Proteomic changes in renal cancer and co‐ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect

Unwin, Richard D.; Craven, Rachel A.; Harnden, Patricia; Hanrahan, Sarah; Totty, Nick; Knowles, Margaret A.; Eardley, Ian; Selby, Peter J.; Banks, Rosamonde E.

doi:10.1002/pmic.200300464

Cited by 220 publications

(187 citation statements)

References 67 publications

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“…Their results showed a drop in the β-F1-ATPase/Hsp60 ratio concurrent with an upregulation of the glyceraldehyde-3-phosphate dehydrogenase potential in most common human tumors [72]. These and other observations indicate that the bioenergetic capacity of tumor cells is largely defective [87][88][89]. Viewed collectively, the bulk of the experimental evidence indicates that mitochondria structure and function is abnormal in cancer cells.…”

Section: Mitochondrial Dysfunction In Cancer Cellsmentioning

confidence: 92%

Cancer as a Metabolic Disease

Seyfried¹

2012

192

291

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Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.

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Section: Mitochondrial Dysfunction In Cancer Cellsmentioning

confidence: 92%

Cancer as a Metabolic Disease

Seyfried¹

2012

192

291

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“…In a proteomic approach, Unwin et al also reported on upregulation of the LDHA isoenzyme and other enzymes involved in glycolysis such as aldolase, pyruvat kinase M2 or glycerinaldehyd-3-phosphate dehydrogenase. 18 These data indicate a global shift from respiration to glycolysis in RCC. Accordingly, Gao and coauthors described elevated levels of LDH and lactate in the serum of RCC patients.…”

Section: Tumor Immunologymentioning

confidence: 93%

“…15,16 Recently, van der Heiden and coauthors proposed that highly proliferating cells switch to glycolysis as mitochondria are needed to supply components for the generation of nucleotides and lipids for new cell structures. 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.…”

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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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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“…The spontaneous overexpression of cofilin has been detected in the invasive subpopulation of tumour cells in mammary tumours of rats 10 . Furthermore, increased levels of cofilin expression is detected in clinical tumour samples of oral squamous-cell carcinoma 76 , renal cell carcinoma 77 and ovarian cancer 78 using proteomic and cDNA microarray approaches. Expression of the wild-type or the non-phosphorylatable cofilin mutant S3A increases melanoma cell invasion through a reconstituted basement membrane 56 .…”

Section: The Cofilin Pathway In Tumour Invasionmentioning

confidence: 99%

The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.Tumour cell motility is the hallmark of invasion and an essential step in metastasis 1,2 . The identification of molecular pathways that contribute to tumour cell motility and invasion is essential for understanding how motility is initiated in tumour cells and how the tumour microenvironment contributes to cell migration. The identification of the molecular pathways of tumour cell invasion will provide new diagnostic approaches and targets for the treatment of metastatic cancer. Recent studies using new technologies, including highdensity microarray-based expression profiling, intravital imaging and the collection of invasive tumour cells from live tumours, have started to extend the traditional model of metastasis and supply new diagnostic and therapeutic markers of metastatic disease.According to the traditional model of metastasis, metastases result from a process similar to Darwinian evolution whereby natural selection works on individual tumour cells to select © 2007 Nature Publishing Group Correspondence to: J.C. Condeeli@aecom.yu.edu. Competing interests statementThe authors declare no competing financial interests. for stable genetic changes. The cells so selected are very rare, and the metastatic cells that arise from this progressive selection of stable genetic mutations within the primary tumour cause metastasis late in tumour progression 3 . However, studies of mammary tumours in mice [4][5][6][7] , expression profiling of both whole human breast tumours 8,9 and the invasive subpopulation of tumour cells isolated from rat and mouse mammary tumours [10][11][12] suggest that the metastatic ability of breast tumours is encoded throughout the bulk of the primary tumour, involves transient changes in gene expression and is acquired at much earlier stages of tumour progression than postulated by the traditional model. These results suggest that a Darwinian-like evolution is accompanied by, and may contribute to, microenvironmentinduced transient changes in gene expression that support the invasive and metastatic phenotype. These results have led to new models where the microenvironment initiates the expression of genes that induce cell motility, invasion and metastasis 11,13 . In the 'tumour microenvironment invasion model' it is proposed that oncogenic mutations in tumour cells lead to microenvironments that are potentially encoded throughout the b...

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Proteomic changes in renal cancer and co‐ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect

Cited by 220 publications

References 67 publications

Cancer as a Metabolic Disease

Cancer as a Metabolic Disease

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

The cofilin pathway in breast cancer invasion and metastasis

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Proteomic changes in renal cancer and co‐ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect

Cited by 220 publications

References 67 publications

Cancer as a Metabolic Disease

Cancer as a Metabolic Disease

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

The cofilin pathway in breast cancer invasion and metastasis

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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