Carcinogenesis Advance Access published online on June 19, 2003
Carcinogenesis, doi:10.1093/carcin/bgg099
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Institut für Pharmakologie und Toxikologie, Abteilung Toxikologie, Universität Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany
* Corresponding author. E-mail: michael.schwarz{at}uni-tuebingen.de.
Received 21 January 2003
; revised 2 June 2003
; accepted 3 June 2003
Connexin32 (Cx32) is the major gap junction forming protein in liver and lack of functional Cx32 enhances hepatocarcinogenesis. Many tumour promoting agents block gap junctional intercellular communication which may favour clonal expansion of neoplastic cells. We could recently demonstrate that liver tumourigenesis is accelerated in Cx32-wildtype but not in Cx32-null mice by the model tumour promoter phenobarbital. In the present study, male Cx32-wildtype and Cx32-null mice were treated with a single injection of 90 µg/g body wt. of N-nitrosodiethylamine (DEN) at 6 weeks of age and were subsequently kept on a diet containing the peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) or on control diet. 38 weeks after DEN treatment, mice were sacrified, frozen liver sections were prepared and (pre)neoplastic lesions were identified by alterations in glucose-6-phosphatase (G-6-Pase) and glutamine synthetase (GS) staining. G-6-Pase-deficient lesions were generally small in size and were observed in all groups of mice. Large focal preneoplastic and benign neoplastic lesions, however, which demonstrated increased rather than decreased activity in G-6-Pase were exclusively present in DEN/Wy-14,643-treated mice. G-6-Pase-positive lesions were strongly promoted by Wy-14,643, both in Cx32-wildtype and Cx32-null mice without significant difference in response between mice of the two genotypes. This contrasts G-6-Pase-negative lesions and lesions overexpressing GS, which were both increased by WY-14,643 treatment in number and size in Cx32-wildtype but not in Cx32-null mice. GS-positive lesions from WY-14,643-treated mice harboured
mouse hepatocarcinogenesis, Wy-14,643, peroxisome proliferators, connexin32, Wy-14,643-mediated promotion of hepatocarcinogenesis in connexin32-wildtype and connexin32-null mice
2 Deutsches Krebsforschungszentrum, Abteilung Zelluläre und Molekulare Pathologie, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
-catenin-mutations, a hallmark of lesions selected during promotion by phenobarbital, while G-6-Pase-positive lesions, which displayed negative or diffuse GS-staining, did not show -catenin-mutations. Our results demonstrate significant differences between mouse liver lesions of differing pheno- and genotype in their response towards selection by Wy-14,643 during the promotional phase of hepatocarcinogenesis.-catenin, tumour promotion
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