glycogen and Cell-Transformation--Neoplastic

Clear cell hepatocellular carcinoma (CCHCC) has hitherto been considered an uncommon, highly differentiated variant of hepatocellular carcinoma (HCC) with a relatively favorable prognosis. CCHCC is composed of mixtures of clear and/or acidophilic ground glass hepatocytes with excessive glycogen and/or fat and shares histology, clinical features and etiology with common HCCs. Studies in animal models of chemical, hormonal and viral hepatocarcinogenesis and observations in patients with chronic liver diseases prone to develop HCC have shown that the majority of HCCs are preceded by, or associated with, focal or diffuse excessive storage of glycogen (glycogenosis) which later may be replaced by fat (lipidosis/steatosis). In ground glass cells, the glycogenosis is accompanied by proliferation of the smooth endoplasmic reticulum, which is closely related to glycogen particles and frequently harbors the hepatitis B surface antigen (HBsAg). From the findings in animal models a sequence of changes has been established, commencing with preneoplastic glycogenotic liver lesions, often containing ground glass cells, and progressing to glycogen-poor neoplasms via various intermediate stages, including glycogenotic/lipidotic clear cell foci, clear cell hepatocellular adenomas (CCHCA) rich in glycogen and/or fat, and CCHCC. A similar process seems to take place in humans, with clear cells frequently persisting in CCHCC and steatohepatitic HCC, which presumably represent intermediate stages in the development rather than particular variants of HCC. During the progression of the preneoplastic lesions, the clear and ground glass cells transform into cells characteristic of common HCC. The sequential cellular changes are associated with metabolic aberrations, which start with an activation of the insulin signaling cascade resulting in pre-neoplastic hepatic glycogenosis. The molecular and metabolic changes underlying the glycogenosis/lipidosis are apparently responsible for the dramatic metabolic shift from gluconeogenesis to the pentose phosphate pathway and Warburg-type glycolysis, which provide precursors and energy for an ever increasing cell proliferation during progression.

Topics: Animals; Carcinoma, Hepatocellular; Cell Proliferation; Cell Transformation, Neoplastic; Disease Progression; Energy Metabolism; Glycogen; Humans; Liver Neoplasms; Phenotype; Precancerous Conditions

Biochemical and molecular biological approaches in situ have provided compelling evidence for early bioenergetic changes in hepatocarcinogenesis. Hepatocellular neoplasms regularly develop from preneoplastic foci of altered hepatocytes, irrespective of whether they are caused by chemicals, radiation, viruses, or transgenic oncogenes. Two striking early metabolic aberrations were discovered: (1) a focal excessive storage of glycogen (glycogenosis) leading via various intermediate stages to neoplasms, the malignant phenotype of which is poor in glycogen but rich in ribosomes (basophilic), and (2) an accumulation of mitochondria in so-called oncocytes and amphophilic cells, giving rise to well-differentiated neoplasms. The metabolic pattern of human and experimentally induced focal hepatic glycogenosis mimics the phenotype of hepatocytes exposed to insulin. The conversion of the highly differentiated glycogenotic hepatocytes to the poorly differentiated cancer cells is usually associated with a reduction in gluconeogenesis, an activation of the pentose phosphate pathway and glycolysis, and an ever increasing cell proliferation. The metabolic pattern of preneoplastic amphophilic cell populations has only been studied to a limited extent. The few available data suggest that thyromimetic effects of peroxisomal proliferators and hepadnaviral infection may be responsible for the emergence of the amphophilic cell lineage of hepatocarcinogenesis. The actions of both insulin and thyroid hormone are mediated by intracellular signal transduction. It is, thus, conceivable that the early changes in energy metabolism during hepatocarcinogenesis are the consequence of alterations in the complex network of signal transduction pathways, which may be caused by genetic as well as epigenetic primary lesions, and elicit adaptive metabolic changes eventually resulting in the malignant neoplastic phenotype.

Topics: Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Energy Metabolism; Glycogen; Humans; Insulin; Liver; Liver Neoplasms; Thyroid Hormones

Topics: Animals; Biological Assay; Brain; Cats; Cell Transformation, Neoplastic; Chick Embryo; Clone Cells; Cricetinae; Culture Media; Culture Techniques; Dogs; Glycogen; Histocytochemistry; Humans; Methods; Mice; Neuroglia; Proteins; Rabbits; Rats

Topics: Carcinogenesis; Cell Transformation, Neoplastic; Glycogen; Humans

Clear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen overload and activation of AKT (v-akt murine thymoma viral oncogene homolog)/mTOR (mammalian target of rapamycin)-signaling. Here, we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We found 14 genes and 22 proteins differentially expressed in CCF and the majority of these were expressed at lower levels in CCF. Using immunohistochemistry, the reduced expressions of STBD1 (starch-binding domain-containing protein 1), USP28 (ubiquitin-specific peptidase 28), monad/WDR92 (WD repeat domain 92), CYB5B (Cytochrome b5 type B), and HSPE1 (10 kDa heat shock protein, mitochondrial) were validated in CCF in independent specimens. Knockout of

Topics: Biomarkers, Tumor; Cell Transformation, Neoplastic; Computational Biology; Gene Expression Profiling; Glycogen; Humans; Immunohistochemistry; Liver Diseases; Liver Neoplasms; Proteomics; Transcriptome

Topics: Amino Acid Transport System ASC; Cell Proliferation; Cell Transformation, Neoplastic; Colonic Neoplasms; Colorectal Neoplasms; Computational Biology; Exosomes; Fibroblasts; Fluorescent Antibody Technique; Glucose Transporter Type 1; Glycogen; Humans; Lactic Acid; Minor Histocompatibility Antigens; Proteomics; Tumor Microenvironment

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

Topics: Animals; Cell Transformation, Neoplastic; DNA; Female; Fibroblasts; Glycogen; Lipids; Necrosis; Neoplasms, Experimental; Proteins; Rats; RNA; Spectrum Analysis, Raman; Uterine Cervical Neoplasms

To confirm the eccrine acrosyringeal differentiation of eccrine syringofibroadenoma (ESFA) and to elucidate the histogenesis of its angiofibrotic stroma, a case of ESFA from a 45-year-old man was examined by light and electron microscopy. Histologically, the parenchyma featured anastomosing, slender epithelial cords containing small cuboidal cells and occasional duct-like structures. The stroma had increased numbers of mast cells, increased capillaries with swollen endothelial cells, and prominent fibrosis. Ultrastructurally, the following findings were characteristic of ESFA: a) abundant glycogen particles in epithelial cells, b) numerous intracytoplasmic and extracellular spaces lined with microvilli, c) intraepithelial duct formation, consisting of microvilli, vesicles, rod-shaped dense bodies, multivesicular dense bodies, and peripheral network of tonofilaments, and d) large numbers of mast cells, closely associated with fibroblasts, surrounding increased numbers of capillaries containing swollen endothelial cells. These ultrastructural features support the acrosyringeal differentiation of ESFA. We hypothesize that mast cell hyperplasia and degranulation may play an important role in the formation of the angiofibrotic stroma.

Topics: Adenofibroma; Adenoma, Sweat Gland; Cell Transformation, Neoplastic; Epithelium; Fibroblasts; Glycogen; Humans; Hyperplasia; Male; Mast Cells; Microscopy, Electron; Microvilli; Middle Aged; Sweat Gland Neoplasms

Mice were treated with griseofulvin (GF) containing diet or control diet for 12 months. The livers from mice fed griseofulvin showed large tumors that were excised and used for analysis. The infrared spectra from control liver tissue and tumor tissue from GF livers were measured and compared as a function of pressure up to 27 kbar. Many changes in the infrared spectral features of the tumor tissue were observed. Results showed that neoplasm formation involved structural modifications of nucleic acids, lipids, carbohydrates, and proteins in the liver cells, which were detected from the abnormal vibrations of the functional groups in these biomolecules. The amount of glycogen was dramatically decreased in the tumor tissue compared to the control tissue. Important changes in the strength of hydrogen-bondings in the phosphodiester backbone of the nucleic acids and in the C-O groups of tissue proteins and carbohydrates were observed. Stronger interchain interactions and thus close interchain packing among the lipids in the GF liver were evident. These results showed very close similarities with those obtained with other types of tumors such as human colon cancer, suggesting that a common pattern of molecular changes has been identified in neoplastic transformation.

Topics: Amides; Animals; Cell Transformation, Neoplastic; Glycogen; Griseofulvin; Hydrogen Bonding; Liver Neoplasms, Experimental; Mice; Mice, Inbred C3H; Phosphates; Pressure; Spectrophotometry, Infrared; Triglycerides

A human cell line, designated L-1, has been established from the ascites of an untreated patient with stage IV (FIGO) endometrioid ovarian cancer. This cell line initially grew uninterupted for 6 months without fibroblast contamination and contact inhibition, and has been subcultured weekly for the past 7 years. L-1 does not contain steroid hormone receptors nor does it demonstrate the presence of oncofetal antigens by immunohistochemical techniques. The doubling time of L-1 is 11.8 hr. Flow cytometric analysis reveals an aneuploid DNA peak, and an abnormal karyotype demonstrates hyperdiploidy, translocations, and deletions. Morphology, growth patterns, cytogenetic analysis, and other features of L-1 are characterized.

Topics: alpha-Fetoproteins; Carcinoembryonic Antigen; Cell Line; Cell Transformation, Neoplastic; Chromosomes; Endometriosis; Female; Flow Cytometry; Glycogen; Humans; Immunohistochemistry; Microscopy, Electron; Middle Aged; Mucins; Ovarian Neoplasms; Receptors, Estrogen; Receptors, Progesterone; Tumor Cells, Cultured

The human colon cancer line Caco-2 exhibits after confluency a concomitant increase of glycogen accumulation and an enterocytic differentiation. The purpose of this work was to investigate whether forskolin (FK), an activator of adenylate cyclase, would induce a permanent glycogenolysis and, if so, whether it would result in modifications of the differentiation pattern of the cells. FK activates adenylate cyclase in Caco-2 cells with an ED50 of 7 X 10(-6)M. Three different treatment protocols with FK (10(-5)M) were applied: 1) the cells were treated during all the time in culture (20 days); 2) the treatment was started after confluency; 3) the treatment was interrupted after confluency. The presence of FK results in a permanent stimulation of cAMP accumulation (10 to 20 fold the basal values) and in a permanently reduced glycogen content (30 or 50% of the control values). The rates of glucose consumption are increased three and five fold in protocols 1 and 3 respectively. These metabolic changes are associated with morphological changes (tightening of the intercellular spaces and shortening of the brush border microvilli) and with a dual inhibition of the activities of brush border hydrolases: a) an inhibition of the post-confluent increase of activity of sucrase, aminopeptidase N and alkaline phosphatase in the brush border enriched fraction; b) an inhibition of the post-confluent increase of activity of sucrase in the cell homogenate. A comparison of the results obtained in each protocol shows that the morphological modifications and the decrease of the enzyme activities in the brush border fraction are regularly associated with an increased cAMP accumulation, whereas the inhibition of the differentiation of sucrase is a direct consequence of the increase in glucose consumption and decrease in glycogen stores.

Topics: Cell Line; Cell Transformation, Neoplastic; Colforsin; Colonic Neoplasms; Cyclic AMP; Diterpenes; Dose-Response Relationship, Drug; Glucose; Glycogen; Humans; Hydrolases; Lactates; Microvilli

Bilaterally ovariectomized rats (Sprague-Dawley) were used to study the early effects of benzo(a)pyrene (BP) on the morphology and cytochemistry of vaginal epithelium. BP (50 mg/kg) was administered subcutaneously in 0.5 ml corn oil and dosing was daily for 2--6 days. Animals were sacrificed 24 hr after the last dose; and vaginal tissue was processed separately for light and electron microscopy, and ultracytochemistry. The results indicate that BP alone induces mucification, mitosis and DNA synthesis in the superificial and basal comportmanets of vaginal epithelium, and DNA synthesis in the submucosal layer. BP also enhances alkaline phosphatase activity and glycogenesis. Alkaline phosphatase is present in the plasma membranes of various cells and in the membranes delimiting secretory granules. Increased alkaline phosphatase is associated with cell growth and proliferation, and also with mucin formation and secretion. Glycogen is relatively abundant in the intermediate cells and parabasal cells. Further, periodic acid-silver methenamine staining indicates that secretory granules and mucin contain glycoproteins. An examination of the fine structure of mucocytes reveals that Golgi complex and granular endoplasmic reticulum are involved in the fabrication of mucin which is secreted by apocrinal and exocytotic processes. Increased mucification was observed after two days (2 doses) and intensified up to 6 days (6 doses). These findings provide evidence that BP is mucinogenic and mitogenic agent to vaginal epithelium in spayed rats without the presence of exogenous ovarian hormone promoting or inducing factors.

Topics: Alkaline Phosphatase; Animals; Benzopyrenes; Castration; Cell Transformation, Neoplastic; DNA, Neoplasm; Dose-Response Relationship, Drug; Epithelium; Female; Glycogen; Glycoproteins; Neoplasms, Experimental; Rats; Vagina; Vaginal Neoplasms

Topics: Animals; Blood; Cell Division; Cell Line; Cell Transformation, Neoplastic; Enzyme Activation; Glycogen; Glycogen Synthase; Insulin; Liver; Protein Biosynthesis; Rats; Receptor, Insulin

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

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

It is shown that human embryonic cells transformed by Rous sarcoma virus (stable cell line 23) and those transformed by polyoma virus (stable cell line P-2) are morphologically distinguished from the normal human embryonic cells. The mitotic activity of P-2 cells was 51% and the mitotic activity of 23 cells was 48%. While the mitosis activity of human embryo fibroblast was 28%. The duration of the mitosis of P-2 cells was 20 hours and that of 23 cells was 18 hr. The duration of the mitotic cycle of human embryo fibroblast was 18 hr. The G1 periods lasted 6 hours for both the cell lines; the S period of P-2 cells lasted 8 hr and the S period of 23 cells was 6 hr. Both the cell lines had a high content of RNA, DNA, protein bound SH-groups, and a high activity of acid phosphatase, acid RNAase and glucose-6-phosphatase. The content of glycogen, and acidic mucopolysaccharides, the activity of NADPH-tetrazolium reductase, succinic dehydrogenase of both the lines were the same as in normal human cells.

Topics: Acid Phosphatase; Avian Sarcoma Viruses; Cell Cycle; Cell Line; Cell Transformation, Neoplastic; Cell Transformation, Viral; DNA, Neoplasm; Glycogen; Humans; Polyomavirus; RNA, Neoplasm

The course of an infantial liver carcinoma is reported. Two liver biopsies and autopsy material were studied by light- and electron microscope. The histological findings and the clinical data are discussed. The first biopsy taken from the liver showed glycogen storage within the hepatic cells. It is suggested that this phenomenon is consistent with the preblastomatous stage of the liver cells. This fact is supported also by experimental way. The detection of this glycogen storage could be used as an early sign of the liver cancer in childhood, and might stress an early surgical intervention.

Topics: Autopsy; Biopsy; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Female; Glycogen; Humans; Infant; Liver; Liver Neoplasms; Microscopy, Electron

Steady-state kinetic tracer analysis and two-dimensional chromatography and autoradiography were used to examine the relation of glucose transport to its metabolism in cultured chick embryo fibroblasts. Cytochalasin B was added to Rous sarcoma virus-infected cells to bring the rate of glucose uptake to the level of uninfected cells. It is concluded for chick cells in culture that: (1) the transport of glucose, rather than its phosphorylation, is the rate limiting step and (2) the difference in aerobic glycolysis between normal and virus-transformed cells at physiological glucose concentration may be a consequence of the difference in the rates of glucose uptake.

Topics: Adenosine Triphosphate; Aerobiosis; Animals; Avian Sarcoma Viruses; Cell Transformation, Neoplastic; Cells, Cultured; Chick Embryo; Citric Acid Cycle; Cytochalasin B; Glucose; Glycogen; Glycolysis; Lactates; Pentosephosphates

The fine structural morphology of dyskeratotic and dysplastic keratinocytes in human oral epithelium was investigated by light microscopy as well as by transmission and scanning-electron microscopy. On the epithelial-connective tissue border, marked changes are seen in the form of polymorphous microinvasive cytoplasmic processes of basal keratinocytes, structural alterations of the basement membrane and rarefaction of the subepithelial connective tissue. Dyskeratotic keratinocytes with abnormal tonofilament configuration are phagocytized by dermal macrophages and are transported to the lamina propria. Ultrastructural signs of atypia are found in the nucleus, nucleolus, cytoplasmic organelles and mitotic apparatus. Furthermore, multiple alterations of the plasma membrane, decrease in numbers of junctional complexes and acantholytic widened intercellular spaces are observed. Intracytoplasmic lumina are formed by endocytotic invagination of desmosome-studed plasma membrane regions at the cell surface. Despite an inverse relationship between the degree of keratinization and the glycogen content of the epithelium at the subcellular level, large amounts of glycogen are found in some keratinocytes. The epithelial surface is formed by hyper-, para-, or orthokeratosis, or shows individual cell keratinization, alteration of the disintegration process and defective keratin synthesis. The ultrastructural analysis of dysplastic keratinocyte populations reveals some morphological criteria common with invasive squamous cell carcinoma, which may be important in the early diagnosis and prognosis of malignant transformation of epithelial dysplasia.

Topics: Cell Membrane; Cell Transformation, Neoplastic; Epithelial Cells; Epithelium; Glycogen; Humans; Intercellular Junctions; Keratins; Leukoplakia; Macrophages; Mouth Mucosa; Organoids; Phagocytosis

Topics: Cell Nucleus; Cell Transformation, Neoplastic; Cytoplasm; Endoplasmic Reticulum; Female; Glycogen; Humans; Hydatidiform Mole; Lipids; Pregnancy; Trophoblasts; Ultrasonography

In cells of human embryo skin--muscle tissue transformed by the Rouse sarcoma virus (23rd cell line) and polyoma virus (P-2 cell line), the mitotic activity was 48 0/00 for 23rd line, 51 0/00 for P-2 line as against 28 0/00 in the control cells. The transformed cells possessed greater amounts of RNA and DNA and protein--bound SH-groups, different forms of glycogen deposits, as well as higher acid phosphatase enzyme activities; there was practically no difference in acid mucopolysaccharide content or NAD-H2-diaphorase and succinate dehydrogenase activities.

Topics: Acid Phosphatase; Avian Sarcoma Viruses; Cell Line; Cell Transformation, Neoplastic; Cells, Cultured; Chromosomes; Dihydrolipoamide Dehydrogenase; DNA; DNA, Neoplasm; Glycogen; Glycosaminoglycans; Humans; Mitosis; Polyomavirus; Polyploidy; RNA; RNA, Neoplasm; Succinate Dehydrogenase; Sulfhydryl Compounds

Topics: Adenoma, Bile Duct; Animals; Autoradiography; Carcinoma, Hepatocellular; Cell Division; Cell Nucleus; Cell Transformation, Neoplastic; Fetal Proteins; Glycogen; Hyperplasia; Immunoelectrophoresis; Liver Neoplasms; Neoplasm Metastasis; Neoplasms, Experimental; p-Dimethylaminoazobenzene; Rats; Thymidine; Tritium

Topics: Administration, Oral; Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; DNA, Neoplasm; Glycogen; Histocytochemistry; Liver Neoplasms; Male; Neoplasms, Experimental; Nitrosamines; Rats; RNA, Neoplasm; Spectrophotometry; Time Factors

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: Agglutination; Agglutination Tests; Animals; Binding Sites, Antibody; Carbohydrates; Cell Line; Cell Membrane; Cell Transformation, Neoplastic; Concanavalin A; Cricetinae; Fibroblasts; Fluorescent Antibody Technique; Glycogen; Leukemia, Experimental; Leukemia, Myeloid, Acute; Lymphocytes; Lymphoma; Male; Mice; Movement; Rats; Tritium; Trypsin

Topics: Adenocarcinoma; Aged; Carcinoma; Carcinoma, Papillary; Cell Transformation, Neoplastic; Chlormadinone Acetate; Cytoplasm; Edema; Epithelium; Female; Follow-Up Studies; Glycogen; Humans; Metaplasia; Middle Aged; Mitosis; Mucus; Uterine Neoplasms

Topics: Animals; Carbon Dioxide; Cell Transformation, Neoplastic; Cells, Cultured; Chick Embryo; Fibroblasts; Glucose; Glycogen; In Vitro Techniques; Lactates; Sarcoma, Avian; Thymidine; Virus Cultivation

Topics: Aged; Cell Membrane; Cell Nucleolus; Cell Transformation, Neoplastic; Chromosomes; Epithelium; Female; Glycogen; Golgi Apparatus; Humans; Inclusion Bodies; Microscopy, Electron; Mitochondria; Mullerian Ducts; Neoplasms, Germ Cell and Embryonal; Uterine Neoplasms; Uterus