@article{anderson_dunn_cattley_corton_2001, title={Hepatocellular proliferation in response to a peroxisome proliferator does not require TNF alpha signaling}, volume={22}, ISSN={["1460-2180"]}, DOI={10.1093/carcin/22.11.1843}, abstractNote={Rodents exposed to peroxisome proliferator xenobiotics respond with marked increases in hepatocellular replication and growth that results in tumor formation. Recently, tumor necrosis factor-alpha (TNFalpha) was proposed as the central mediator of this maladaptive response. To define the role of TNFalpha signaling in hepatocellular growth induced by peroxisome proliferators we administered three daily gavage doses of the potent peroxisome proliferator, Wy-14 643, to mice nullizygous for TNF-receptor I (TNFR1), TNFR2, or both receptors. We demonstrate here that regardless of genotype the mice responded with almost identical increases in liver to body weight ratios and hepatocyte proliferation. Lacking evidence that TNFalpha signaling mediates these effects, we then examined the possible contribution of alternative cytokine pathways. Semi-quantitative, reverse transcriptase polymerase chain reaction analysis revealed that wild type mice acutely exposed to Wy-14 643 had increased hepatic expression of Il1beta, Il1r1, Hnf4, and Stat3 genes. Moreover, hepatic adenomas from mice chronically exposed to Wy-14 643 had increased expression of Il1beta, Il1r1, Il6, and Ppargamma1. Expression of Il1alpha, Tnfalpha, Tnfr1, Tnfr2, Pparalpha, or C/ebpalpha was not altered by acute Wy-14 643 exposure or in adenomas induced by Wy-14643. These data suggest that the hepatic mitogenesis and carcinogenesis associated with peroxisome proliferator exposure is not mediated via TNFalpha but instead may involve an alternative pathway requiring IL1beta and IL6.}, number={11}, journal={CARCINOGENESIS}, author={Anderson, SP and Dunn, CS and Cattley, RC and Corton, JC}, year={2001}, month={Nov}, pages={1843–1851} }
 @article{miller_anderson_corton_cattley_2000, title={Apoptosis, mitosis and cyclophilin-40 expression in regressing peroxisome proliferator-induced adenomas}, volume={21}, ISSN={["0143-3334"]}, DOI={10.1093/carcin/21.4.647}, abstractNote={Chronic exposure to peroxisome proliferators (PP), including certain industrial and pharmaceutical chemicals, causes liver cancer in rodents. Continuous exposure to PP is needed for tumor development since the frequency of hepatocellular neoplasms is decreased in animals returned to control diet. To determine cellular and molecular events responsible for enhanced growth in PP-induced liver tumors, we evaluated the relationships of WY-14,643 levels, apoptosis, mitosis and cyclophilin-40 (Cyp-40) expression in regressing tumors induced by WY-14,643, a potent PP. Male F344 rats were fed WY-14,643 (0.1%) in the diet for 43 weeks and then switched to control diet for 2, 3, 5 or 36 days. Mean serum and hepatic concentrations of WY-14,643 were decreased as early as 2 days following removal of WY-14,643 as compared with rats continuously fed WY-14,643. Adenomas from rats maintained on WY-14,643 markedly compressed surrounding parenchyma. Evidence of adenoma regression was observed by 3 days of WY-14,643 withdrawal and was characterized by loss of compression. Decreased compression corresponded to increases in the apoptotic index and decreases in the mitotic index in regressing adenomas at 2, 3, and 5 days following the switch to control diet. Cyclophilins are multifunctional receptor proteins involved in numerous signal transduction pathways, including those mediated by cyclosporin, a liver tumor promoter in rats. Cyp-40 expression was markedly increased in adenomas from continuously exposed rats, but expression returned to levels similar to surrounding parenchyma in adenomas after 5 days of WY-14,643 withdrawal. Taken together, these results indicate that WY-14, 643-induced adenomas regress rapidly following withdrawal of the PP in association with declining liver WY-14,643 levels, suggesting that peroxisome proliferator-activated receptor alpha may mediate PP-induced alterations in mitogenic and/or apoptotic regulation in growing tumors, in conjunction with alterations in Cyp-40 signal transduction.}, number={4}, journal={CARCINOGENESIS}, author={Miller, RT and Anderson, SP and Corton, JC and Cattley, RC}, year={2000}, month={Apr}, pages={647–652} }
 @article{christensen_romach_healy_gonzales_anderson_malarkey_corton_fox_cattley_goldsworthy_1999, title={Altered bcl-2 family expression during non-genotoxic hepatocarcinogenesis in mice}, volume={20}, ISSN={["1460-2180"]}, DOI={10.1093/carcin/20.8.1583}, abstractNote={Dysregulation of apoptosis is an important component of multistage hepatocarcinogenesis. Members of the bcl-2 protein family are important in the regulation of apoptosis and their expression is altered in several cancers. The objectives of the present study were to determine whether the expression of members of the bcl-2 protein family are altered in mouse liver during acute treatment with non-genotoxic carcinogens and throughout non-genotoxic hepatocarcinogenesis. Acute treatment of B6C3F1 mice with phenobarbital resulted in increased levels of bcl-2 and decreased levels of bax protein, while acute treatment with WY-14,643 resulted in increased bcl-2 and BAG-1 protein in the liver. Following chronic treatment, altered hepatic foci and adenomas were classified as: small-cell, heterogeneous basophilic lesions (spontaneous or tetrachlorodibenzo-p-dioxin-induced); large-cell, homogeneous basophilic lesions (WY-14,643-induced); acidophilic lesions (phenobarbital- or chlordane-induced). Of the small-cell heterogeneous basophilic lesions, 86% of foci (31/36) and 85% of adenomas (35/41) exhibited increased bcl-2 protein levels compared with surrounding normal hepatocytes, whereas only 12.5% of foci (4/36) and 12% of adenomas (5/41) exhibited increased bcl-X(L) levels. Of the large-cell, homogenous, basophilic lesions, 100% of foci (3/3) and 90% of adenomas (9/10) expressed bcl-2 protein, whereas 100% of foci (3/3) and 80% of adenomas (8/10) exhibited increased bcl-X(L) protein levels compared with surrounding normal hepatocytes. Of the acidophilic lesions, the majority of foci (28/32, 88%) and adenomas (47/50, 94%) expressed increased bcl-X(L), whereas increased bcl-2 was observed in only 12.5% of acidophilic preneoplastic foci (4/32) and 14% of acidophilic adenomas (7/50). Of the carcinomas analyzed, 81% expressed increased bcl-2 (54/67), 78% expressed increased bcl-X(L) (52/67) and 69% expressed increased levels of both bcl-2 and bcl-X(L) (46/67). Collectively, only 8% of preneoplastic foci, 3% of adenomas and 1.5% of carcinomas did not express either bcl-2 or bcl-X(L). These results suggest that regulation of apoptotic proteins is altered during non-genotoxic carcinogenesis in mouse liver. Furthermore, there were both chemical- and lesion-specific aspects of expression of apoptotic proteins during hepatocarcinogenesis in mice.}, number={8}, journal={CARCINOGENESIS}, author={Christensen, JG and Romach, EH and Healy, LN and Gonzales, AJ and Anderson, SP and Malarkey, DE and Corton, JC and Fox, TR and Cattley, RC and Goldsworthy, TL}, year={1999}, month={Aug}, pages={1583–1590} }
 @article{anderson_cattley_corton_1999, title={Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators}, volume={26}, ISSN={["0899-1987"]}, DOI={10.1002/(SICI)1098-2744(199912)26:4<226::AID-MC2>3.0.CO;2-Q}, abstractNote={Concern exists regarding peroxisome proliferator (PP) xenobiotic exposure because many PPs are potent hepatocarcinogens in rodents. The mechanism of carcinogenicity induced by PPs is atypical compared with those of other hepatocarcinogens in that the former appears to involve alterations in expression of PP‐activated receptor (PPAR) target genes rather than direct mutagenicity. To begin to identify some of these genes, we used differential display to compare mRNA expression between hepatic adenomas and adjacent non‐tumor liver from rats fed the potent PP Wy‐14643 (WY) for 78 wk. Here, we report increased expression of the acute‐phase protein (APP) gene α‐1 antitrypsin (AT) and decreased expression of α2‐urinary globulin in the tumors. Similar changes were seen in hepatic adenomas induced by a diethylnitrosamine and phenobarbital protocol, indicating a lack of specificity for PP‐induced tumors. Additional APP genes, including ceruloplasmin, haptoglobin, β‐fibrinogen, and α1‐acid glycoprotein were also upregulated in WY‐induced tumors but were downregulated in the livers of rats administered a different PP for 13 wk. Mice treated with either WY or di(2‐ethylhexyl) phthalate for 3 wk had decreased hepatic AT expression but increased expression of ceruloplasmin and haptoglobin. PPARα‐null mice showed no hepatic APP gene alteration after PP treatment but had higher basal expression than did wild‐type controls. We conclude that PPARα activation by several different PPs leads to dysregulation of hepatic APP gene expression in rats and mice. This dysregulation may indicate alterations in cytokine signaling networks regulating both APP gene expression and hepatocellular proliferation. Mol. Carcinog. 26:226–238, 1999. © 1999 Wiley‐Liss, Inc.}, number={4}, journal={MOLECULAR CARCINOGENESIS}, author={Anderson, SP and Cattley, RC and Corton, JC}, year={1999}, month={Dec}, pages={226–238} }