Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.
- MeSH
- epitel enzymologie patologie MeSH
- fosfohydroláza PTEN metabolismus MeSH
- HEK293 buňky MeSH
- heterozygot MeSH
- lidé MeSH
- metastázy nádorů MeSH
- mutantní proteiny metabolismus MeSH
- myši inbrední C57BL MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty enzymologie MeSH
- progrese nemoci MeSH
- prostata enzymologie patologie MeSH
- protein-serin-threoninkinasy nedostatek genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Previous studies have described elevated lipid peroxidase, myeloperoxidase and xanthine oxidoreductase/xanthine oxidase levels on the ocular surface of patients suffering from autoimmune dry eye (Sjogren's syndrome, SS). Reactive oxygen species generated by various enzymatic systems may be dangerous to the eye if they are not sufficiently cleaved by antioxidants. Because antioxidants have not been investigated in dry eye, the aim of this study was to examine the expression of antioxidant enzymes that cleave reactive oxygen species and play a key role in antioxidant protection. Conjunctival epithelial cells of dry eye (SS) patients were obtained by the method of impression cytology using Millicell membranes. Normal eyes served as controls. In the conjunctival epithelium superoxide dismutase, catalase and glutathione peroxidase were examined immunohistochemically. The enzyme expression levels were determined by image analysis and statistical evaluation. In contrast to normal eyes, where antioxidant enzymes were highly expressed in the conjunctival epithelium, in dry eye their expression was much less pronounced in correlation with the increasing severity of dry eye symptoms. Our study suggests that the decreased expression of antioxidant enzymes in dry eye disease (SS) contributes to the development of anterior eye surface oxidative injuries.
- MeSH
- antioxidancia metabolismus MeSH
- epitel enzymologie MeSH
- financování organizované MeSH
- glutathionperoxidasa biosyntéza MeSH
- imunohistochemie MeSH
- katalasa biosyntéza MeSH
- konjunktiva enzymologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- oxidační stres fyziologie MeSH
- počítačové zpracování obrazu MeSH
- Sjögrenův syndrom enzymologie MeSH
- superoxiddismutasa biosyntéza MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- MeSH
- adenosintrifosfatasy MeSH
- alkalická fosfatasa MeSH
- epitel anatomie a histologie enzymologie MeSH
- histocytochemie metody MeSH
- mezonefros anatomie a histologie enzymologie MeSH
- proximální tubuly ledvin anatomie a histologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- ependym embryologie metabolismus MeSH
- epitel enzymologie metabolismus MeSH
- fukosa farmakokinetika MeSH
- krysa rodu rattus MeSH
- polysacharidy MeSH
- přední mozek embryologie metabolismus MeSH
- ventriculi laterales embryologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- alkalická fosfatasa analýza MeSH
- epitel enzymologie chemie ultrastruktura MeSH
- intracelulární membrány MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- lektiny MeSH
- plicní alveoly cytologie enzymologie chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- techniky in vitro MeSH
- MeSH
- amfotericin B terapeutické užití MeSH
- cyklosporiny toxicita MeSH
- epitel cytologie enzymologie účinky léků MeSH
- krysa rodu rattus MeSH
- ledvinové kanálky cytologie účinky léků MeSH
- moč cytologie MeSH
- nemoci ledvin chemicky indukované MeSH
- xenobiotika toxicita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
The immunocytochemical distribution of three cell surface peptidases was investigated in samples of developing infant breast ranging in age from newborn to 9.5 months. We have previously demonstrated that in the adult breast these enzymes identify subpopulations of epithelial cells and fibroblasts. We therefore wished to address two questions: (a) At what stage in breast development can fibroblast subpopulations be identified, and (b) Is the distribution of these peptidases related to cellular differentiation and morphogenesis? At the histological level there was a cuff of stromal cells closely associated with the developing ductular and lobular structures. At all stages of ductular and lobular development the fibroblasts in this layer were consistently negative for dipeptidyl peptidase IV (DPP IV) and clearly distinguished from the fibroblasts in the surrounding matrix, some of which expressed DPP IV in an age-dependent manner. Within the infant breast aminopeptidase N (APN) was localised to luminal epithelial cells and all fibroblasts, whilst neutral endopeptidase (NEP) was specifically localised to myoepithelial cells. These results are considered in relation to the role of stromal-epithelial interactions during morphogenesis and the proposed function of these enzymes.
- MeSH
- aminopeptidasy analýza MeSH
- antigeny CD13 MeSH
- dipeptidylpeptidasa 4 MeSH
- dipeptidylpeptidasy a tripeptidylpeptidasy analýza MeSH
- epitel enzymologie ultrastruktura MeSH
- fibroblasty enzymologie ultrastruktura MeSH
- kojenec MeSH
- lidé MeSH
- membránové proteiny analýza MeSH
- morfogeneze MeSH
- neprilysin analýza MeSH
- novorozenec MeSH
- prsy cytologie enzymologie růst a vývoj MeSH
- svalové proteiny analýza MeSH
- svaly hladké cévní enzymologie ultrastruktura MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- epitel enzymologie MeSH
- lidé MeSH
- plíce anatomie a histologie enzymologie MeSH
- plod MeSH
- Check Tag
- lidé MeSH
