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Effect of TGFβ on the production of extracellular matrix proteins by mesenchymal cells in the glioblastoma microenvironment
Vepřková, Jana ; Bušek, Petr (advisor) ; Přechová, Magdalena (referee)
Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor, characterized by extracellular matrix (ECM). These changes may be caused by transforming growth factor beta (TGFβ), which is overexpressed in GBM. TGFβ induces the expression of fibroblast activating protein (FAP), which is found in GBM on mesenchymal cells surrounding blood vessels, where ECM proteins collagen type I and fibronectin are typically found. This study aimed to determine the effect of TGFβ on the expression of collagen type I and fibronectin by FAP+ mesenchymal cells in the GBM and to determine the effect of ECM produced by these cells on glioma cell migration. Bioinformatic and tissue analyses demonstrate a correlation between TGFβ, FAP, collagen type I, and fibronectin expression in GBM. Using immunohistochemistry, TGFβ expression was detected diffusely in GBM including areas of stroma that contained FAP+ mesenchymal cells and collagen type I. In in vitro experiments, FAP+ mesenchymal cells showed increased production of collagen type I and fibronectin after TGFβ stimulation. In contrast, glioma cells showed very low production of these proteins even after TGFβ stimulation. ECM produced by FAP+ mesenchymal cells significantly increased the migration of the glioma cell line U251. However, no further...
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Molecular mechanisms of carcinogenic effects of alcohol
Vepřková, Jana ; Kábelová, Adéla (advisor) ; Novotná, Božena (referee)
Alcohol (ethanol) enters the human body mainly through ingestion of alcoholic beverages and its chronic consumption is considered a worldwide socio-economic problem. Besides others, alcohol consumption increases the risk of development of breast, liver, colorectal and upper aerodigestive tract cancer. In the liver, ethanol is metabolised into toxic acetaldehyde which is the main cause of DNA damage leading to cancer development. Acetaldehyde covalently interacts with nucleotides in the DNA forming DNA adducts such as N2 -ethylidene-2'-deoxyguanosine or S- and R-α-methyl-γ-hydroxy-1,N2 - propano-2′-deoxyguanosine. Acetaldehyde can also interact with proteins and disrupt their function. Ethanol metabolism by cytochrome P450 2E1 leads to production of reactive oxygen species, that subsequently damage cellular molecules such as lipides and DNA. Ethanol also initiates carcinogenesis through aberant DNA methylation or interference with retinoic acid metabolism. In cancer development, alcohol interacts with other environmental and genetic factors, which can increase the risk of developing cancer in predisposed individuals.
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