Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the development of liver tumors in male transforming growth factor alpha (TGF-alpha) transgenic mice of the CD1 strain and examined the expression of the transgene by immunohistochemistry and in situ hybridization. Livers of 4-5-week-old transgenic mice contained areas of centribobular hypertrophy with low glucose-6-phosphatase activity. These areas progressively expanded, and hypertrophy and dysplasia became generalized in livers of mice at 10-12 months of age. The expression of the transgene, determined by either immunohistochemistry or in situ hybridization, was uneven in animals that were 10 weeks old or older. The positive hepatocytes formed patches with a predominant centrilobular distribution. We studied a total of 23 liver tumors (7 hepatocellular carcinomas and 16 adenomas) obtained from 11 mice at 13-15 months of age and from one 7-month-old animal which received zinc sulfate to induce the transgene. The carcinomas were well differentiated tumors, without glucose-6-phosphatase or gamma-glutamyltranspeptidase activity, that developed from the dysplastic parenchyma and occasionally within an adenoma. In all carcinomas and in 56% of the adenomas there was overexpression of the transgene in relationship to the surrounding tissue. The majority of the tumors that overexpressed TGF-alpha were alpha-fetoprotein positive, while alpha-fetoprotein staining was not detected in tumors (all adenomas) that did not show excessive transgene expression. We conclude that TGF-alpha functions as a promoter of liver carcinogenesis through its effect as an autocrine inducer of hepatocyte proliferation. Further, the data indicate that TGF-alpha overexpression may favor tumor progression.
 ...
PMID:Development of liver tumors in transforming growth factor alpha transgenic mice. 132 2

The cellular origin of estrogen-induced kidney tumors in male Syrian hamsters has been repeatedly the subject of controversy. Several authors have proposed that the tumors arise from proximal tubules, from a combination of tubular and interstitial stromal cells, or solely from interstitial cells. Because of the model character of this tumor for hormone-associated cancer, it was further investigated in this study with respect to morphology, enzyme and intermediate filament pattern, the expression of alpha-smooth muscle actin and the extracellular matrix proteins fibronectin and tenascin. These analyses were carried out with early and late tumors as well as metastases to determine possible changes in expression of biochemical parameters during the development and progression of this neoplasm. The enzyme histochemical and intermediate filament patterns were usually the same as those described previously for proliferative foci and early tumors, i.e. highly elevated activities of glucose-6-phosphate dehydrogenase, adenylate cyclase and alkaline phosphatase, a lack of glucose-6-phosphatase and gamma-glutamyltransferase and coexpression of vimentin and desmin, alpha-smooth muscle actin could not be detected in early lesions. In five of 24 advanced tumors inclusions of kidney tubules were found which showed various degrees of alteration in their morphology and enzyme histochemical pattern, but were often directly connected with tubular segments of normal appearance outside the tumor. Like the normal tubules, the enclosed tubular segments were strongly positive for cytokeratin but never expressed vimentin or desmin. Among the 24 tumors studied, two contained cysts which expressed cytokeratin and sometimes also vimentin but not desmin. The enzyme histochemistry of the cells lining the cysts was similar to that of the surrounding tumor mass, except adenylate cyclase was lacking and alkaline phosphatase was not uniformly distributed. In tumors containing cytokeratin-positive cysts, there often were cytokeratin-positive, vimentin-negative and desmin-negative tumor formations in close contact to these cysts. With the exception of cyst formation, the pattern of metastases were identical to that of the primary tumors. All large tumors and the main component of the metastases expressed vimentin, desmin and fibronectin. Mesothelia surrounding metastatic tumor complexes were positive for vimentin, desmin, alpha-smooth muscle actin, fibronectin, cytokeratin and tenascin. It was concluded from these and previous observations on early stages of tumor development that the estrogen-induced hamster kidney tumor originates from mesenchymal interstitial cells (probably pericytes) which may rarely acquire an epithelial phenotype by metaplastic transformation during tumor progression.
 ...
PMID:Changes in the cellular phenotype and extracellular matrix during progression of estrogen-induced mesenchymal kidney tumors in Syrian hamsters. 171 81

Basophilic hepatic foci, nodules, and trabecular hepatocellular carcinomas, collectively referred to as focal hepatic lesions, were induced by single injections of 5.0 micrograms of diethylnitrosamine (DEN) per gram body weight in 15-day-old C57BL/6J X C3HeB/FeJ F1 (B6C3 F1) mice. Groups of eight experimental and eight control mice were killed at 3 days and at 1, 2, 4, 10, 20, 28, 36 and 41 weeks after injection. The only observable acute hepatic toxic effect of DEN, a mild steatosis, was noted at 3 days, but this had disappeared by 7 days following injection. Basophilic foci, composed entirely of altered hepatocytes, were first noted, when very small, at 10 weeks. At later times, some of the foci also contained small collections of proliferated ductules, apparently a result of secondary ingrowth from nearby interlobular bile ducts. The hepatocytes within basophilic foci were characterized by their abundant cytoplasmic RNA, a high nuclear to cytoplasmic ratio (two times greater than normal), which gave them a "crowded appearance," and decreased glucose-6-phosphatase activity. During the course of the study, basophilic foci appeared to increase in size and number. Cytologic anaplasia also became more evident, ultimately culminating in the development of typical trabecular hepatocellular carcinomas by 44 weeks. Invasion of hepatic veins by basophilic foci, first noted at 10 weeks, was prominent by 20 weeks and indicated that many of the lesions manifested this characteristic of malignancy well in advance of the anaplastic features that are also diagnostic of hepatocellular carcinoma. The high growth rates of basophilic foci were confirmed by their greatly increased 3H-thymidine labeling indices, which were 20 times greater than background hepatocytes at 20 weeks following DEN injection. Tumor progression during the course of the study was also suggested by a doubling of labeling indices of hepatocytes in the basophilic foci between 20 to 28 weeks. (The term tumor progression is used in a broad biological sense to encompass any or all of the qualitative and quantitative changes describing the stepwise development of initiated cells to highly malignant neoplasms. This definition differs from the more clinical usage which restricts the process to qualitative changes during the late stages in the development of fully autonomous neoplasms.) An analysis of the number and size of transections through basophilic foci and in some cases, actual reconstructions of the foci from serial sections, indicated that, in aggregate, they grew exponentially between 10 to 36 weeks, with a volume doubling time of 2.5 weeks. The combined morphologic and kinetic data support the view that trabecular hepatocellular carcinomas develop from basophilic foci. Because of their ease of quantitation on conventional H&E stained sections, their rather uniformly spherical shapes, and the high probability of their clonal origin, the induced focal hepatic lesions should provide a useful model for studying tumor growth kinetics during carcinogenesis.
 ...
PMID:Preneoplastic and neoplastic progression during hepatocarcinogenesis in mice injected with diethylnitrosamine in infancy. 687 10

von Hippel Lindau (VHL) disease is a hereditary cancer syndrome caused by biallelic inactivation of the VHL tumor suppressor gene. The most widely known function of VHL is to limit normoxic protein expression of hypoxia-inducible factor-alpha (HIF-alpha). Loss of the functional VHL gene causes constitutive stabilization of HIF-alpha that primarily up-regulates hypoxia-inducible genes even at normal oxygen concentration, which in turn contribute to VHL tumor progression. We report on the novel function of VHL in hepatic glucose storage and disposal. VHL deletion in adult mouse liver quickly leads to increased accumulation of glycogen granules as well as lipid droplets. This abnormal glycogen storage in VHL-inactivated liver arises at least in part from significantly reduced expression of two key liver-specific glucose metabolism genes, glucose transporter-2 (GLUT2) and glucose-6-phosphatase (G-6-Pase). The expression pattern of these genes in VHL knock-out liver was in contrast to that of well-known HIF target genes, such as PGK, Glut-1, VEGF, and EPO, all of which are highly elevated upon VHL inactivation. Our findings suggest that two distinct signaling pathways exist at the downstream of VHL controlling different sets of gene expression. Following VHL inactivation, one pathway causes oxygen-independent overexpression of classic hypoxia-inducible genes and the other one described here suppresses expression of the genes important for liver glucose metabolism.
 ...
PMID:von Hippel Lindau tumor suppressor regulates hepatic glucose metabolism by controlling expression of glucose transporter 2 and glucose 6-phosphatase. 1720 15