Maronpot R.R.,Maronpot Consulting LLC |
Yoshizawa K.,Kansai Medical University |
Nyska A.,Tel Aviv University |
Harada T.,Institute of Environmental Toxicology |
And 4 more authors.
Toxicologic Pathology | Year: 2010
Hepatic enzyme induction is generally an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. The additive growth and functional demands that initiated the response to hepatic enzyme induction cover a wide range of stimuli including pregnancy and lactation, hormonal fluctuations, dietary constituents, infections associated with acute-phase proteins, as well as responses to exposure to xenobiotics. Common xenobiotic enzyme inducers trigger pathways involving the constitutive androstane receptor (CAR), the peroxisome proliferator-activated receptor (PPAR), the aryl hydrocarbon receptor (AhR), and the pregnane-X-receptor (PXR). Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia. The hypertrophy may show a lobular distribution, with the pattern of lobular zonation and severity reflecting species, strain, and sex differences in addition to effects from specific xenobiotics. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced enzymes generate toxic metabolites. These undesirable consequences are influenced by the type and dose of xenobiotic and show considerable species differences in susceptibility and severity that need to be understood for assessing the potential effects on human health from similar exposures to specific xenobiotics. Copyright © 2010 by The Author(s).
Qu A.,U.S. National Cancer Institute |
Jiang C.,U.S. National Cancer Institute |
Cai Y.,U.S. National Cancer Institute |
Kim J.-H.,U.S. National Cancer Institute |
And 5 more authors.
Journal of Hepatology | Year: 2014
Background & Aims Myc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. Whether it is essential for hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. This study used a novel genetic model to investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice. Methods Temporal hepatocyte-specific Myc disruption was achieved by use of the tamoxifen-inducible Cre-ERT2 recombinase system under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor α (PPARα) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis. Results Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc fl/fl,ERT2-Cre mice. When treated with a known hepatocellular proliferative stimulus Wy-14,643, Mycfl/fl,ERT2-Cre mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to Mycfl/fl mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Mycfl/fl mouse livers, but not in Wy-14,643-treated Mycfl/fl,ERT2-Cre livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Mycfl/fl,ERT2-Cre and Mycfl/fl mice, consistent with no differences in the expression of several PPARα target genes involved in fatty acid β-oxidation. Moreover, when subjected to the diethylnitrosamine liver cancer bioassay, Mycfl/fl,ERT2-Cre mice exhibited a markedly lower incidence of tumor formation compared with Mycfl/fl mice. Conclusions Myc plays an essential role in hepatocellular proliferation and liver tumorigenesis.
Lakritz J.R.,Massachusetts Institute of Technology |
Poutahidis T.,Massachusetts Institute of Technology |
Poutahidis T.,Aristotle University of Thessaloniki |
Mirabal S.,Massachusetts Institute of Technology |
And 13 more authors.
Oncotarget | Year: 2015
Recent studies suggest that gastrointestinal tract microbiota modulate cancer development in distant non-intestinal tissues. Here we tested mechanistic hypotheses using a targeted pathogenic gut microbial infection animal model with a predilection to breast cancer. FVB-Tg(C3-1-TAg)cJeg/JegJ female mice were infected by gastric gavage with Helicobacter hepaticus at three-months-of-age putting them at increased risk for mammary tumor development. Tumorigenesis was multifocal and characterized by extensive infiltrates of myeloperoxidase-positive neutrophils otherwise implicated in cancer progression in humans and animal models. To test whether neutrophils were important in etiopathogenesis in this bacteria-triggered model system, we next systemically depleted mice of neutrophils using thrice weekly intraperitoneal injections with anti-Ly-6G antibody. We found that antibody depletion entirely inhibited tumor development in this H. hepaticus-infected model. These data demonstrate that host neutrophil-associated immune responses to intestinal tract microbes significantly impact cancer progression in distal tissues such as mammary glands, and identify gut microbes as novel targets for extra-intestinal cancer therapy.
Kurotani R.,U.S. National Institutes of Health |
Kurotani R.,Yokohama City University |
Kumaki N.,Tokai University |
Naizhen X.,U.S. National Institutes of Health |
And 3 more authors.
Lung Cancer | Year: 2011
Secretoglobin (SCGB) 3A2, also called uteroglobin-related protein (UGRP) 1, is a downstream target for a homeodomain transcription factor NKX2-1, which is critical for the development of lung, thyroid and ventral forebrain. Both SCGB3A2 and NKX2-1 are expressed in airway epithelial cells and the latter also in alveolar Type II cells. NKX2-1 has been used clinically for diagnosis of human pulmonary tumors. Recently, the expression of SCGB3A2 was reported in human carcinomas, suggesting the use of this protein as a tumor marker. In this study, 28 lung tumors from aging B6;129 mice and nine lung adenocarcinomas from CC10TAg transgenic mice that express SV40 large T antigen under the mouse Scgb1a1 (CC10) gene promoter, were subjected to histopathological and immunohistochemical analyses for the expression of NKX2-1 and SCGB3A2. NKX2-1 was expressed in all types of tumors albeit more focally in carcinomas. In contrast, SCGB3A2 normally expressed in Clara cells, was negative in Type II cell hyperplasias and adenomas. However, it was expressed in alveolar Type II cell carcinomas and Clara cell adenocarcinomas. In these carcinomas, SCGB3A2 expression was observed in the portion of the tumor where NKX2-1 expression was reduced or almost abolished. As a comparison, the expression of SCGB3A2 and NKX2-1 from 23 human non-small cell lung carcinoma specimens was also examined. The results demonstrate that SCGB3A2 is a useful marker for diagnosis of pulmonary tumors both in mice and humans. © 2010.
Cullen J.M.,North Carolina State University |
Ward J.M.,Global VetPathology |
Thompson C.M.,ToxStrategies Inc.
Toxicologic Pathology | Year: 2016
Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response. © The Author(s) 2015.
Ward J.M.,Global VetPathology |
Ward J.M.,U.S. National Institutes of Health |
Rehg J.E.,St Jude Childrens Research Hospital
Veterinary Pathology | Year: 2014
Immunohistochemistry (IHC) is a common adjunct in pathology for morphologic diagnosis, research pathology, and studying the pathogenesis of the disease. Proper technique and interpretation of an immunohistochemistry assay is of utmost importance. A variety of problems, including the presence of artifacts (nonspecific background or other staining problems) and the differentiation between nonspecific and specific staining, commonly occur. It is essential that antibody quality and IHC technique be optimized. We review the histologic patterns of specific and nonspecific staining after using IHC techniques, as well as basic troubleshooting procedures, and provide some examples of nonspecific staining and other artifacts especially in formalin-fixed, paraffin-embedded tissues (FFPE) of mice. © The Author(s) 2013.
PubMed | Global VetPathology, ToxStrategies Inc. and North Carolina State University
Type: Journal Article | Journal: Toxicologic pathology | Year: 2016
Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response.
Ward J.M.,Global VetPathology |
Treuting P.M.,University of Washington
Toxicologic Pathology | Year: 2014
Colon cancer is a major human malignancy that afflicts millions of people throughout the world each year. Genetics and diet play large roles in colon carcinogenesis although chemicals may also contribute. For the past 40 years, scientists have studied experimentally induced intestinal carcinogenesis in rodents in order to elucidate the etiology and mechanisms involved. Comparative histopathology has revealed many similarities of rodent and human intestinal cancers. Comparative molecular pathology has also shown genetic similarities. More recently, genetically engineered mice and inflammatory colon cancer models have been used for investigating mechanisms and potential chemopreventive and treatment modalities. This review will focus on comparative histopathology and nonclinical models. © 2013 by The Author(s).
Schofield P.N.,University of Cambridge |
Schofield P.N.,The Jackson Laboratory |
Ward J.M.,Global VetPathology |
Sundberg J.P.,The Jackson Laboratory
DMM Disease Models and Mechanisms | Year: 2016
Reproducibility of data from experimental investigations using animal models is increasingly under scrutiny because of the potentially negative impact of poor reproducibility on the translation of basic research. Histopathology is a key tool in biomedical research, in particular for the phenotyping of animal models to provide insights into the pathobiology of diseases. Failure to disclose and share crucial histopathological experimental details compromises the validity of the review process and reliability of the conclusions. We discuss factors that affect the interpretation and validation of histopathology data in publications and the importance of making these data accessible to promote replicability in research. © 2016. Published by The Company of Biologists Ltd.
Ward J.M.,Global VetPathology
Asian Pacific Journal of Cancer Prevention | Year: 2010
With developments in the philosophy behind animal testing for carcinogenicity and toxicity, with increasing emphasis on Mode of Action analysis, the future usefulness of the 2 year rodent carcinogenesis bioassay is in doubt.