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Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common form of human kidney cancer. Histological and molecular analyses suggest that ccRCCs have significantly altered metabolism. Recent human studies of lung cancer and intracranial malignancies demonstrated an unexpected preservation of carbohydrate oxidation in the tricarboxylic acid (TCA) cycle. To test the capacity of ccRCC to oxidize substrates in the TCA cycle, we infused 13C-labeled fuels in ccRCC patients and compared labeling patterns in tumors and adjacent kidney. After infusion with [U-13C]glucose, ccRCCs displayed enhanced glycolytic intermediate labeling, suppressed pyruvate dehydrogenase flow, and reduced TCA cycle labeling, consistent with the Warburg effect. Comparing 13C labeling among ccRCC, brain, and lung tumors revealed striking differences. Primary ccRCC tumors demonstrated the highest enrichment in glycolytic intermediates and lowest enrichment in TCA cycle intermediates. Among human tumors analyzed by intraoperative 13C infusions, ccRCC is the first to demonstrate a convincing shift toward glycolytic metabolism.

SUBMITTER: Courtney KD

PROVIDER: S-EPMC6221993 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo.

Courtney Kevin D KD Bezwada Divya D Mashimo Tomoyuki T Pichumani Kumar K Vemireddy Vamsidhara V Funk Alexander M AM Wimberly Jennifer J McNeil Sarah S SS Kapur Payal P Lotan Yair Y Margulis Vitaly V Cadeddu Jeffrey A JA Pedrosa Ivan I DeBerardinis Ralph J RJ Malloy Craig R CR Bachoo Robert M RM Maher Elizabeth A EA

Cell metabolism 20180823 5

Clear cell renal cell carcinoma (ccRCC) is the most common form of human kidney cancer. Histological and molecular analyses suggest that ccRCCs have significantly altered metabolism. Recent human studies of lung cancer and intracranial malignancies demonstrated an unexpected preservation of carbohydrate oxidation in the tricarboxylic acid (TCA) cycle. To test the capacity of ccRCC to oxidize substrates in the TCA cycle, we infused <sup>13</sup>C-labeled fuels in ccRCC patients and compared label ...[more]

PMID: 30146487

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Project description:Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma. Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma and compare them to non-sarcomatoid clear cell renal cell carcinoma. We examined the transcriptome of the epithelioid and sarcomatoid components of advanced stage sarcomatoid clear cell renal cell carcinoma (n=43) and non-sarcomatoid clear cell renal cell carcinoma (n=37) from independent discovery and validation cohorts using the cDNA microarray and RNA-seq platforms. We analyzed DNA copy number profiles, generated using SNP arrays, from patients with sarcomatoid clear cell renal cell carcinoma (n=10) and advanced non-sarcomatoid clear cell renal cell carcinoma (n=155). The epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma had similar gene expression and DNA copy number signatures that were, however, distinct from those of high-grade, high-stage non-sarcomatoid clear cell renal cell carcinoma. Prognostic clear cell renal cell carcinoma gene expression profiles were shared by the biphasic components of sarcomatoid clear cell renal cell carcinoma and the sarcomatoid component showed a partial epithelial-to-mesenchymal transition signature. Our genome-scale microarray-based transcript data were validated in an independent set of sarcomatoid and non-sarcomatoid clear cell renal cell carcinomas using RNA-seq. Sarcomatoid clear cell renal cell carcinoma is molecularly distinct from non-sarcomatoid clear cell renal cell carcinoma, with its genetic programming largely shared by its biphasic morphological components. These data explain why a low percentage of sarcomatoid histology augurs a poor prognosis; suggest the need to modify the pathological grading system and introduce the potential for candidate biomarkers to detect sarcomatoid change preoperatively without specifically sampling the histological sarcomatoid component.

Project description:BackgroundNa+/H+ exchanger (NHE) maintains the alkaline pH of epithelial cells working at the cellular membrane and exchanging H+/Na+ ions. In renal tubular epithelial cells, the reabsorption of NaCl is implemented by NHE3 isoform, which is regulated by NHE regulatory factor-1 (NHERF1). Normally situated at the apical zones of proximal tubular cells, NHERF1 participates in cytoskeletal reorganization and signal transduction facilitating structural stability and ion exchange. Based on an extensive search in English literature, NHERF1/EBP50 immunoexpression has been studied in breast, colon, and other tumors with only one study on 21 cases of renal cell carcinomas (RCC).MethodsUsing NHERF1/EBP50 immunohistochemistry (IHC) on 64 (82%) RCCs (34 clear cells, 21 papillary and 9 chromophobe types) and 14 (18%) oncocytomas, we evaluated and scored NHERF1/EBP50 immunoexpression depending on the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading system followed by ultrastructural identification of microlumen-like structures (MLS) in clear cell renal cell carcinomas (ccRCC).ResultsStaining patterns varied throughout the tumors and within individual tumors. Only ccRCC showed unique MLS within the cytoplasm of tumor cells. All neoplasia-transformed tubular cells, regardless of the tumor grade and stage, had altered immunoexpression of NHERF1/EBP50 ranging from complete absence to aberrant expression in the luminal cell membrane, nuclear or cytoplasmic localizations.ConclusionsOnly ccRCC showed unique dot-like condensations of immunostaining/MLS at membranous, submembranous, and paranuclear localizations. The latter two localizations were mainly observed in the combined WHO/ISUP grade 1 and 2 group compared to the combined group of grade 3 and 4 tumor samples (P=0.0146 and P<0.0001, respectively). Ultrastructurally, the MLS were identified as thick microvilli trapped by a single-layer membrane, displaced into the cytoplasm and ranging from 400 nm to 3.5 µm. These significant ultrastructural reorganizations may contribute to tumor progression, metastasis, and drug resistance.

Dataset Information

Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo.

Publications

Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo.

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