Hepatocarcinogenesis in Female Mice With Mosaic Expression of Connexin32

Moennikes, Oliver; Buchmann, Albrecht; Willecke, Klaus; Traub, Otto; Schwarz, Michael

doi:10.1053/jhep.2000.16598

Cited by 17 publications

(8 citation statements)

References 28 publications

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“…Much remains to be learned about how the specific combination of connexins facilitates tissue interactions, but it is clear, again, that generalizations should be avoided, as the expression patterns (and probably the function) of connexins are tissue dependent and change during tumour progression 17,18 . For example, some breast cancer cells upregulate connexin 32 (Cx32) 19 , but loss of Cx32 contributes to hepatocellular carcinoma 20,21 ; Cx43 inhibits tumorigenicity of lung, cervical and bladder carcinoma cells [22][23][24] , but has no effect on squamous cell carcinomas 25 ; and other connexins can facilitate cell adhesion during metastasis 26 .…”

Section: Box 1 Epithelial Cell Polarity and Tumorigenesis In Drosophilamentioning

confidence: 99%

Putting tumours in context

2001

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The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

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Section: Box 1 Epithelial Cell Polarity and Tumorigenesis In Drosophilamentioning

confidence: 99%

Putting tumours in context

2001

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“…For example, the expression level or cellular localization of Connexin32, which has an important role in gap junction formation, is decreased by PB-treatment. PBmediated promotion of hepatic tumors is abolished in Connexin32-deficient mice, and it is likely that Connexin32 is necessary for the tumor promotion effects of PB [26]. Since an inverse correlation between the expression level of CYP2B1/2 and Connexin32 has been observed [27], it is possible that Connexin 32 contributes in some way to CYP2B1/2 expression, although the details are not known.…”

Section: Induction Of Cyp2b and Tumor Promotionmentioning

confidence: 99%

Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism

Yamada

Ishii²,

Yamamoto

et al. 2006

CDM

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The cytochrome P450 belonging to the CYP2B subfamily has long been of great interest because it can be induced by xenobiotics. While a well known diagnostic ligand-receptor theory explains the induction of the CYP1A subfamily, the mechanism by which xenobiotics induce the CYP2B subfamily is not fully understood. Although the constitutive androstane receptor (CAR) undoubtedly plays a crucial role in the induction, many questions regarding the mechanism of CAR activation by xenobiotics have not yet been answered. It is a puzzle that many structurally-unrelated chemicals can increase the expression of the CYP2B subfamily. This may support a mechanism(s) distinct from the signaling induced by ligand-receptor binding. Indeed, phenobarbital, a typical inducer, cannot associate with CAR. Thus, no one is able to answer a fundamental question: what is the initial target of xenobiotics to produce induced expression of CYP2B enzymes? In this review, we survey the research history of CYP2B induction, list the inducers reported so far, and discuss the mechanism of induction including the target site of inducers.

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“…injection of DEN (90 mg/g body weight) at 6 weeks of age. After a treatment-free interval of 3 weeks, groups of animals were either kept on a standard diet (7PB) or on a diet containing 0.05% PB (+PB) for 39 weeks (for further details see Moennikes et al, 2000). For mutation spectra see Table 1 speculate about a link between this genetic alteration and the observed phenotype of tumors.…”

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confidence: 99%

Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of β-catenin-mutated mouse liver tumors

et al. 2001

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Tumor promoters are non-mutagenic chemicals which increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. Phenobarbital (PB) is an antiepileptic drug which promotes hepatocarcinogenesis in rodents when administered subsequent to an initiating carcinogen like diethylnitrosamine (DEN). Here we have investigated the prevalence and patterns of mutations in two genes, Haras and b-catenin, both known mutational targets in mouse hepatocarcinogenesis. Liver tumors were generated by a single administration of DEN to 6 week old mice followed by feeding of PB (0.05%) containing or control diet for 39 weeks. Mutations at Ha-ras codon 61 were screened by allele-speci®c oligonucleotide hybridization; b-catenin mutations were detected by direct sequencing of PCR products spanning exon 2. In tumors from mice treated with DEN alone, the prevalence of Ha-ras mutations was *30% (6/20), while no b-catenin mutations (0/13) were detectable in tumors of this treatment group. By contrast, Ha-ras mutations were undetectable in tumors from mice treated with DEN/PB (0/32), while *80% (37/46) of tumors from this group showed b-catenin mutations. These results demonstrate that PB strongly aects the prevalence of mutations in the two cancer-related genes, presumably by positive and negative selection for cells harboring the respective mutation. Oncogene (2001) 20, 7812 ± 7816

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Hepatocarcinogenesis in Female Mice With Mosaic Expression of Connexin32

Cited by 17 publications

References 28 publications

Putting tumours in context

Putting tumours in context

Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism

Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of β-catenin-mutated mouse liver tumors

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