Investigative Urology: Immunohistochemical Localization of Glucose Transporters in Human Renal Cell Carcinoma

Nagase, Yasushi; Takata, Kuniaki; Moriyama, Nobuo; Aso, Yoshio; Murakami, Toshikazu; Honda, Hiroshi

doi:10.1016/s0022-5347(01)67725-5

Cited by 77 publications

(55 citation statements)

References 17 publications

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“…18,19 GLUT-1 is expressed in a variety of carcinomas, including carcinoma of the breast, head and neck, ovary, renal cell carcinoma, lung, and malignant pleural mesothelioma. [20][21][22][23][24][25][26] Positron emission tomography (PET) imaging using [18F]2-fluoro-2-deoxy-D-glucose (FDG) has Immunostaining for CA-IX, 16,32 another hypoxic marker and a major downstream target of HIF-1a, was also significantly stronger in the thymic carcinomas (staining score: 110), the same as immunostaining for GLUT-1, but its specificity was lower (58% of thymic carcinomas and 28% of type B3 thymomas stained positive for CA-IX).…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical differential diagnosis between thymic carcinoma and type B3 thymoma: diagnostic utility of hypoxic marker, GLUT-1, in thymic epithelial neoplasms

et al. 2009

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There are only a few immunohistochemical markers that are useful for differentiating thymic carcinomas from type B3 thymomas. The purpose of this study is to examine the additional markers that would be useful for differentiating between thymic carcinoma and thymoma type B3. We performed a tissue microarray analysis of surgically resected thymic tumor specimens from12 cases of thymic carcinoma, 7 cases of type B3 thymoma, and 68 cases of other types of thymoma. Immunostaining using 49 antibodies was scored based on staining intensity and the percentage of cells that stained positive. Seven proteins that were selected by the staining scores, namely, GLUT-1 (167 vs 4), CA-IX (110 vs 15), c-kit (162 vs 44), CD5 (33 vs 0), MUC-1 (54 vs 0), CEA (42 vs 0), and CK18 (110 vs 42), were significantly higher in the thymic carcinomas than in the type B3 thymomas. The staining sensitivity and specificity of the antibodies for thymic carcinoma were GLUT-1, sensitivity 72% and specificity 100%; CA-IX, 58 and 71%; c-kit, 72 and 85%; CD5, 33 and 100%; CK18, 58 and 71%; MUC-1, 25 and 100%; and CEA, 33 and 100%. Glucose transporter 1 (GLUT-1) is the best marker for thymic carcinoma because it had the highest sensitivity and specificity. Positive immunostaining for a combination of three markers, namely, GLUT-1, CD5, and CEA, enabled differentiation of thymic carcinoma with 91.6% sensitivity and 100% specificity. In conclusion, we identified GLUT-1 as an additional marker that will be useful for differentiating thymic carcinoma from type B3 thymoma, especially in biopsy specimens that have been crushed or are otherwise difficult to examine morphologically in thymic tumors.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical differential diagnosis between thymic carcinoma and type B3 thymoma: diagnostic utility of hypoxic marker, GLUT-1, in thymic epithelial neoplasms

et al. 2009

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“…35 GLUT-1 expression has been revealed in a variety of carcinomas, such as those of the breast, head and neck, bladder, and renal cells. [15][16][17][18][19]23 In the lung, about 34.3-100% of lung adenocarcinomas 16,[20][21][22]24 and 100% of lung squamous cell carcinomas [20][21][22]24 are reported to express GLUT-1 at the primary site. With regard to MPM, only one article has describe that two of four studied cases were positive for GLUT-1.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 In contrast, GLUT-1 is expressed in a variety of carcinomas such as those of the breast, head and neck, bladder, renal cells, and lung. [15][16][17][18][19][20][21][22][23][24] Previous reports suggest that the expression of GLUT-1 may be a potential marker for malignancy.…”

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confidence: 99%

Immunohistochemical detection of GLUT-1 can discriminate between reactive mesothelium and malignant mesothelioma

et al. 2007

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The separation of benign reactive mesothelium (RM) from malignant mesothelial proliferation can be a major challenge. A number of markers have been proposed, including epithelial membrane antigen, p53 protein, and P-glycoprotein. To date, however, no immunohistochemical marker that allows unequivocal discrimination of RM from malignant pleural mesothelioma (MPM) has been available. A family of glucose transporter isoforms (GLUT), of which GLUT-1 is a member, facilitate the entry of glucose into cells. GLUT-1 is largely undetectable by immunohistochemistry in normal epithelial tissues and benign tumors, but is expressed in a variety of malignancies. Thus, the expression of GLUT-1 appears to be a potential marker of malignant transformation. Recently, in fact, some studies have shown that GLUT-1 expression is useful for distinguishing benign from malignant lesions. The purpose of the present study was to evaluate the diagnostic utility of GLUT-1 expression for diagnostic differentiation between RM and MPM. Immunohistochemical staining for GLUT-1 was performed in 40 cases of RM, 48 cases of MPM, and 58 cases of lung carcinoma. Immunohistochemical GLUT-1 expression was seen in 40 of 40 (100%) MPMs, and in all cases the expression was demonstrated by linear plasma membrane staining, sometimes with cytoplasmic staining in addition. GLUT-1 expression was also observed in 56 out of 58 (96.5%) lung carcinomas. On the other hand, no RM cases were positive for GLUT-1. GLUT-1 is a sensitive and specific immunohistochemical marker enabling differential diagnosis of RM from MPM, whereas it cannot discriminate MPM from lung carcinoma. Modern Pathology (2007) 20, 215-220.

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“…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][8][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 dehydrogenase (LDH) A.…”

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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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Investigative Urology: Immunohistochemical Localization of Glucose Transporters in Human Renal Cell Carcinoma

Cited by 77 publications

References 17 publications

Immunohistochemical differential diagnosis between thymic carcinoma and type B3 thymoma: diagnostic utility of hypoxic marker, GLUT-1, in thymic epithelial neoplasms

Immunohistochemical differential diagnosis between thymic carcinoma and type B3 thymoma: diagnostic utility of hypoxic marker, GLUT-1, in thymic epithelial neoplasms

Immunohistochemical detection of GLUT-1 can discriminate between reactive mesothelium and malignant mesothelioma

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

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Investigative Urology: Immunohistochemical Localization of Glucose Transporters in Human Renal Cell Carcinoma

Cited by 77 publications

References 17 publications

Immunohistochemical differential diagnosis between thymic carcinoma and type B3 thymoma: diagnostic utility of hypoxic marker, GLUT-1, in thymic epithelial neoplasms

Immunohistochemical differential diagnosis between thymic carcinoma and type B3 thymoma: diagnostic utility of hypoxic marker, GLUT-1, in thymic epithelial neoplasms

Immunohistochemical detection of GLUT-1 can discriminate between reactive mesothelium and malignant mesothelioma

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

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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