glycogen and Kidney-Neoplasms

The majority of kidney cancers are clear-cell carcinomas (ccRCC), characterized by the accumulation of cholesterol, cholesterol esters, other neutral lipids and glycogen. Rather than being a passive bystander, the clear-cell phenotype is suggested to be a biomarker of deregulated cholesterol and lipid biosynthesis, which plays an important role in development of the disease. One clue to this relationship has come from the elucidation of the hereditary kidney cancer gene, TRC8, which functions partly to degrade key regulators of endogenous cholesterol and lipid biosynthesis. In addition, deregulation of the mevalonate pathway has been shown to play a key role in cellular transformation and invasion. These findings are supported by considerable epidemiologic data linking obesity and the deregulation of lipid biosynthesis to ccRCC.

Topics: Animals; Carcinoma, Renal Cell; Cholesterol; Cholesterol Esters; Glycogen; Humans; Kidney Neoplasms; Lipids; Mevalonic Acid; Obesity; Receptors, Cell Surface

Topics: Adenocarcinoma; Aflatoxins; Age Factors; Animals; Carcinogens; Cricetinae; Cytoplasm; Glycogen; Humans; Hydrocarbons; Kidney; Kidney Neoplasms; Lead; Lipids; Microscopy, Electron; Neoplasms, Experimental; Nitrosamines; Plants; Sex Factors

The primary subtypes of renal cell carcinoma (RCC) include clear cell, papillary and chromophobe RCC. RCC occurs often due to loss of von Hippel‑Lindau (VHL) and accumulation of lipids and glycogen, and RCC cells may exhibit sensitivity to the disruption of normal metabolism or homologous recombination gene defect. Although the application of molecular‑targeted drugs (tyrosine kinase inhibitors) and immune checkpoint inhibitors has been recommended for the treatment of advanced RCC, more targets of DNA damage repair (DDR) signaling pathway involved in the synthetic lethal effect have been investigated. However, although achievements has been made in the exploration of the roles of DDR genes on RCC progression, their association has not been systematically summarized. Poly (ADP‑ribose) polymerase (PARP) 1 inhibitors are used in tumors with BRCA1/2 DNA repair‑associated mutations. PARP family enzymes perform post‑translational modification functions and participate in DDR and cell death. Inhibitors of PARP, ataxia telangiectasia mutant gene and polymerase θ serve key roles in the treatment of specific RCC subtypes. PARP1 may serve as an important biological marker to predict the therapeutic effect of immune checkpoint inhibitors and evaluate the prognosis of patients with ccRCC with polybromo 1 mutation. Therefore, the roles of DDR pathway on RCC progression or treatment may hold promises for the treatment of certain specific types of RCC.

Topics: Adenosine Diphosphate; Carcinoma, Renal Cell; DNA Damage; DNA Repair; Glycogen; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Lipids; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Ribose

Glycogen accumulation is a highly consistent, distinguishable characteristic of clear cell renal cell carcinoma (ccRCC)

Topics: Carcinoma, Renal Cell; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Glycogen; Glycogen Synthase; Humans; Kidney Neoplasms; Tumor Microenvironment

Metabolism reprogramming is a hallmark of many cancer types. We focused on clear cell renal carcinoma (ccRCC) which is characterized by its clear and glycogen-enriched cytoplasm with unknown reasons. The aim of this study was to identify the clinical significance, biological function, and molecular regulation of glycogen synthase 1 (GYS1) in ccRCC glycogen accumulation and tumor progression.

Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Disease Progression; Glycogen; Glycogen Synthase; Humans; Immunohistochemistry; Kidney Neoplasms; Male; Metabolome; Mice; Mice, Inbred BALB C; NF-kappa B; Prognosis; Signal Transduction

Topics: Biopsy, Needle; Carcinoma, Renal Cell; Cell Nucleus; Diagnosis, Differential; Glycogen; Humans; Intranuclear Inclusion Bodies; Kidney; Kidney Neoplasms; Male; Middle Aged; Thyroid Cancer, Papillary; Thyroid Neoplasms

Herein, a technique to analyze air-dried kidney tissue impression smears by means of attenuated total reflection infrared (ATR-IR) spectroscopy is presented. Spectral tumor markers-absorption bands of glycogen-are identified in the ATR-IR spectra of the kidney tissue smear samples. Thin kidney tissue cryo-sections currently used for IR spectroscopic analysis lack such spectral markers as the sample preparation causes irreversible molecular changes in the tissue. In particular, freeze-thaw cycle results in degradation of the glycogen and reduction or complete dissolution of its content. Supervised spectral classification was applied to the recorded spectra of the smears and the test spectra were classified with a high accuracy of 92% for normal tissue and 94% for tumor tissue, respectively. For further development, we propose that combination of the method with optical fiber ATR probes could potentially be used for rapid real-time intra-operative tissue analysis without interfering with either the established protocols of pathological examination or the ordinary workflow of operating surgeon. Such approach could ensure easier transition of the method to clinical applications where it may complement the results of gold standard histopathology examination and aid in more precise resection of kidney tumors.

Topics: Glycogen; Humans; Intraoperative Period; Kidney; Kidney Neoplasms; Spectrophotometry, Infrared; Time Factors

Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. 'Clear cell' tumors contain large, proliferating cells with 'clear cytoplasm', and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis. A zebrafish model with a homozygous inactivation in the VHL gene (vhl(-/-)) recapitulates several aspects of the human disease, including development of highly vascular lesions in the brain and the retina and erythrocytosis. Here, we characterize for the first time the epithelial abnormalities present in the kidney of the vhl(-/-) zebrafish larvae as a first step in building a model of ccRCC in zebrafish. Our data show that the vhl(-/-) zebrafish kidney is characterized by an increased tubule diameter, disorganized cilia, the dramatic formation of cytoplasmic lipid vesicles, glycogen accumulation, aberrant cell proliferation and abnormal apoptosis. This phenotype of the vhl(-/-) pronephros is reminiscent of clear cell histology, indicating that the vhl(-/-) mutant zebrafish might serve as a model of early stage RCC. Treatment of vhl(-/-) zebrafish embryos with a small-molecule HIF2a inhibitor rescued the pronephric abnormalities, underscoring the value of the zebrafish model in drug discovery for treatment of VHL disease and ccRCC.

Topics: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Cell Proliferation; Cytoplasmic Vesicles; Embryonic Development; Glycogen; Humans; Kidney Neoplasms; Kidney Tubules; Larva; Neoplasm Staging; Phenotype; Pronephros; Tumor Suppressor Proteins; Zebrafish; Zebrafish Proteins

Activation of the PI3K/AKT/mTOR pathway is a crucial molecular event in human clear cell renal cell carcinoma (ccRCC), and is also upregulated in diabetic nephropathy. In diabetic rats metabolic changes affect the renal distal tubular epithelium and lead to glycogen-storing Armanni-Ebstein lesions (AEL), precursor lesions of RCC in the diabetes induced nephrocarcinogenesis model. These lesions resemble human sporadic clear cell tubules (CCT) and tumor cells of human ccRCC.Human sporadic CCT were examined in a collection of 324 nephrectomy specimen, in terms of morphologic, metabolic and molecular alterations, and compared to preneoplastic CCT and RCC developed in the rat following streptozotocin-induced diabetes or N-Nitrosomorpholine administration. Diabetic and non-diabetic rats were subjected to the dual PI3K/mTOR inhibitor, NVP/BEZ235.Human sporadic CCT could be detected in 17.3% of kidney specimens. Human and rat renal CCT display a strong induction of the PI3K/AKT/mTOR pathway and related metabolic alterations. Proteins involved in glycolysis and de novo lipogenesis were upregulated. In in vivo experiments, dual inhibition of PI3K and mTOR resulted in a reduction of proliferation of rat diabetes related CCT and increased autophagic activity.The present data indicate that human sporadic CCT exhibit a pattern of morphologic and metabolic alterations similar to preneoplastic lesions in the rat model. Activation of the PI3K/AKT/mTOR pathway in glycogenotic tubuli is a remarkable molecular event and suggests a preneoplastic character of these lesions also in humans.

Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus, Experimental; Glycogen; Humans; Immunohistochemistry; Kidney Neoplasms; Male; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred Lew; Signal Transduction; TOR Serine-Threonine Kinases

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Gene Expression Regulation, Neoplastic; Glycogen; Humans; Kidney Neoplasms; Kidney Tubules

Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1α (HIF1α) and HIF2α has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2α (P405A, P530A, and N851A, named as HIF2αM3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1αM3 oncogenesis when coexpressed with constitutively active HIF1αM3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), γH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2α is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2α activation is critical for ccRCC tumorigenesis.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Glycogen; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Kidney Neoplasms; Kidney Tubules; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation

Clear cell carcinoma (CCC) is a histologically distinct carcinoma subtype that arises in several organ systems and is marked by cytoplasmic clearing, attributed to abundant intracellular glycogen. Previously, transcription factor hepatocyte nuclear factor 1-beta (HNF1B) was identified as a biomarker of ovarian CCC. Here, we set out to explore more broadly the relation between HNF1B and carcinomas with clear cell histology. HNF1B expression, evaluated by immunohistochemistry, was significantly associated with clear cell histology across diverse gynecologic and renal carcinomas (P<0.001), as was hypomethylation of the HNF1B promoter (P<0.001). From microarray analysis, an empirically-derived HNF1B signature was significantly enriched for computationally-predicted targets (with HNF1 binding sites) (P<0.03), as well as genes associated with glycogen metabolism, including glucose-6-phophatase, and strikingly the blood clotting cascade, including fibrinogen, prothrombin and factor XIII. Enrichment of the clotting cascade was also evident in microarray data from ovarian CCC versus other histotypes (P<0.01), and HNF1B-associated prothrombin expression was verified by immunohistochemistry (P = 0.015). Finally, among gynecologic carcinomas with cytoplasmic clearing, HNF1B immunostaining was linked to a 3.0-fold increased risk of clinically-significant venous thrombosis (P = 0.043), and with a 2.3-fold increased risk (P = 0.011) in a combined gynecologic and renal carcinoma cohort. Our results define HNF1B as a broad marker of clear cell phenotype, and support a mechanistic link to glycogen accumulation and thrombosis, possibly reflecting (for gynecologic CCC) derivation from secretory endometrium. Our findings also implicate a novel mechanism of tumor-associated thrombosis (a major cause of cancer mortality), based on the direct production of clotting factors by cancer cells.

Topics: Adenocarcinoma, Clear Cell; Blood Coagulation; Blood Coagulation Factors; Carcinoma, Renal Cell; Computational Biology; DNA Methylation; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Glucose-6-Phosphatase; Glycogen; Hepatocyte Nuclear Factor 1-beta; Humans; Immunohistochemistry; Kidney Neoplasms; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Risk; Venous Thrombosis

Papillary renal cell carcinoma (PRCC) includes two different morphological subtypes. The differences of genetics and ultrastructure of the two subtypes have been rarely reported. Also, new biomarkers related to the diagnosis and prognosis of PRCC have still not been well elucidated. Immunohistochemistry, fluorescence in situ hybridization (FISH) and transmission electron microscopy were used systematically to determine the characteristics of 56 cases of PRCC and to reveal new diagnostic and prognostic information. Type 1 PRCC presented higher expression rates of EMA and CK7, whereas type 2 presented a higher expression rate of CD10. New immunohistochemical markers, including: p504s, PAX-2, PAX-8 and CA-IX showed extensive immunostaining in PRCC. We first revealed a distinct immunostaining pattern of CA-IX, which was located in multiple foci in PRCC. All tumors had at least one chromosomal aberration including loss of Y, gains of 7 or 17. Gain of chromosome 17 was common in type 1; losses of chromosome 18, 11 and 8 appeared in type 2. Ultrastructurally, glycogen granules and secondary lysosomes were seen in type 1, mitochondria and smooth endoplasmic reticulum were scattered in type 2. Tumor subtype, nuclear grade, TNM stage, clear cell renal cell carcinoma (CCRCC) component and sarcomatoid elements, metastasis, CAIX expression, losses of chromosome 18 and 8 were related to poor outcome of PRCC. We conclude that the two subtypes of PRCC originate from different renal cells, and arise from partially common genetic pathways. EMA, CK7, CD10, p504s, PAX-2, PAX-8 and CA-IX are helpful markers in the differential diagnosis of PRCC. CA-IX expression, losses of chromosome 18 and 8 are new prognostic factors of PRCC.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Renal Cell; Chromosome Aberrations; Endoplasmic Reticulum, Smooth; Female; Glycogen; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Kidney Neoplasms; Lysosomes; Male; Microscopy, Electron, Transmission; Middle Aged; Mitochondria; Prognosis; Survival Rate

Cardiac steroids (CS), an important class of naturally occurring compounds, are synthesized in plants and animals. The only established receptor for CS is the ubiquitous Na(+),K(+)-ATPase, a major plasma membrane transporter. The binding of CS to Na(+),K(+)-ATPase causes the inhibition of Na(+) and K(+) transport and elicits cell-specific activation of several intracellular signaling mechanisms. It is well documented that the interaction of CS with Na(+),K(+)-ATPase is responsible for numerous changes in basic cellular physiological properties, such as electrical plasma membrane potential, cell volume, intracellular [Ca(2+)] and pH, endocytosed membrane traffic, and the transport of other solutes. In the present study we show that CS induces the formation of dark structures adjacent to the nucleus in human NT2 and ACHN cells. These structures, which are not surrounded by membranes, are clusters of glycogen and a distorted microtubule network. Formation of these clusters results from a relocation of glycogen and microtubules in the cells, two processes that are independent of one another. The molecular mechanisms underlying the formation of the clusters are mediated by the Na(+),K(+)-ATPase, ERK1/2 signaling pathway, and an additional unknown factor. Similar glycogen clusters are induced by hypoxia, suggesting that the CS-induced structural change, described in this study, may be part of a new type of cellular stress response.

Topics: Adenocarcinoma; Bufanolides; Cardiotonic Agents; Cell Hypoxia; Digoxigenin; Glycogen; Humans; Kidney Neoplasms; MAP Kinase Signaling System; Microscopy, Electron; Microtubules; Neural Stem Cells; Nocodazole; Ouabain; Potassium; RNA, Small Interfering; Sodium-Potassium-Exchanging ATPase; Stress, Physiological; Tubulin Modulators; Tumor Cells, Cultured

Clear cell (CRCC) and papillary (PRCC) renal cell carcinomas (RCC) are the two most frequent subtypes of RCC. In this study, we studied RCC which displayed a hybrid morphology with areas of PRCC and CRCC or which contained papillary structures with clear cell changes (CCC). Consecutive cases of RCC collected over a 12-year period were reviewed to identify RCC with papillary structures and a possible admixture between CRCC and non-oncocytic PRCC. Special stains for glycogen and immunostaining for cytokeratin 7 were applied to sections containing both areas of classical PRCC and PRCC with CCC. Of the total of 541 RCC retrieved, there were 68 non-oncocytic RCC having papillary structures that could be grouped into: (a) group 1 (15 cases), CRCC with areas of papillary formation; (b) group 2a (9 cases), PRCC with extensive CCC with areas of foamy epithelial cells or macrophages; (c) group 2b (18 cases), RCC with areas of classical PRCC with focal CCC; and (d) group 3 (26 cases), RCC with features of groups 2a and 2b and containing areas of classical CRCC. There was a high rate (12/68) of sarcomatous transformation in the study cases. Groups 2 and 3 were associated with a higher rate of vascular invasion, distant metastasis, and mortality than classical PRCC and a higher rate of lymph node metastasis than CRCC. Our study identifies two groups of RCC (referred to as groups 2 and 3) that exhibit characteristic cytohistopathologic hybrid features that set them apart from classical RCC. This type of hybrid tumor seems to be associated with a more aggressive biologic behavior, and its recognition may facilitate the classification of RCC with ambiguous morphology.

Topics: Adenocarcinoma, Clear Cell; Adenocarcinoma, Papillary; Biomarkers, Tumor; Canada; Carcinoma, Renal Cell; Glycogen; Humans; Immunoenzyme Techniques; Keratin-7; Kidney Neoplasms; Survival Rate

A peripheral primitive neuroectodermal tumor (pPNET), most consistent with a human Ewing's sarcoma, is described in a 5-month-old male Australian Shepherd puppy. The first tumor site detected was in the left frontal bone of the skull with apparent subsequent rapid metastases to multiple sites in the axial and appendicular skeleton and bone marrow, kidneys, and perihyphophyseal meninges. Radiographically, all bone lesions were lytic and there was also a humeral bone fracture. Histologically, the tumor was diagnosed as a small round blue cell tumor. At this stage, the differential diagnosis included a lymphoma, rhabdomyosarcoma, and a PNET of the peripheral nervous system. However, the cells had positive expression of triple neurofilament antigens as detected immunocytochemically. The cells were negative for a broad panel of canine-specific leucocyte cell marker antigens for desmin, smooth muscle actin, synaptophysin, and CD99. Ultrastructurally, the cells contained occasional dense core neurosecretory granules and intermediate filaments with intercellular desmosomal-like junctions and abundant glycogen clusters. Based on the age of the dog, the clinical history, the distribution of gross lesions, histologic characteristics of a small round blue cell tumor, and immunocytochemical and ultrastructural evidence of neuroectodermal differentiation, a diagnosis of a pPNET similar to a human Ewing's sarcoma was made.

Topics: Animals; Bone Marrow Neoplasms; Bone Neoplasms; Desmosomes; Dog Diseases; Dogs; Glycogen; Immunohistochemistry; Intermediate Filaments; Kidney Neoplasms; Male; Meningeal Neoplasms; Neuroectodermal Tumors, Primitive, Peripheral; Neurofilament Proteins

Renal angiomyolipomas are highly vascular tumors that occur sporadically, in women with pulmonary lymphangiomyomatosis (LAM), and in tuberous sclerosis complex (TSC). The goal of this study was to determine whether the distinctive vessels of angiomyolipomas are neoplastic or reactive. We studied angiomyolipomas with loss of heterozygosity (LOH) in the TSC2 region of chromosome 16p13 from patients with LAM. We found that angiomyolipomas contain five morphologically distinct vessel types: cellular, collagenous, hemangiopericytic, glomeruloid, and aneurysmatic. Using laser capture microdissection, we determined that four of the vessel types have TSC2 LOH and are therefore neoplastic. One vessel type, collagenous vessels, did not have LOH, and is presumably reactive. Recently, activation of S6 Kinase and its target S6 ribosomal protein (S6) was demonstrated in cells lacking TSC2 expression. We found that angiomyolipoma vessel types in which LOH were detected were immunoreactive with anti-phospho-S6 antibodies. Angiomyolipoma cells without LOH, including the endothelial component of the vessels, were not immunoreactive. To our knowledge, angiomyolipomas are the first benign vascular tumor in which the vascular cells, rather than the stromal cells, have been found to be neoplastic. Angiomyolipomas appear to reflect novel vascular mechanisms that may be the result of activation of cellular pathways involving S6 Kinase.

Topics: Angiomyolipoma; Chromosome Mapping; Chromosomes, Human, Pair 13; Gene Deletion; Genes, Tumor Suppressor; Genetic Markers; Glycogen; Humans; Kidney Neoplasms; Loss of Heterozygosity; Lymphangioleiomyomatosis; Repressor Proteins; Ribosomal Protein S6; Ribosomal Protein S6 Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Clear cell tumors of the lung are commonly primary, clear-cell, bronchial carcinomas or metastasis of a renal cell carcinoma. Compared to this, pulmonary sugar tumor is a rare entity. A large intracellular content of glycogen and immunohistochemical procedures lead to diagnosis. The demonstration of the premelanosomal protein HMB-45 is considered as proof, but this is not airtight. We present a case of metachronic, benign, and HMB-45-negative sugar tumor of the lung after hypernephroma and give a review of the literature.

Topics: Adenocarcinoma, Clear Cell; Antigens, Neoplasm; Biomarkers, Tumor; Diagnosis, Differential; Glycogen; Humans; Kidney Neoplasms; Lung; Lung Neoplasms; Male; Melanoma-Specific Antigens; Middle Aged; Neoplasm Proteins; Neoplasms, Multiple Primary; Nephrectomy; Pneumonectomy; Postoperative Complications; Thoracoscopy; Tomography, X-Ray Computed

Clear cell adenocarcinoma of salivary glands (CCASG) is a relatively rare tumor, composed entirely of clear cells of putative ductal origin. It bears striking morphologic similarities to renal cell carcinoma (RCC) of clear cell type on hematoxylin and eosin stains. Differentiation between CCASG and metastatic RCC to the salivary glands has been considered problematic or even impossible on morphologic grounds. We examined three cases of CCASG and 12 cases of RCC (6 primary and 6 metastatic) by hematoxylin and eosin staining, immunohistochemistry, and electron microscopy. Two distinctive immunohistochemical and ultrastructural patterns emerged from this analysis. CCASG showed positivity for high molecular weight cytokeratin and carcinoembryonic antigen and ultrastructurally showed prominent squamoid differentiation, glycogen pools, and absence of lipid. In contrast, RCC was characterized by positivity for vimentin and complete absence of staining for high molecular weight cytokeratin and carcinoembryonic antigen. On ultrastructural studies, RCC lacked any squamoid differentiation, and the tumor cells contained abundant cytoplasmic lipid in addition to glycogen. Thus, based on the consistent differences on the immunohistochemical staining patterns and their characteristic subcellular morphology, CCASG and RCC can be distinguished on pathologic evaluation. The different direction of differentiation of the cells in CCASG and RCC (i.e., ductal in the former and renal tubular and mesodermal in the latter) results in their distinctive immunophenotypical and ultrastructural features.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Carcinoembryonic Antigen; Carcinoma, Renal Cell; Diagnosis, Differential; Female; Glycogen; Humans; Immunoenzyme Techniques; Keratins; Kidney Neoplasms; Lipids; Male; Middle Aged; Salivary Gland Neoplasms; Vimentin

Streptozotocin-induced tumours in the kidneys of experimental animals have been shown to be histologically similar to human renal cell carcinoma. We report the ultrastructural features of renal tumours induced in 15 mice by a single intravenous bolus of 2.5% streptozotocin administered in a dose of 250 mg streptozotocin/kg mouse body weight. Animals were sacrificed 232-361 days after the administration of streptozotocin. On examination both kidneys from each animal contained 1-4 dysplastic tubules and 1-3 discrete tumours per kidney. Twelve dysplastic proximal convoluted tubules showing varying degrees of epithelial atypia and nine tumours exhibiting either a papillary or solid architecture were examined. Dysplastic epithelial cells and tumours of papillary and solid type exhibited complex cell borders with well-developed junctional complexes. The majority of cells contained surface microvilli, and in some cells microvilli-lined intracytoplasmic lumina were observed. Occasional dysplastic epithelial cells and tumour cells contained double-membrane vesicles 120-200 nm in diameter. These were similar to the intracytoplasmic vesicles characteristic of human chromophobe renal cell carcinoma. Intracytoplasmic collections of glycogen granules and flocculant protein were identified in both dysplastic and neoplastic cells, and where prominent they resulted in compression of cytoplasmic organelles. Coated vesicles were commonly observed. These were free within the cytoplasm and were also seen budding from strands of rough endoplasmic reticulum. The distribution of these vesicles suggested a role in protein transport from the rough endoplasmic reticulum. It is concluded that while streptozotocin-induced renal tumours have some ultrastructural features in common with human chromophobe renal cell carcinoma, the overall ultrastructural morphology differs significantly from that described for the various histological types of human renal cell carcinoma.

Topics: Animals; Anti-Bacterial Agents; Carcinoma; Cytoplasm; Disease Models, Animal; Female; Gap Junctions; Glycogen; Humans; Kidney Neoplasms; Mice; Mice, Inbred CBA; Microvilli; Streptozocin

Four new permanent cell lines (RCC-A, -B, -C, and -D) derived from different human renal cell carcinomas of the clear cell type were established in tissue culture. The cell lines displayed characteristic differences in cell size and shape, which allowed individual identification by phase contrast microscopy. Ultrastructurally, the cell lines exhibited varying amounts of cytoplasmatic glycogen and lipid. Immunohistochemistry revealed co-expression of vimentin and cytokeratin in all cell lines. The mean population doubling time ranged from 27 h (RCC-A) to 104 h (RCC-D). RCC-B and -C cells produced slowly growing tumours after heterotransplantation into nude mice, whereas RCC-A and RCC-D cells were non-tumorigenic. The modal chromosome number was either near-diploid (RCC-A, -B, and -C) or near triploid (RCC-D). Clonal abnormalities affecting the short arm of chromosome 3 were seen in all cell lines. Northern blot analysis revealed no expression of the proto-oncogenes c-fos, c-ros, and c-mos, whereas c-Ki-ras expression was observed in all cell lines. Expression of c-myc was observed in RCC-A, RCC-B, and RCC-D cells, whereas c-raf expression could be detected in RCC-B and RCC-D. Tumour suppressor gene p53 mRNA was observed in the cell line RCC-D.

Topics: Adenocarcinoma, Clear Cell; Animals; Cell Line; Chromosome Aberrations; Chromosomes, Human, Pair 3; Genes, myc; Genes, p53; Genes, ras; Glycogen; Humans; Keratins; Kidney Neoplasms; Mice; Mice, Nude; Microscopy, Phase-Contrast; Neoplasm Transplantation; Ploidies; Vimentin

We report a comparative study of 3 clear cell tumors of the lung (CCTL) and 3 angiomyolipomas (AML) of the kidney. Morphological analysis shows that the cells of CCTL are identical to the perivascular epithelioid component of AML. Phenotypically they both consistently expressed melanoma-associated antigens recognized by Moabs HMB45 and HMSA-1, while they were negative for HMSA-5. A minority of cells also expressed S-100 protein, vimentin and actin. In addition, one case of CCTL showed mature adipose tissue entrapped in the proliferation, thus suggesting an intermediate form between CCTL and AML. Based on morphological and phenotypical similarities, it is suggested that CCTL and AML belong to the same family of lesions, characterized by the presence of a peculiar muscle cell, expressing different melanoma-associated antigens.

Topics: Adult; Angiomyolipoma; Blood Vessels; Epithelioid Cells; Female; Glycogen; Humans; Immunohistochemistry; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged

A total of 49 dimethylnitrosamine (DMN)-induced rat renal cell tumors were analyzed and classified cytomorphologically at an early stage of development. Of these, 17 were basophilic-tubular tumors, two of which showed a direct transition to proximal tubules of the P3-segment; 21 lesions were vacuolated and contained glycogen; these were defined cytomorphologically as a separate tumor type the histogenetic derivation of which from the collecting duct system was established by documentation of a direct transition. Morphological similarities point to the lipid-storing variant of the basophilic tumor, but a carcinoma of the ducts of Bellini is another possible human equivalent of this tumor type. Another seven lesions were clear and granular cell tumors. In two of these a direct transition from the collecting duct system was found, thus confirming that this only recently established origin of experimentally induced rat renal clear cell tumors also applies to lesions induced by DMN. The proliferation kinetics of DMN-induced lesions were studied in autoradiograms after pulse-labeling with tritiated thymidine. The basal proliferation of these early tumor stages displayed a marked proliferative advantage over the normal parenchyma. The lesions were still subject to physiological growth stimulation as determined by 3H-TdR-continuous-labeling with osmotic mini-pumps following unilateral nephrectomy. However, compared with normal kidney parenchyma, the 3H-TdR-labeling index of the lesions was even higher indicating a response modification during early neoplasia.

Topics: Animals; Basement Membrane; Cell Cycle; Cell Division; Dimethylnitrosamine; Female; Glycogen; Kidney Neoplasms; Kidney Tubules, Collecting; Kidney Tubules, Proximal; Rats; Rats, Inbred Strains; Thymidine; Vacuoles

Renal cell carcinomas can be subclassified into clear cell carcinomas, chromophobe cell carcinomas, chromophilic cell carcinomas, and oncocytomas. Previous studies, in which no distinction among the different types of renal cell tumors and their grades of malignancy was performed, showed that these tumors had high glycolytic rates.. The carbohydrate metabolism of control human kidney samples and renal clear cell carcinomas with different degrees of cytologic malignancy (G I, G II, and G III) was studied by determining the glycogen and glucose-6-phosphate levels and the activities of key enzymes involved in glycolysis (hexokinase, glucokinase, pyruvate kinase), gluconeogenesis (glucose-6-phosphatase, fructose-1,6-diphosphatase), and the pentose phosphate pathway (glucose-6-phosphate dehydrogenase) in these tissues and compared with those of a limited number of chromophilic cell carcinomas, chromophobe cell carcinomas, and oncocytomas.. The glycogen and glucose-6-phosphate levels were significantly higher in G I, G II, and G III clear cut carcinomas than in control kidneys; glucokinase, hexokinase, and glucose-6-phosphate dehydrogenase activities remained unchanged, pyruvate kinase activity was enhanced, and glucose-6-phosphatase as well as fructose-1,6-diphosphatase activities were strongly reduced when compared with control kidney values. In chromophilic cell carcinomas glycogen content, glucose-6-phosphate dehydrogenase, and pyruvate kinase activities were elevated, while fructose-1,6-diphosphatase activity was reduced. In chromophobe cell carcinomas glycogen content was elevated and gluconeogenesis was reduced, whereas glycolysis was not activated. In oncocytomas glycogen was not detected and glucose-6-phosphate dehydrogenase, pyruvate kinase, and fructose-1,6-diphosphatase activities remained unchanged.. It has been demonstrated that a series of characteristic changes occur in the carbohydrate metabolism of renal clear cell carcinomas: glycogen and glucose-6-phosphate levels increase, glycolysis is activated, and gluconeogenesis is reduced. Furthermore, the alterations of the carbohydrate metabolism within clear cell carcinomas are clearly distinct from those observed in chromophilic cell carcinomas, chromophobe cell carcinomas, and oncocytomas.

Topics: Adenocarcinoma; Carbohydrate Metabolism; Glucokinase; Glucose-6-Phosphate; Glucosephosphate Dehydrogenase; Glucosephosphates; Glycogen; Hexokinase; Humans; Kidney; Kidney Neoplasms; Reference Values

Renal clear cell tubules and clear/acidophilic cell tumors were induced in male Sprague-Dawley rats by 7 weeks oral administration (stop model) of N-nitrosomorpholine (NNM) at a concentration of 12 mg/100 ml in the drinking water. Twelve, 23 and 34 weeks after withdrawal of NNM serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: glucose transporter proteins (GLUT1, GLUT2), glycogen content and the activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), alkaline phosphatase (ALP), acid phosphatase (ACP) and gamma-glutamyltransferase (GGT). Clear cell (glycogenotic) tubules first appeared at 23 weeks, and clear/acidophilic cell tumors at 34 weeks after withdrawal of the carcinogen. G6Pase, ALP, GGT and GLUT2 were absent in clear cell tubules, clear/acidophilic cell tubules, and clear/acidophilic cell tumors indicating a sequential origin of all these types of lesions from the collecting duct system, in line with previous morphological findings. In comparison to the collecting duct epithelium, glycogenotic tubules demonstrated an increased activity of PHO and reduced activities of glycolytic and mitochondrial enzymes, which were accompanied by a strongly reduced expression of GLUT1. Moderately increased activities of glycolytic and mitochondrial enzymes were observed in the clear cells of clear/acidophilic cell tubules and tumors compared with those in glycogenotic tubules. They had slightly increased activities of the glycolytic enzymes GAPDH and PK compared with normal collecting duct epithelium, while most of them were nearly lacking in GLUT1. Our findings suggest that glycogen storage is not due to an increased uptake of glucose from the blood, but results from a disturbance in intracellular flux of metabolites. The development of clear cell tubules from the normal collecting duct epithelium is accompanied by a markedly decreased expression of GLUT1 along with a reduction in glycolytic and mitochondrial enzymes. This reduction of enzyme activities is replaced by an increase in enzyme activities in clear/acidophilic cell tumors indicating a fundamental shift in carbohydrate metabolism during progression from preneoplastic to neoplastic lesions.

Topics: Animals; Carcinoma, Renal Cell; Glycogen; Immunohistochemistry; Kidney Neoplasms; Kidney Tubules, Collecting; Male; Monosaccharide Transport Proteins; Nitrosamines; Rats; Rats, Sprague-Dawley

The study was concerned with evaluating the quantitative histochemical and histoenzymatic peculiarities of renal cell carcinoma of various grade of malignancy. It involved measuring levels of lipids, glycogen, protein, nucleic acids and sugar as well as the activities of dehydrogenases, phosphatases, non-specific esterase and lipase in tumor cells. Grade I neoplasms were found to be associated with low proliferative activity matched by relatively high energy production thus causing excessive synthesis of lipids and glycogen to occur. Higher cell proliferative activity in grade II and III tumors accounts for a significantly lower level of lipids and glycogen. Those metabolic peculiarities appeared to correlate with prognosis.

Topics: Carcinoma, Renal Cell; Esterases; Glycogen; Histocytochemistry; Kidney; Kidney Neoplasms; Lipase; Lipids; Nucleic Acids; Oxidoreductases; Phosphoric Monoester Hydrolases; Prognosis; Proteins

Five cases of a recently characterized renal neoplasm, chromophobe cell carcinoma, encountered during an ultrastructural and DNA flow cytometric study of renal cortical neoplasms are described. These tumors usually are dark on gross examination and often are associated with focal hemorrhage or necrosis. Microscopically the tumor cell cytoplasm ranges from clear to eosinophilic, potentially eliciting a broad differential diagnosis encompassing renal cell carcinoma and oncocytoma. Ultrastructural studies disclosed the diagnostically required numerous complex cytoplasmic vesicles of unknown composition and origin, and DNA ploidy studies revealed an aneuploid cell population in three of five cases, which correlates with the malignant potential.

Topics: Adult; Carcinoma; Cell Membrane; Cell Nucleus; Cytoplasm; DNA, Neoplasm; Female; Flow Cytometry; Glycogen; Humans; Kidney Neoplasms; Male; Microscopy, Electron; Microvilli; Middle Aged; Mitochondria; Organelles; Ploidies

This paper reports on 32 chromophobe cell renal carcinomas observed in 697 renal cell cancers (RCC) of adults (peak in the sixth decade of life). The chromophobe cell-type differs from other types of RCC macroscopically, the cut-surface being predominantly of grey-beige colour. Histologically, there are two variants: one is the typical (light) variant (n = 22) and the other is eosinophilic (n = 10). Both variants have in common (a) reaction of the cytoplasm with Hale's acid iron colloid; (b) electron microscopic detection of cytoplasmic microvesicles (150-300 nm), frequently with 'inner vesicles', and (c) low glycogen content in comparison with the clear cell carcinoma. Immunocytochemical investigations on the intermediate filaments show a positive reaction for cytokeratins No. 18 (uniformly) and Nos. 7 and 19 (to varying extents) for both variants, whereas vimentin was not found in any of these carcinomas, in contrast to the clear-cell type. The cytomorphological grading revealed predominantly G II tumours. A lymph node metastasis was found in one patient. On the basis of the mortality curves determined, the prognosis for patients with chromophobe cell carcinomas is more favourable than that of the clear-cell type. In terms of differential diagnosis, on the one hand, the typical (light) variant of the chromophobe cell RCC must be delimited from the clear-cell RCC, and on the other hand, the eosinophilic variant must be distinguished from the chromophilic or 'granular' RCC. Microscopic, histological, histochemical, electron microscopic, and intermediate filament analysis results document that the chromophobe cell type of RCC is a distinct entity. The implications for the nomenclature of RCC, especially with regard to the 'granular' type, are discussed.

Topics: Adult; Aged; Carcinoma, Renal Cell; Eosine Yellowish-(YS); Female; Glycogen; Humans; Intermediate Filaments; Keratins; Kidney Neoplasms; Male; Microscopy, Electron; Middle Aged; Prognosis; Staining and Labeling; Vacuoles; Vimentin

Basing on quantitative morphological and histochemical findings, 170 cases of renal carcinoma were divided into 3 (I, II, III) grades of malignancy. This grading system is of a high prognostic significance. Histological variant, i.e. the predominance of clear or granular cells in the tumor specimens, is not prognostically significant. The clear cells differ from the granular ones by high lipid and glycogen content and by low proliferation rate. In tumors of a high malignancy grade the lipid and glycogen levels are low. The authors offer to divide all cases of renal carcinoma not into clear- and granular-cell tumors, but on lipid-rich and lipid-poor ones because the lipid content is in good correlation with the grade of malignancy and therefore prognostically valuable.

Topics: Adenocarcinoma; Adult; Aged; Carcinoma; DNA, Neoplasm; Female; Glycogen; Histocytochemistry; Humans; Kidney; Kidney Neoplasms; Lipid Metabolism; Male; Middle Aged; Prognosis

112 cases of renal cell carcinoma were studied histologically and histochemically. Variants of renal cell carcinoma were found to have certain histochemical peculiarities: accumulation of neutral fat and cholesterol esters in the clear-cell tumor variant and bound lipids and proteins in the tumors of granular cell, sarcoma-like and glandular variants. These characteristics become less distinct with decrease of differentiation degree of tumor cells. These features can be used for differential diagnosis of renal cell carcinoma.

Topics: Adult; Aged; Carcinoma, Renal Cell; Cholesterol; Glycogen; Histocytochemistry; Humans; Kidney Neoplasms; Lipid Metabolism; Middle Aged; Neoplasm Proteins; Sulfhydryl Compounds

We report the third case of renal hemangiopericytoma associated with spontaneous hypoglycemia. The clinical and pathological features suggest that excessive glucose storage by the tumor is an important factor in the pathogenesis of the hypoglycemia. Other possible mechanisms producing hypoglycemia associated with mesenchymal tumors are reviewed.

Topics: Adult; Angiography; Electroencephalography; Female; Glycogen; Hemangiopericytoma; Humans; Hypoglycemia; Kidney; Kidney Neoplasms; Microscopy, Electron; Ultrasonography; Urography

A case of renal cell carcinoma presenting as a nosebleed of three-week duration is described. Light microscopy of a nasal lesion showed a richly vascular tumor, forming glands and uniformly consisting of clear cells. Cytochemically and ultrastructurally, the presence of abundant lipid droplets and glycogen within the neoplastic cells indicated a renal origin. An extended clinical search for a primary kidney tumor was undertaken in view of a negative intravenous tomographic pyelography and renal scan findings. An angiogram finally revealed an intrarenal mass which was proven pathologically as a renal cell carcinoma.

Topics: Adenocarcinoma; Epistaxis; Glycogen; Humans; Kidney Neoplasms; Lipid Metabolism; Liver Glycogen; Male; Middle Aged; Nose Neoplasms

Topics: Animals; Cell Transformation, Neoplastic; Glycogen; Glycogen Storage Disease; Kidney Neoplasms; Kidney Tubules; Mitochondria; Morpholines; Nitroso Compounds; Precancerous Conditions; Rats

Topics: Adenocarcinoma; Adenylyl Cyclases; Adult; Aged; Enzyme Activation; Female; Glucagon; Glycogen; Humans; In Vitro Techniques; Kidney Cortex; Kidney Neoplasms; Male; Middle Aged; Parathyroid Hormone; Prostaglandins E; Sodium Fluoride

An angiomyolipoma from a twenty-six-year-old woman was studied by electron microscopy. The tumor was composed of a mixture of mature smooth muscle cells, fat cells, and abnormal blood vessels. MAny of the smooth muscle cells showed excessive intracytoplasmic accumulation of glycogen, while the abnormal blood vessels lacked a normal media.

Topics: Adipose Tissue; Adult; Female; Glycogen; Hemangioma; Humans; Kidney Neoplasms; Lipoma; Microscopy, Electron; Muscle, Smooth

Topics: Animals; Cell Transformation, Neoplastic; Glycogen; Kidney Neoplasms; Mitochondria; Morpholines; Neoplasms, Experimental; Nitrosamines; Rats

Twelve cases of ovarian clear cell carcinoma were studied histologically. Four cases were examined electron microscopically and compared with other conditions. Five tumors were directly connected with ovarian endometriosis. They were histologically classified into a tubular type with hobnail cells and a solid type without tubular pattern or hobnail cells. Electron microscopic figures of the tumor cells are identical having large nuclei, abundant glycogen, lamellated RER, few lipid droplets, and sparse but well-developed microvilli. The basophilic dark cells frequently encountered in the tubular type are morphologically quite similar to clear cells excepting for sparsity of glycogen and lipid droplets. Alveolar arrangement of 6 to 10 tubular structures (honeycomb structure) resembling alveolate structure seen in late secretory endometrium was found in tumor cells of one case. Ultrastructural feature of clear cell carcinoma closely resemble those of Arias-Stella endometrium and clear cell carcinoma of endocervix suggesting their Muellerian origin.

Topics: Adenocarcinoma; Adult; Endometriosis; Endometrium; Female; Glycogen; Humans; Kidney Neoplasms; Mesonephroma; Microscopy, Electron; Middle Aged; Neoplasms, Multiple Primary; Ovarian Neoplasms; Uterine Cervical Neoplasms

Fluorescent cytochemical techniques, chiefly end-group methods, have been employed in the characterization of cells in calid and algid normal and LUCKE tumor-bearing kidneys of the leopard frog, Rana pipiens. Cytoplasmic RNA and glycogen distribution reflect the known patterns of general metabolic activity of the respective cells in question. Protein sulfhydryl distribution is similar in normal distal tubules and tumors while both differ significantly from proximal tubules. Viral inclusions in nuclei of algid tumor cells contain demonstrable DNA, protein sulfhydryls and disulfides, arginine and lysine-rich basic proteins, also both C-terminal and side chain carboxyl groups. Significant amounts of DNA are demonstrable in the cytoplasm of algid tumors. Fluorescence cytochemical methods directed toward end-groups or specific classes of macromolecules offer a particularly favorable option, because of increased sensitivity and higher levels of contrast, for comparative cytological investigations of the LUCKE tumor and of similar systems.

Topics: Adenocarcinoma; Animals; Anura; Arginine; Carboxylic Acids; Cell Nucleus; Cytoplasm; Disulfides; DNA, Neoplasm; Fluorescent Dyes; Glycogen; Histocytochemistry; Inclusion Bodies, Viral; Kidney Neoplasms; Kidney Tubules; Lysine; Neoplasm Proteins; Rana pipiens; RNA, Neoplasm; Seasons; Sulfhydryl Compounds

Electron microscopic study of bilateral renal angiomyolipoma in a case of tuberous sclerosis showed two cell types: smooth muscle cells and fibroblasts. There were no tubular or glomerular elements within the tumor mass. To our knowledge this study represents the first ultrastructural demonstration of smooth muscle cells occurring in the renal lesions of this complex.

Topics: Adult; Basement Membrane; Cytoplasmic Granules; Glycogen; Humans; Kidney Neoplasms; Male; Muscle, Smooth; Tuberous Sclerosis

Topics: Adenoma; Adenoma, Acidophil; Adenoma, Basophil; Adenoma, Chromophobe; Administration, Oral; Animals; Cell Transformation, Neoplastic; Cystadenoma; Female; Glycogen; Histocytochemistry; Kidney; Kidney Neoplasms; Male; Morpholines; Neoplasms; Neoplasms, Experimental; Nitrosamines; Rats

Topics: Acid Phosphatase; Adenocarcinoma; Adult; Aged; Alkaline Phosphatase; Dihydrolipoamide Dehydrogenase; Electron Transport Complex IV; Female; Glucose-6-Phosphatase; Glycogen; Glycosaminoglycans; Humans; Kidney Neoplasms; L-Lactate Dehydrogenase; Lipid Metabolism; Male; Middle Aged; NADPH Dehydrogenase; Nucleic Acids; Oxidoreductases; Phosphorylases; Succinate Dehydrogenase

Topics: Adenoma; Aged; Basement Membrane; Carcinoma; Cytoplasm; Epithelium; Glycogen; Humans; Kidney Neoplasms; Kidney Tubules; Kidney Tubules, Proximal; Male; Methenamine; Microscopy, Electron; Middle Aged; Mitochondria; Silver

Topics: Adenocarcinoma; Basement Membrane; Carcinoma; Carcinoma, Basal Cell; Cell Membrane; Cell Nucleus; Cilia; Connective Tissue; Cytoplasm; Cytoplasmic Granules; Epithelial Cells; Fibroblasts; Glycogen; Golgi Apparatus; Humans; Inclusion Bodies; Intercellular Junctions; Kidney; Kidney Neoplasms; Leiomyosarcoma; Microscopy, Electron; Mitochondria; Mitosis; Muscle, Smooth; Neuroblastoma; Wilms Tumor

Topics: Aged; Biopsy; Bone Marrow; Carcinoma, Squamous Cell; Fats; Female; Glycogen; Glycosaminoglycans; Histocytochemistry; Humans; Inhalation; Kidney Neoplasms; Lymphadenitis; Lymphoma, Non-Hodgkin; Male; Methods; Neoplasms; Pancreatic Neoplasms

Topics: Acid Phosphatase; Adenocarcinoma; Alkaline Phosphatase; Aminopeptidases; Glucose-6-Phosphatase; Glycogen; Humans; Kidney Neoplasms; Lipid Metabolism; Nucleotidases; Staining and Labeling

Topics: Adenocarcinoma; Cytoplasm; Glycogen; Humans; Kidney; Kidney Neoplasms; Microscopy, Electron; Nephrectomy; Staining and Labeling; Triglycerides

Cells which contain glycogen, and which may arise from the connective tissue matrix, can be demonstrated in the estrogen-induced renal tumor of the hamster when the tumor tissue used has either been lyophilized or frozen and then substituted in absolute alcohol containing mercuric chloride. Glycogen has not been found previously in this type of tumor. Studies of the role of glycogen in this type of neoplasm nmay elucidate mechanisms of tumorigenesis.

Topics: Animals; Biochemical Phenomena; Biochemistry; Cricetinae; Estrogens; Glycogen; Kidney Neoplasms; Neoplasms; Research; Toxicology

Topics: Glycogen; Humans; Kidney Neoplasms; Male; Neoplasms; Testicular Neoplasms; Testis; Urinary Bladder Neoplasms