Ultrastructural Observations on Mitochondria and Microvesicles in Renal Oncocytoma, Chromophobe Renal Cell Carcinoma, and Eosinophilic Variant of Conventional (Clear Cell) Renal Cell Carcinoma

Tickoo, Satish K.; Lee, Min Won; Eble, John N.; Amin, Mitual; Christopherson, T; Zarbo, Richard J.; Amin, Mahul B.

doi:10.1097/00000478-200009000-00008

Cited by 146 publications

(92 citation statements)

References 31 publications

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“…However, the expression of parvalbumin in 70% of renal oncocytomas should not be surprising in the light of the recent morphologic (11,25), ultrastructural (13,26,27), histochemical (13), and genetic (28) findings suggesting common features for both chromophobe carcinomas and oncocytomas from the distal nephron. Moreover, the absence of parvalbumin expression in the 30% of the oncocytomas may suggest the existence of differences in this group of tumors as also supported by genetic findings (29).…”

Section: Discussionmentioning

confidence: 99%

Parvalbumin Is Constantly Expressed in Chromophobe Renal Carcinoma

et al. 2001

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Chromophobe renal carcinoma is composed of neoplastic cell showing several features similar to those found in the intercalated cells of the collecting ducts. Because the distal nephron expresses calcium-binding proteins playing a role in calcium homeostasis, we reasoned that these proteins could be expressed by chromophobe carcinoma and therefore represent a diagnostic marker. We studied the immunohistochemical expression of different calcium-binding proteins (parvalbumin, calbindin-D28K, and calretinin) in 140 renal tumors, including 75 conventional (clear cell) carcinomas, 32 chromophobe carcinomas, 17 papillary renal cell carcinomas, and 16 oncocytomas. Parvalbumin was strongly positive in all primary chromophobe carcinomas and in one pancreatic metastasis; it was positive in 11 of 16 oncocytomas and absent in conventional (clear cell) and papillary renal cell carcinomas, either primary or metastatic. Calbindin-D28K and calretinin were negative in all tumors, with the exception of two chromophobe carcinomas, four oncocytomas, and two papillary renal cell carcinomas showing inconspicuous calretinin expression. Our data demonstrate that parvalbumin may be a suitable marker for distinguishing primary and metastatic chromophobe carcinoma from conventional (clear cell) and papillary renal cell carcinoma. Moreover, they suggest a relationship between chromophobe renal carcinoma and renal oncocytoma and indicate that chromophobe carcinoma exhibits differentiation toward the collectingduct phenotype.

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Section: Discussionmentioning

confidence: 99%

Parvalbumin Is Constantly Expressed in Chromophobe Renal Carcinoma

et al. 2001

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“…Isolated JG cells from primary cultures were fixed with 4% paraformaldehyde then postfixed in 2% osmium tetroxide, dehydrated through a gradient of ethanol, and embedded in araldite after the methods of Tickoo et al 17 Ultrathin sections were obtained with an LKB Nova ultra microtome, stained with lead citrate and uranyl acetate, and viewed with a Philips 208 electron microscope by our institutional electron microscopic imaging core in the Department of Pathology. Images were taken at ϫ13 500 magnification.…”

Section: Transmission Electron Microscopymentioning

confidence: 99%

Decreased Intracellular Calcium Stimulates Renin Release via Calcium-Inhibitable Adenylyl Cyclase

et al. 2007

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Abstract-Intracellular calcium and cAMP are the 2 second messengers that regulate renin release; cAMP stimulates renin release from juxtaglomerular (JG) cells, whereas increased intracellular calcium inhibits it. We hypothesized that decreased intracellular calcium acts by activating calcium-inhibitable isoforms of adenylyl cyclase, increasing cAMP, and stimulating renin secretion. We used a primary culture of JG cells isolated from C-57/B6 mice. Cells were plated to a density of 70% in serum-free medium and incubated for 2 hours with or without 100 mol/L of the cytosolic calcium chelator 5Ј5-dimethyl-1,2-bis-(2-aminophenoxy)-ethane-N,N,NЈ,NЈ-tetra-acetic acid (BAPTA-AM) to decrease intracellular calcium. JG cell cAMP content and renin release were determined by radioimmunoassay. Key Words: renin Ⅲ adenylyl cyclase Ⅲ calcium Ⅲ juxtaglomerular cell Ⅲ cAMP R enin is the rate-limiting enzymatic step in the formation of angiotensin (Ang); thus, control of renin secretion by the kidney is a critical element in regulating systemic blood pressure and renal function. The common element in all of the renin-stimulating pathways is the second messenger cAMP, 1 the product of adenylyl cyclase activity. 2 However, it is also well established that renin secretion by the JG cells, unlike almost all secretory cells, is inversely related to intracellular calcium concentration such that paradoxically elevated intracellular calcium is a potent inhibitor of renin release. [3][4][5] Increased calcium in the juxtaglomerular (JG) cells suppresses basal renin release and blunts stimulation of renin secretion. 6 -9 Decreased JG cell intracellular calcium increases basal renin secretion and amplifies stimulated renin levels. 3,6,9 -11 Although the influence of these 2 "second messenger" regulatory signals, cAMP and calcium, has been established for years, 1,5,6,10,12 the precise nature of their interactions is unresolved and an area of considerable interest and debate.There are at least 9 isoforms of adenylyl cyclase, 2 including 2 (types V and VI) that are inhibited by increased intracellular calcium. 13 Because renin release is inhibited by increased intracellular calcium and stimulated by cAMP, we hypothesized that reducing intracellular calcium stimulates renin release by activating a calcium-inhibitable adenylyl cyclase, types V and/or VI in JG cells, enhancing cAMP levels, and thereby stimulating renin release. To test this hypothesis, we used primary cultures of isolated mouse JG cells, which exhibit the classic phenotypic character of the JG cell but are unencumbered by the many extracellular signaling pathways that can influence renin secretion in vivo or in less homogeneous in vitro preparations. Our results provide a unique answer to this longstanding question of how these 2 classic second messengers interact to control the release of renin from the JG cell.

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“…A characteristic feature of oncocytomas is the accumulation of a large number of mitochondria (14). This hyperproliferation of mitochondria was first found in thyroid tumors (Hü rthle cell carcinoma) and was called an oxyphilic change in the cells.…”

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confidence: 99%

Loss of Complex I due to Mitochondrial DNA Mutations in Renal Oncocytoma

Mayr¹,

Meierhofer²,

Zimmermann³

et al. 2008

Clinical Cancer Research

154

151

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Purpose: Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase and succinate dehydrogenase have been identified in certain tumor types, thus demonstrating a direct link between mitochondrial energy metabolism and tumorigenesis. Although mutations in the mitochondrial genome (mitochondrial DNA, mtDNA) also can affect aerobic metabolism and mtDNA alterations are frequently observed in tumor cells, evidence linking respiratory chain deficiency in a specific tumor type to a specific mtDNA mutation has been lacking. Experimental Design: To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues.Results: Here, we show that loss of respiratory chain complex I (NADH/ubiquinone oxidoreductase) is associated with renal oncocytoma. Enzymatic activity of complex I was undetectable or greatly reduced in the tumor samples (n = 15). Blue Native gel electrophoresis of the multisubunit enzyme complex revealed a lack of assembled complex I. Mutation analysis of the mtDNA showed frame-shift mutations in the genes of either subunit ND1, ND4, or ND5 of complex I in 9 of the 15 tumors. Conclusion: Our data indicate that isolated loss of complex I is a specific feature of renal oncocytoma and that this deficiency is frequently caused by somatic mtDNA mutations.A shift in cellular energy production from aerobic oxidation in mitochondria to anaerobic glycolysis is a fundamental property of cancer cells, also called the Warburg effect (1, 2). Otto Warburg postulated that damage of the aerobic energy metabolism is a primary and irreversible event in tumor formation (2). Recently, this hypothesis has been supported by the demonstration that mutations of single enzymes of the mitochondrial energy metabolism are associated with tumorigenesis (3, 4). Germline mutations in distinct subunits of succinate dehydrogenase predispose to hereditary paragangliomas and pheochromocytomas (4, 5). Germline mutations in the fumarate hydratase gene can either cause leiomyoma, leiomyosarcoma, and renal cell carcinoma (3) or Leydig cell tumor (6). Therefore, succinate dehydrogenase and fumarate hydratase are regarded as mitochondrial tumor suppressors for these types of tumors (5).Mitochondrial DNA (mtDNA), the small genome of the mitochondrion, is essential for aerobic energy metabolism and encodes some of the subunits of respiratory chain complexes I, III, and IV, as well as the F 1 F 0 -ATP synthase. Complex I consists of 46 different subunits, with a molecular mass totaling 980 kDa. Seven of these subunits (ND1 -ND6 and ND4L) are encoded by mtDNA; the other complex I genes are located on nuclear chromosomes.Because of its essential role in energy metabolism, the mitochondrial genome has long been suspected of contributing to metabolic alterations in tumors. Such investigations d...

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Ultrastructural Observations on Mitochondria and Microvesicles in Renal Oncocytoma, Chromophobe Renal Cell Carcinoma, and Eosinophilic Variant of Conventional (Clear Cell) Renal Cell Carcinoma

Cited by 146 publications

References 31 publications

Parvalbumin Is Constantly Expressed in Chromophobe Renal Carcinoma

Parvalbumin Is Constantly Expressed in Chromophobe Renal Carcinoma

Decreased Intracellular Calcium Stimulates Renin Release via Calcium-Inhibitable Adenylyl Cyclase

Loss of Complex I due to Mitochondrial DNA Mutations in Renal Oncocytoma

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