Misdiagnosis of clear cell renal cell carcinoma

Valera, Vladimir; Merino, María J.

doi:10.1038/nrurol.2011.64

Cited by 32 publications

(25 citation statements)

References 74 publications

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“… Clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer 1 , is characterized by elevated glycogen and fat deposition 2 . These consistent metabolic alterations are associated with normoxic stabilization of hypoxia inducible factors (HIFs) 3 , secondary to von hippel-lindau ( VHL ) mutations that occur in over 90% of ccRCC tumours 4 .…”

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confidence: 99%

Fructose-1,6-bisphosphatase opposes renal carcinoma progression

Qiu

Lee

et al. 2014

Nature

444

508

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Clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer1, is characterized by elevated glycogen and fat deposition2. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia inducible factors (HIFs)3, secondary to von hippel-lindau (VHL) mutations that occur in over 90% of ccRCC tumours4. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation5, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed loss of several chromatin remodelling enzymes in a subset of ccRCC (polybromo 1 [PBRM1] ~40%, SET domain containing 2 [SETD2] ~15%, BRCA1 associated protein-1 [BAP1] ~15%, etc.)6–9, indicating that epigenetic perturbations are likely important contributors to the natural history of this disease. Here we utilized an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis, and determined that the gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1)10 is uniformly depleted in over six hundred ccRCC tumours examined. Importantly, the human FBP1 locus resides on chromosome 9q22, whose loss is associated with poor prognosis for ccRCC patients11. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms: 1) FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin12, thereby inhibiting a potential “Warburg effect”13,14, and 2) in pVHL-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis, and the pentose phosphate pathway in a catalytic activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF “inhibitory domain”. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously-identified tumour suppressors (PBRM1, SETD2, BAP1, etc.) which are not consistently mutated in all tumours6,7,15.

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confidence: 99%

Fructose-1,6-bisphosphatase opposes renal carcinoma progression

Qiu

Lee

et al. 2014

Nature

444

508

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“…Clear cell RCC (ccRCC) is the most common (~75%) type of human kidney cancer and is highly lethal when metastatic (35,36). Genetically, ccRCC is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which encodes an E3 ubiquitin ligase that degrades HIF1α and HIF2α (37).…”

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confidence: 99%

Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Xu¹,

Pham²,

Albanese³

et al. 2016

Journal of Clinical Investigation

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tory mechanisms concerning the activation of WT mTORC1 have been proposed, which involves mTOR-interacting proteins RAG, Ras homolog enriched in brain (RHEB), DEP domain containing MTOR-interacting protein (DEPTOR), RAPTOR, PRAS40, and FKBP38 (2,[4][5][6][7][8][9][10]19,[60][61][62][63]. Indeed, a recent study surveyed cancer-derived mTOR activation mutations, which exploited the DEPTOR-centered mechanism (64). However, how activating mutations contribute to the pathogenesis of cancer, especially kidney cancer, and what molecular mechanisms underlie individual activating mutations beyond DEPTOR remain unknown.

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“…2. In tumor regions, a classic alveolar growth pattern and clear cytoplasm was observed for all clear cell RCC specimens (Valera and Merino 2011). Irregular nuclei and perinuclear halos were observed in the chromophobe RCC tumor cells (Stec et al 2009).…”

Section: Resultsmentioning

confidence: 92%

“…A very intense vimentin positivity was observed at the delicate vascular network and the branching connective tissue that typically separate nested tumor cells in these tumors (Valera and Merino 2011). Also, vimentin highlighted the well-demarcated tumor cell membranes (Valera and Merino 2011). In all other cases (except for the vimentin negative clear cell carcinoma case), CPM and vimentin located alongside each other in the micro-(and macro-) vasculature and stromal cells.…”

Section: Resultsmentioning

confidence: 96%

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Mapping of Carboxypeptidase M in Normal Human Kidney and Renal Cell Carcinoma

Denis

Acker

Schepper

et al. 2012

J Histochem Cytochem.

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Although the kidney generally has been regarded as an excellent source of carboxypeptidase M (CPM), little is known about its renal-specific expression level and distribution. This study provides a detailed localization of CPM in healthy and diseased human kidneys. The results indicate a broad distribution of CPM along the renal tubular structures in the healthy kidney. CPM was identified at the parietal epithelium beneath the Bowman’s basement membrane and in glomerular mesangial cells. Capillaries, podocytes, and most interstitial cells were CPM negative. Tumor cells of renal cell carcinoma subtypes lose CPM expression upon dedifferentiation. Tissue microarray analysis demonstrated a correlation between low CPM expression and tumor cell type. CPM staining was intense on phagocytotic tumor-associated macrophages. Immunoreactive CPM was also detected in the tumor-associated vasculature. The absence of CPM in normal renal blood vessels points toward a role for CPM in angiogenesis. Coexistence of CPM and the epidermal growth factor receptor (EGFR) was detected in papillary renal cell carcinoma. However, the different subcellular localization of CPM and EGFR argues against an interaction between these h proteins. The description of the distribution of CPM in human kidney forms the foundation for further study of the (patho)physiological activities of CPM in the kidney.

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Misdiagnosis of clear cell renal cell carcinoma

Cited by 32 publications

References 74 publications

Fructose-1,6-bisphosphatase opposes renal carcinoma progression

Fructose-1,6-bisphosphatase opposes renal carcinoma progression

Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Mapping of Carboxypeptidase M in Normal Human Kidney and Renal Cell Carcinoma

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