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E P Sandgren

Publications and source records attributed to E P Sandgren.

13 recordsLinked to original sources
PubMed1992

DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice.

Hepatocyte-directed production of urokinase-type plasminogen activator (uPA) in transgenic mice is hepatotoxic. Infrequently, hepatocytes arise that do not express uPA, due to physical loss of transgene DNA, and these cells clonally repopulate the entire liver within 3 months of birth. Surprisingly, hepatic tumors appear in these mice beginning at 8 months of age despite the fact that uPA is not oncogenic or genotoxic. Analysis of the transgene locus reveals that tumors arise only from a particular subclass of transgene-deficient cells in which the entire transgene array, and possibly a significant amount of flanking DNA, is deleted. Considering that all transgene-deficient regenerative nodules undergo extensive replication but only a subset gives rise to tumors, we propose that loss of genomic DNA, not mitogenesis per se, is a primary carcinogenic determinant in this model of hepatocarcinogenesis.

Alanine Transaminase↗
PubMed1992

Odontogenic tumors in mice carrying albumin-myc and albumin-rats transgenes.

Odontogenic tumors that produce abnormal tooth-like structures are repeatedly observed in mandibles of mice that carry both albumin-myc and albumin-ras transgenes. The earliest lesions appear among the periodontal ligament mesenchymal cells, but later lesions include an epithelial component. Subsequent tumor development recapitulates the process of normal tooth formation, which requires multiple sequential cell signals, and results in cell differentiation, matrix secretion, and mineralization. Tumor cells with epithelial morphology produce ras oncoprotein, consistent with an epithelial origin of these tumors. As albumin regulatory sequences direct oncogene expression in these mice, our findings also suggest that some of the albumin present in normal teeth may be locally produced and have a role in tooth mineral formation. The reproducibility of this phenotype makes these mice an excellent model for studies of both normal and neoplastic odontogenesis.

Animals↗
PubMed1992

Possible role of transforming growth factor alpha in the pathogenesis of Ménétrier's disease: supportive evidence form humans and transgenic mice.

Ménétrier's disease is an uncommon disorder of unknown etiology characterized by enlarged gastric folds with foveolar hyperplasia and cystic dilatation of gastric glands. Biochemical features that are seen frequently include hypoproteinemia, hypochlorhydria, and increased gastric mucus. Because transforming growth factor alpha (TGF alpha) is an epithelial cell mitogen that inhibits gastric acid secretion and increases gastric mucin content, we hypothesized that its altered expression might be involved in the pathogenesis of this disease. Therefore, we characterized TGF alpha immunoreactivity in the gastric mucosa of 4 patients with Ménétrier's disease. In contrast to the normal pattern of TGF alpha immunostaining in which TGF alpha appears most concentrated in parietal cells, there was intense staining in the majority of mucous cells in the gastric mucosa of patients with Ménétrier's disease. In one patient from whom sufficient fresh tissue was obtained to isolate RNA, expression of TGF alpha and the epidermal growth factor receptor was higher in the gastric mucosa relative to a normal control. In addition, metallothionein-TGF alpha transgenic mice, which overexpress TGF alpha in gastric mucosa, show a number of features characteristic of Ménétrier's disease. These include foveolar hyperplasia and glandular cystic dilatation, increased gastric neutral mucin staining, and reduced basal and histamine-stimulated rates of acid production. Taken together, observations derived from the human material and correlation with data from a transgenic mouse model support an important role for TGF alpha in the pathogenesis of Ménétrier's disease.

Animals↗
PubMed1991

Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.

We previously demonstrated that expression of an albumin-urokinase-type plasminogen activator (Alb-uPA) fusion construct in transgenic mice resulted in elevated plasma uPA concentration, hypofibrinogenemia, and neonatal hemorrhaging. Two lines of Alb-uPA mice were established in which only one half of the transgenic pups died at birth; surprisingly, plasma uPA concentrations in survivors gradually returned to normal by 2 months of age. The basis for this phenomenon is DNA rearrangement within hepatocytes that affects the transgene tandem array and abolishes transgene expression. Transgene-deficient cells selectively proliferate relative to surrounding liver, and this process culminates in replacement of the entire liver by clonal hepatic nodules derived from transgene-deficient progenitor cells. In some cases as few as two nodules can reconstitute over 90% of liver mass, highlighting the remarkable regenerative capacity of individual liver cells.

Animals↗
PubMed1991

Heterologous introns can enhance expression of transgenes in mice.

In a previous study we showed that genomic constructs were expressed more efficiently in transgenic mice than constructs that were identical except for the lack of introns. Using the mouse metallothionein promoter-rat growth hormone gene construct as a model, we show that the first intron of the rat growth hormone gene is essential for high-level expression, whereas the other three introns are less effective. Several heterologous introns placed 3' of the coding region of an intronless rat growth hormone gene are also ineffective. However, insertion of some heterologous introns between the metallothionein promoter and the growth hormone gene improves expression. To determine whether addition of heterologous introns would provide a general strategy for improving expression, we have tested them in conjunction with other intronless genes and with different promoters.

Animals↗
PubMed1991

Pancreatic tumor pathogenesis reflects the causative genetic lesion.

Transgenic mice in which c-myc expression is targeted to pancreatic acinar cells develop mixed acinar/ductal pancreatic adenocarcinomas between 2 and 7 months of age. This contrasts with the effect on pancreas of the simian virus 40 tumor antigen or activated ras, which in adult mice causes lesions composed exclusively of acinar-like cells. Furthermore, during an early stage of myc-induced pathology, transformed acinar-derived cells appear within islets, suggesting that islet hormones may influence the progression of these exocrine pancreatic tumors. These findings demonstrate that the initial oncogenic alteration can influence the pattern of subsequent tumor pathogenesis and, given that human exocrine pancreatic tumors are predominantly ductal adenocarcinomas, support the suggestion that transformed acinar cells may contribute to the genesis of this serious disease in man.

Adenocarcinoma↗
PubMed1991

Antisense oligodeoxynucleoside methylphosphonate inhibition of mouse c-myc p65 protein expression in E mu-c-myc transgenic mice.

In transgenic mice bearing a murine immunoglobulin enhancer/c-myc fusion transgene (E mu-myc), it was found that methylphosphonates do not induce acute toxicity following intravenous administration of a 300 nmol dose. In addition, recovery of methylphosphonates from the blood plasma of treated mice indicated that the oligomers remained intact up to 3 hours, while their concentrations decreased rapidly for the first hour, then slowly decreased over the next two hours. Finally, methylphosphonate oligomers targeted against c-myc mRNA inhibited production of c-myc p65 protein in peripheral and splenic lymphocytes, relative to a scrambled sequence oligomer, 4 hours after injection of a 300 nmol dose, as indicated by immunofluorescence of fixed cells stained with an anti-c-myc antiserum.

Animals↗
PubMed1990

Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator.

Spontaneous intestinal and intra-abdominal bleeding was observed in a high percentage of newborn transgenic mice carrying the murine urokinase-type plasminogen activator (uPA) gene linked to the albumin enhancer/promoter. These hemorrhagic events were directly related to transgene expression in the liver and the development of high plasma uPA levels. Two lines were established from surviving founder mice that displayed multigenerational transmission of the bleeding phenotype. Fatal hemorrhaging developed between 3 and 84 hr after birth in about half of the transgenic offspring of these lines; transgenic pups that did not bleed nevertheless passed the phenotype to their young. The phenotypic variability could not be explained by differences in transgene expression. All transgenic neonates were severely hypofibrinogenemic and displayed loss of clotting function that extended beyond the risk period for bleeding. These mice provide a means of studying the pathophysiology of plasminogen hyperactivation and evaluating therapeutic protocols designed to prevent bleeding.

Animals↗
PubMed1990

Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast.

Metallothionein-directed expression of TGF alpha in transgenic mice induced a spectrum of changes in the growth and differentiation of certain adult tissues. First, TGF alpha promoted a uniform epithelial hyperplasia of several organs without otherwise causing major alterations in tissue architecture. Second, in pancreas it promoted proliferation of both acinar cells and fibroblasts and focally altered acinar cell differentiation. The magnitude of this response was proportional to the level of local, tissue-specific TGF alpha expression and was reproduced when expression of TGF alpha was placed under the control of the elastase promoter, implying an autocrine or paracrine mechanism. Third, TGF alpha was oncogenic in vivo. It caused dramatic hyperplasia and dysplasia of the coagulation gland epithelium, which displayed evidence of carcinoma in situ, and in postlactational mammary gland it induced secretory mammary adenocarcinomas. Thus, TGF alpha displays characteristics of both a potent epithelial cell mitogen and an oncogenic protein in vivo.

Animals↗
PubMed1989

Oncogene-induced liver neoplasia in transgenic mice.

Models of hepatocarcinogenesis were generated by directing the expression of SV40 T-antigens, an oncogenic mutant of c-H-ras, or c-myc to the liver of transgenic mice using the albumin enhancer/promoter. The majority of mice carrying the ras transgene (group A) were born with enlarged livers and atypical hepatic architecture, and these all died within several days of birth. The remaining ras transgenic mice (group B) had lower levels of hepatic ras expression, exhibited mild hepatic dysplasia but no liver enlargement, and all ultimately died from development of lung tumors. In contrast, the livers of mice expressing T-antigens were relatively normal at birth, by one month displayed marked dysplasia, and by three to seven months developed multiple nodular adenomas and carcinomas. Myc expression caused mild to severe hepatic dysplasia in young mice, and focal hepatic adenomas in some mice over fifteen months of age. Lines of mice expressing ras (group B), T-antigen, or myc were established and crossed with each other to generate dual transgenic mice expressing oncogene pairs. Each combination resulted in accelerated tumor development, suggesting that these oncoproteins can cooperate with one another during multistep hepatic transformation.

Animals↗
PubMed1989

Elevation of 1,2-diacylglycerol in ras-transformed neonatal liver and pancreas of transgenic mice.

Expression of the activated Harvey-ras (H-ras) oncogene in cultured cells is associated with an elevated steady-state concentration of 1,2-diacylglycerol (DG), an intracellular second messenger capable of promoting cell division. To explore the biochemistry of ras expression in vivo, we measured DG in ras-transformed neonatal liver and pancreas of transgenic mice. DG was elevated over 2-fold in these tissues compared to controls, but was not elevated in transgenic neonatal liver expressing normal H-ras, the nuclear oncogene myc, or the Simian Virus 40 T-antigens. DG was also not elevated in ras-induced lung adenomas in transgenic mice. These findings demonstrate an association between activated ras expression and DG concentration in neonatal tissue, but suggest that marked elevation of DG is not necessary for the development of ras-induced tumors in lung.

Animals↗
PubMedDate not supplied

Pulmonary carcinogenesis in transgenic mice.

Use of genetically engineered mice offers a unique approach to identifying and investigating factors that may influence tumor development. We have used conventional histopathologic and ultrastructural techniques to characterize lung tumors in three lines of transgenic mice bearing an albumin enhancer/promoter linked to a mutated human H-ras gene. Mice in all three lines developed multiple alveolar-bronchiolar (A/B) adenocarcinomas that are eventually lethal. The large diversity in tumor morphological features and differential tumor growth rates suggests that secondary events contribute to tumor phenotype and biological behavior. Two of the transgenic lines developed numerous A/B neoplasms within 6 to 8 weeks and thus may be useful animal models for testing potential anticancer chemotherapeutic agents. The other line lived for approximately 10 months, had fewer A/B tumors, but also developed bronchiogenic tumors. All three transgenic lines may be useful models for studying factors that affect lung tumor development.

Albumins↗