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Immunological features of esophageal carcinoma in prognosis and therapy
Šnajdauf, Martin ; Lischke, Robert (advisor) ; Vrba, Radek (referee) ; Stříž, Ilja (referee)
Esophageal cancer belongs to the gastrointestinal malignancies with the worst prognosis. Current treatment options, including surgical resection, chemotherapy, radiotherapy, or a combination of these methods, have low efficacy and the five-year survival rate for patients with esophageal cancer is approximately 10 to 15 %. In the last decade, immunotherapy has become the leading treatment modality for metastatic tumors. However, the success of immunotherapeutic approaches does not only depend on the infiltration of the tumor microenvironment with immune cells but also on the phenotype of these infiltrating cells. The aim of this project was to evaluatethe immunological features of tumor-infiltrating lymphocytes obtained from different tissue compartments (tumor, peritumoral tissue, adjacent healthy tissue, and lymph node) of patients during surgical resection and to compare them with clinical and histopathological data of patients. We observed that the distribution of NK (natural killer) cells, CD8 and CD4 positive T cells was different in each tissue compartment. While the lymph nodes had the highest percentage of T cells, the opposite was seen in NK cells. The proportion of NK cells was the lowest in the lymph nodes. The expression of death receptors FasR and DR3 (death receptor 3) was the lowest...
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Charakterizace vlivu senescence na indukci a regulaci smrti nádorových buněk
Nováková, Gita ; Anděra, Ladislav (advisor) ; Truksa, Jaroslav (referee)
4 Abstract Senescence is a specific cell state distinquished by cessation of cell division and proliferation and changes in gene expression. Normal cells enter senescence after distinct number of cell divisions or in case of an unrepairable damage. Senescence in cancer cells can be induced by subliminal stress as sublethal treatment with certain drugs. Senescent cancer cells persist in the tissue and may secrete a number of factors and nutrients affecting surrounding cells. Senescence can thus change the response of cancer cells to various apoptogens during cancer therapy. In this study, we focused on the elucidation of presumed differences between normal proliferating and senescent cancer cells in their response to selected apoptogens. Implementing bromodeoxyuridine (BrdU)-mediated replication stress in cancer cells derived from pancreatic (PANC-1) or mesothelioma (H28) tumors, we efficiently forced these cells to acquire senescent phenotype. We document that these senescent cells gain higher resistance to combined TRAIL and homoharringtonine (HHT) treatment and enhance sensitivity to other apoptogens such as FasL, camptothecin and mVES. These cells also showed increased expression of anti-apoptotic protein c-FLIP in senescent cells and changes in the expression of some Bcl-2 family proteins....
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Charakterizace vlivu senescence na indukci a regulaci smrti nádorových buněk
Nováková, Gita ; Anděra, Ladislav (advisor) ; Truksa, Jaroslav (referee)
4 Abstract Senescence is a specific cell state distinquished by cessation of cell division and proliferation and changes in gene expression. Normal cells enter senescence after distinct number of cell divisions or in case of an unrepairable damage. Senescence in cancer cells can be induced by subliminal stress as sublethal treatment with certain drugs. Senescent cancer cells persist in the tissue and may secrete a number of factors and nutrients affecting surrounding cells. Senescence can thus change the response of cancer cells to various apoptogens during cancer therapy. In this study, we focused on the elucidation of presumed differences between normal proliferating and senescent cancer cells in their response to selected apoptogens. Implementing bromodeoxyuridine (BrdU)-mediated replication stress in cancer cells derived from pancreatic (PANC-1) or mesothelioma (H28) tumors, we efficiently forced these cells to acquire senescent phenotype. We document that these senescent cells gain higher resistance to combined TRAIL and homoharringtonine (HHT) treatment and enhance sensitivity to other apoptogens such as FasL, camptothecin and mVES. These cells also showed increased expression of anti-apoptotic protein c-FLIP in senescent cells and changes in the expression of some Bcl-2 family proteins....
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Charakterizace TRAILem indukované, receptor-specifické signalizace v nádorových buňkách.
Peterka, Martin ; Anděra, Ladislav (advisor) ; Rohlena, Jakub (referee)
TNF-related apoptosis-inducing ligand (TRAIL) is a member of TNF family expressed mainly by hematopoietic cells. TRAIL brought significant attention mainly for its ability to trigger apoptosis in a number of cancer cells. In addition to apoptosis, TRAIL can induce several other signaling pathways such as activation of MAP kinases or canonical NF-B signaling. Human TRAIL can bind to five receptors but only two of them (death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5) can trigger TRAIL-mediated apoptotic and non-apoptotic signaling in target cells. Both receptors are ubiquitously expressed on normal and cancer cells, but the relative contribution of DR4 and DR5 to TRAIL-induced signaling is not well known. Using DR4/DR5-specific variants of TRAIL, we examined how individual receptor contributes to the induction of apoptosis and NF-B, JNK, p38, ERK1/2 and TAK1 signaling pathways in selected colorectal cells. We found that in DLD-1 cells, apoptosis and activation of JNKs are mainly mediated by DR4-selective ligand. In TRAIL-resistant HT-29 cells, we show that though DISC formation and activation of caspase-8 proceeds mainly via DR4-specific signaling, activation of NF-B pathway is mainly triggered by DR5 selective ligand. In other cells and analyzed signaling pathways both receptor-specific ligands triggered very...
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