malignant tumors in adults. It is a very heterogeneous malignancy, which is subdivided in different histological subtypes. The most common type of RCC is clear cell carcinoma with an incidence of 75% whereas the papillary (10-15%) and the chromophobe subtypes (5%) are less frequent. 1,2 Clear cell carcinoma arises from cells of the proximal tubule and is characterized by a clear cytoplasm, which stores glycogen. It is associated with a large number of gene mutations most notably in the von Hippel Lindau (VHL) gene. 3,4 The VHL protein is crucially involved in the regulation of the hypoxia inducible transcription factor HIF1. In the absence of VHL, HIF is stabilized and induces the expression of proteins that are involved in angiogenesis and glucose metabolism, e.g., vascular endothelial growth factor (VEGF), erythropoietin and glucose-transporter 1 (GLUT-1). 5,6 Overexpression of GLUT-1 has been described in different malignancies 7-9 and polymorphisms of GLUT-1 seems to be associated with clear cell carcinoma. 10 Beside HIF stabilization through loss of the tumor suppressor gene VHL or hypoxia, oncogenic transformation, caused by loss of p53, 11,12 mutation of KRAS/BRAF 13 or c-myc overexpression 14 reduces respiration accompanied by an upregulation of glycolytic enzymes such as lactate dehydrogena...

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Section: Tumor Immunologymentioning

confidence: 98%

mentioning

confidence: 99%

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Singer

Kastenberger

Gottfried³

et al. 2011

Intl Journal of Cancer

137

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“…[23][24][25] Comprehensive metabolic profiles have been generated from biofluids including urine, serum, bile and intact tissue. 24,[26][27][28][29][30][31][32] …”

Section: In Vitro Metabolic Profilingmentioning

confidence: 99%

Magnetic Resonance Spectroscopy: Principles and Techniques: Lessons for Clinicians

Tognarelli

Dawood

Shariff

et al. 2015

Journal of Clinical and Experimental Hepatology

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Magnetic resonance spectroscopy (MRS) provides a non-invasive 'window' on biochemical processes within the body. Its use is no longer restricted to the field of research, with applications in clinical practice increasingly common. MRS can be conducted at high magnetic field strengths (typically 11-14 T) on body fluids, cell extracts and tissue samples, with new developments in whole-body magnetic resonance imaging (MRI) allowing clinical MRS at the end of a standard MRI examination, obtaining functional information in addition to anatomical information. We discuss the background physics the busy clinician needs to know before considering using the technique as an investigative tool. Some potential applications of hepatic and cerebral MRS in chronic liver disease are also discussed. ( J CLIN EXP HEPATOL 2015;5:320-328) T he biomedical applications of nuclear magnetic resonance (NMR) are twofold: magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). The applications of MRS as a research tool are extremely diverse, encompassing studies on isolated cells, body fluids and perfused organs at high magnetic field strengths in an experimental, laboratory-based setting and also in vivo studies using clinical MR systems. 1 In vivo clinical MRS on whole-body MRI scanners has been used to study the metabolism of well-defined regions of the human body, affording a non-invasive 'metabolic window' on a wide range of biochemical processes in the body, including the composition and function of human organs in vivo. 2 Clinical MRS developments have exploited many of the advances in MRI at the magnetic field strengths now used (typically 1.5-3.0 T) and the use of magnetic field gradients. The sensitivity and spatial resolution of MRS is a limiting factor in vivo, but parallel utilisation of in vitro MR spectroscopy of tissue extracts, body fluids and cell lines at much higher magnetic field strengths (typically 11.7-14.1 T) allows more definitive interpretation of the in vivo data. In this article, we aim to equip the clinician with knowledge of the background physics involved in MRS, so that informed decisions can be made for research studies. NUCLEAR MRSNMR refers to the behaviour of atoms subjected to a magnetic field. The phenomenon was first described in 1946 by Bloch and Purcell. Atoms with an odd mass number such as 1 H, 31 P and 13 C possess the quantum property of ''spin'' and behave as dipoles aligning along the axis of an applied magnetic field (Figure 1). During relaxation following excitation, radiofrequency signals are generated which can be expressed as a frequency spectrum. Hydrogen is the most abundant atom in living organisms and using high power magnetic fields on in vitro samples, high resolution metabolic spectra can be obtained with clearly defined metabolite peaks of small molecules (<2 kDa). NUCLEAR SPIN AND ORIENTATIONSNuclear resonance occurs because the nuclei of at least one of the isotopes of most elements possess a magnetic moment. A magnetic moment arises because the nucleus m...

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“…4 Metabolomics, as a combination of spectroscopic measurement of biological samples with multivariate data analysis, has been employed extensively to address the diagnosis and evaluation of cancer patients, and to identify potential biomarkers. [5][6][7][8] Another related term "metabonomics" was initially defined as "the quantitative measurement of the multi-parametric metabolic response of living systems to pathophysiological stimuli or genetic modifications". 9 The definition of metabolomics is evolving rapidly towards its "brother"-metabonomics.…”

Section: Introductionmentioning

confidence: 99%

NMR-based Metabolomic Analysis of Human Bladder Cancer

et al. 2012

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Metabonomic profiling of renal cell carcinoma: High-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis

Cited by 119 publications

References 38 publications

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Magnetic Resonance Spectroscopy: Principles and Techniques: Lessons for Clinicians

NMR-based Metabolomic Analysis of Human Bladder Cancer

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Metabonomic profiling of renal cell carcinoma: High-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis

Cited by 119 publications

References 38 publications

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8+ T‐cell infiltration in the tumor

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8+ T‐cell infiltration in the tumor

Magnetic Resonance Spectroscopy: Principles and Techniques: Lessons for Clinicians

NMR-based Metabolomic Analysis of Human Bladder Cancer

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Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor