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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄭文芳(Wen-Fang Cheng) | |
dc.contributor.author | Ching-Ting Huang | en |
dc.contributor.author | 黃靖婷 | zh_TW |
dc.date.accessioned | 2021-06-15T13:42:47Z | - |
dc.date.available | 2016-02-24 | |
dc.date.copyright | 2016-02-24 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-12-25 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51648 | - |
dc.description.abstract | 類胰島素生長因子被證實能藉由刺激癌細胞增殖與抑制癌细胞凋亡來促進腫瘤生成。本論文探討類胰島素生長因子是否會調控樹突細胞調控的抗癌免疫及其可能的作用機轉。首先,晚期卵巢癌婦女的腹水檢體中的第一型類胰島素生長因子與第二型類胰島素生長因子的表現量被發現均遠高於早期卵巢癌的婦女。此外早期卵巢癌婦女的腹水檢體中的第一型類胰島素生長因子表現量與腹水檢體中的介白素2、介白素6、介白素10、介白素12以及腫瘤壞死因子α的表現量都具有正相關性,晚期卵巢癌婦女的腹水檢體中則沒有發現相關性。而在早期和晚期卵巢癌婦女的腹水檢體中的第二型類胰島素生長因子表現量與腹水檢體中的介白素2、介白素6、介白素10、介白素12以及腫瘤壞死因子α的表現量都不具有相關性。為了闡明類胰島素生長因子在調控樹突細胞和抗癌免疫中所扮演的角色,進一步在使用顆粒單核球群落刺激生長因子進行體外誘導免疫健全小鼠骨髓單核細胞向樹突細胞分化及成熟的過程中添加類胰島素生長因子。在測定經類胰島素生長因子處理過的樹突細胞的成熟狀態與功能後,發現類胰島素生長因子能抑制樹突細胞的成熟和呈現抗原的能力,以及活化具有抗原專一性的CD8+毒殺T細胞的能力。經類胰島素生長因子處理過的樹突細胞能分泌較多的介白素10和腫瘤壞死因子α,此外還發現有ERK1/2磷酸化與p38去磷酸化的減少的情形。在帶有高度表現第一型類胰島素生長因子或第二型類胰島素生長因子的WF-3腫瘤細胞的老鼠中,同樣發現老鼠腹水中的成熟樹突細胞的的比例有顯著的降低。而使用類胰島素生長因子受體的抑制劑NVP-AEW541能阻斷類胰島素生長因子在樹突細胞上的作用,增強ERK1/2磷酸化與p38去磷酸化的過程,來達到回復樹突細胞成熟狀態和回復抗癌免疫的目的。總結來說,類胰島素生長因子能抑制樹突細胞的成熟和功能,進而抑制抗癌免疫。而使用類胰島素生長因子受體的抑制劑NVP-AEW541能回復樹突細胞的抗癌免疫。因此阻斷類胰島素生長因子可以成為癌症免疫治療的有效策略之一。 | zh_TW |
dc.description.abstract | Insulin-like growth factors (IGFs) can promote tumorigenesis via stimulating cell proliferation and inhibiting the apoptosis of cancer cells. The relationship and the possible mechanism between IGFs and dendritic cell (DC)-mediated immunity were investigated. Advanced-stage epithelial ovarian cancer (EOC) patients were evaluated to show higher IGF-1 and IGF-2 concentrations in their ascites than early-stage patients. In addition, concentrations of IGF-1 also positively correlated with IL-2, IL-6, IL-10, IL-12 and TNF-α cytokines in early-stage EOC patients, but not in advanced-stage. There was no strong correlation between IGF-2 and the cytokines in the early-stage and advanced-stage EOC patients. To elucidate the exact function of IGFs on host immunity and especially with respect to DCs, bone marrow monocyte -derived DCs were first acquired and cultured with GM-CSF and IGFs from immune-competent mice. The maturation status and functions of IGF-treated DCs were analyzed. IGFs could suppress DCs' maturation, antigen presenting abilities, and the ability to activate antigen-specific CD8+ cytotoxic T cells. IGF-treated DCs also secreted higher concentrations of IL-10 and TNF-α. IGF-treated DCs showed decreased ERK1/2 phosphorylation and reduced p38 dephosphorylation. The percentages of matured DCs in the ascites were significantly lower in the IGF-1 or IGF-2 highly-expressing WF-3 tumor-bearing mice. The IGF1R inhibitor NVP-AEW541 could block the effects of IGFs to rescue DCs' maturation and to restore DC-mediated antigen-specific immunity through enhancing ERK1/2 phosphorylation and p38 dephosphorylation. In conclusion, IGFs can inhibit DC-mediated anti-tumor immunity through suppressing maturation and function and the IGF1R inhibitor NVP-AEW541 could restore the DC-mediated anti-tumor immunity. Blockade of IGFs could be a potential strategy for cancer immunotherapy. | en |
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dc.description.tableofcontents | 誌謝............................................................................................................... i
中文摘要........................................................................................................ ii Abstract............................................................................................................. iv Contents........................................................................................................... vi List of Figures.................................................................................................. xi List of Tables ................................................................................................... xiv Chapter 1: Background Information................................................................................. 1 1.1. Tumor Development and Tumor Microenvironment ............................. 1 1.2. Generation and Regulation of Anti-tumor Immunity ............................. 1 1.3. Insulin like Growth Factor System......................................................... 3 1.4. Clinical Outcome of Epithelial Ovarian Cancer..................................... 4 1.5. Aims of the Study ................................................................................... 5 Chapter 2: Ascitic Insulin-like Growth Factor-1 Correlate with IL-2, IL-6, IL-10, IL-12 and TNF-α Cytokines in Ascites of Patients with Early-stage Epithelial Ovarian Cancer......................................................................................................... 7 2.1. Introduction ............................................................................................7 2.2. Materials and Methods ........................................................................... 7 2.2.1. Patients .............................................................................................7 2.2.2. Specimens collection and preparation .............................................. 9 2.2.3. Measurement of IGF-1 and IGF-2 concentrations in the ascites of the EOC patients by ELISA ............................................................................. 9 2.2.4. Concentrations of cytokines in the ascites of the EOC patients by cytokine bead array........................................................................................... 9 2.2.5. Statistical analysis and clinical correlation....................................... 9 2.3. Results ..................................................................................................10 2.3.1. The clinic-pathologic characteristics of EOC patients ................... 10 2.3.2. Ascitic IGFs concentration correlated with different stages of tumor progression in EOC women ................................................................. 10 2.3.3. Concentrations of IGF-1 correlated with IL-2, IL-6, IL-10, IL-12 and TNF-α cytokines in early-stage EOC patients ..........................................11 Chapter 3: IGFs Inhibit Dendritic Cell-Mediated Anti-tumor Immunity through Regulating ERK1/2 Phosphorylation and p38 Dephosphorylation........................ 12 3.1. Introduction ..........................................................................................12 3.2. Materials and Methods ......................................................................... 13 3.2.1. Cell lines......................................................................................... 13 3.2.2. RNA isolation and RT–PCR........................................................... 14 3.2.3. Measurement of IGFs levels of the IGF-1 or IGF-2 highly-expressing WF-3 tumor cell lines by ELISA ...................................... 14 3.2.4. Proliferative assays for mock, IGF-1, or IGF-2 highly-expressing WF-3 tumor cells............................................................................................ 14 3.2.5. Mice................................................................................................ 15 3.2.6. Preparation of bone marrow monocyte (BMM)-derived DCs........ 15 3.2.7. Analysis of the maturation status of the BMM-derived DCs treated with IGFs and/or NVP-AEW541 by flow cytometric analysis ...................... 16 3.2.8. Antigen presenting abilities of the BMM-derived DCs treated with IGFs and/or NVP-AEW541 by flow cytometric analysis .............................. 16 3.2.9. Antigen processing abilities of the BMM-derived DCs treated with IGFs and/or NVP-AEW541 by flow cytometric analysis .............................. 16 3.2.10. Antigen presentation abilities of the BMM-derived DCs treated with IGFs and/or NVP-AEW541 for the activation of antigen-specific cytotoxic CD8+ T lymphocytes analyzed by flow cytometric analysis ......... 17 3.2.11. In vitro tumor killing activity of antigen-specific cytotoxic CD8+ T lymphocytes activated by BMM-derived DCs treated with IGFs............... 17 3.2.12. Cytokine secretion of the BMM-derived DCs treated with IGFs analyzed by bead-based immunoassays ......................................................... 18 3.2.13. Western blot analysis of the BMM-derived DCs and BMM-derived DCs treated with IGFs and/or NVP-AEW541 ....................... 18 3.2.14. In vivo tumor challenge of mock, IGF-1, or IGF-2 highly-expressing WF-3 tumor cells .............................................................. 18 3.2.15. Statistical analysis........................................................................... 19 3.3. Results ..................................................................................................19 3.3.1. IGF-1 receptor kinase inhibitor-NVP-AEW541 could reverse the suppressive effect of the IGFs on the maturation of BMM-derived DCs....... 19 3.3.2. IGFs activate IGF-IGF1R signaling pathway in DCs via ERK1/2 phosphorylation .............................................................................................. 20 3.3.3. NVP-AEW541 could inhibit the suppressive effect of IGFs on the antigen presenting abilities of the BMM-derived DCs................................... 20 3.3.4. IGFs could not affect the antigen processing abilities of the BMM-derived DCs......................................................................................... 21 3.3.5. NVP-AEW541 could restore the activation ability of the BMM-derived DCs to stimulate IFN-γ-secretion of antigen-specific CD8+ cytotoxic T lymphocytes suppressed by the IGFs .......................................... 21 3.3.6. Tumor killing activities of antigen-specific cytotoxic CD8+ T lymphocytes were lower when activated by BMM-derived DCs treated with IGFs 22 3.3.7. IGFs regulated the cytokine secretion of the BMM-derived DCs.. 22 3.3.8. IGFs inhibited the maturation of BMM-derived DCs via suppressing ERK1/2 phosphorylation and p38 de-phosphorylation .............. 23 3.3.9. IGF-1 or IGF-2 highly-expressing WF-3 bearing mice showed higher concentrations of IL-6 and IL-10 in the ascites................................... 24 3.3.10. Percentage of immature DCs increased in the ascites-associated cells (AACs) of IGF-1 or IGF-2 highly-expressing WF-3 bearing mice ....... 24 Chapter 4: Discussions .................................................................................... 26 Figures ............................................................................................................ 30 Tables.......................................................................................................... 59 References .................................................................................................. 62 Appendices ................................................................................................. 72 | |
dc.language.iso | en | |
dc.title | 卵巢癌中類胰島素生長因子抑制樹突細胞調控的抗癌免疫之研究 | zh_TW |
dc.title | Insulin-like Growth Factors Inhibit Dendritic Cell-Mediated Anti-tumor Immunity in Epithelial Ovarian Cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 何志明,許駿,葉坤輝,劉士任 | |
dc.subject.keyword | 腹水,樹突細胞,類胰島素生長因子,類胰島素生長因子受體,卵巢癌, | zh_TW |
dc.subject.keyword | ascites,dendritic cells,insulin-like growth factor,insulin-like growth factor 1 receptor,ovarian cancer, | en |
dc.relation.page | 72 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-12-25 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 腫瘤醫學研究所 | zh_TW |
顯示於系所單位: | 腫瘤醫學研究所 |
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