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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 潘建源(Chien-Yuen Pan) | |
| dc.contributor.author | Jui-Ling Tsai | en |
| dc.contributor.author | 蔡瑞玲 | zh_TW |
| dc.date.accessioned | 2021-06-08T02:13:54Z | - |
| dc.date.copyright | 2016-02-19 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-12-23 | |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19695 | - |
| dc.description.abstract | 抗血管新生治療是現今癌症治療的方法之一，很遺憾的是，針對抗VEGF-A的抗血管新生療法，則出現抗藥性且增加癌症轉移等問題。抗藥性來自腫瘤內無血管供應氧氣造成嚴重「缺氧」，癌細胞為求生存，本身會分泌VEGF-A，不斷地回饋刺激VEGFR2-HIF-1α-VEGF路徑，形成自泌回饋環(autocrine loop)，讓癌細胞儘快逃離目前惡劣的環境因而造成轉移。為了獲得更有效的癌症治療藥物及降低藥物抗藥性，我們在六種VEGF-A異構物 (isoform)中，測試挑選出缺乏Heparin binding domain的VEGF121及VEGF165的兩個單體(monomer)為基本單元，透過連接一段人類抗體IgG1的Fc固定區，利用多胜肽鏈連接的方式，建構出VEGF121-VEGF165二聚蛋白嵌合體。連接Fc區域不僅可增強二聚體的結合、增強蛋白嵌合體的穩定度、還可增強免疫細胞的活性。我們試圖以拮抗弱化的理論，用VEGF121-VEGF165來競爭取代，分別由自泌 (autocrine)及旁泌(paracrine)兩大方面來抑制，弱化下游的訊號傳遞，以避免癌細胞中心出現嚴重缺氧的情況。由in vitro及in vivo實驗證實，VEGF121-VEGF165可競爭VEGF165二聚體，使VEGF165旁泌和自泌的現象降低，且使得在內皮細胞或是癌細胞的增殖、遷移、侵襲或形成管狀結構的能力也大幅度的下降。機制方面，嵌合蛋白質會拮抗癌細胞所產生抗藥性的路徑: 透過
PI3K-AKT-mTOR途徑來抑制HIF-1α-VEGF165/Lon。總結，VEGF121-VEGF165，它透過競爭VEGFR2接受體，調控細胞內訊號傳導訊息來降低細胞外過量的VEGF-A。因此VEGF121-VEGF165不僅能阻斷內皮細胞進行血管新生外，亦能解決癌細胞的HIF-1α-Lon過度表現產生抗藥性的問題，這將是一個具有發展潛力的拮抗血管生成之癌症治療蛋白質藥物，有機會成為癌症病人的一道新曙光。 | zh_TW |
| dc.description.abstract | Anti-angiogenesis therapy is one major approach of cancer therapies nowadays. Unfortunately, anti-angiogenesis therapy targeting VEGF-A was recently stumbled by the drug-resistance that results from adaptive responses. Accumulating study suggested that intratumor hypoxia has a critical role in many adaptive mechanisms. To obtain a more efficient therapeutic response and attenuate the drug-resistance, we created and identified a novel chimeric fusion of VEGF121 and VEGF165, which was connected by Fc region of human IgG1 to enhance dimerization. We found that the treatment of VEGF121-VEGF165 chimeric protein reduces proliferation, migration, invasion, and tube formation of endothelial and/or cancer cells through competing VEGF165 homodimer in a paracrine and an autocrine manner. Furthermore, the fusion protein attenuated autocrine VEGFR2-HIF-1α-VEGF165/Lon signaling through PI3K-AKT-mTOR pathway in cancer cells. In conclusion, our data demonstrated that the chimeric VEGF121-VEGF165 arrests the tube formation of endothelial cells and interferes with tumor cell growth, migration and invasion, suggesting that it could be a potential drug as an angiogenesis antagonist in cancer therapy. The VEGF121-VEGF165 targets not only paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR mediated VEGFR2-HIF-1α-VEGF165/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to combat drug resistance to antiangiogenic therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T02:13:54Z (GMT). No. of bitstreams: 1 ntu-104-D97B41008-1.pdf: 2190487 bytes, checksum: f0d4c4e4fac6436ac6b13b569e291798 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | Table of contents
中文摘要………..…..…………………………………………….……..….….4 English abstract………………………………………………….………..……5 List of Abbreviation….…………………………………………….…….….…7 1.Introduction 1.1 Angiogenesis and tumor microenvironment………………….…………..8 1.2 Many different types of targeted therapies are used to treat cancer…........8 1.3 Hypoxia, Drug resistance and metastasis 1.3.1 Hypoxia……………………………………………………………...11 1.3.2 Drug resistance………………………………………………………12 1.3.2.1 Extrinsic resistance…………………………………………….12 1.3.2.2 Intrinsic resistance……………………………………………..12 1.3.3 Metastasis……………………………………………………………..14 1.4 The Vascular endothelial growth factor (VEGF) isoforms……………......15 1.5 Targeting PI3K/AKT/mTOR signaling in cancer represses HIF-1αactivation …………………………………………………………………………………18 1.6 Motivation…………………………………………………………………20 2. Materials and Methods 2.1 Gene construction of pcDNA3.1-VEGF121-VEGF165……..…………...22 2.2 Cell lines and cell cultures………………………………………….….22 2.3 Purification of VEGF121-VEGF165 recombinant proteins……….…..22 2.4 Cell proliferation assay….………………………………………….….23 2.5 Colony formation assay…………………………………………….….23 2.6 Cell migration assay…………………………………………………....24 2.7 Tube formation assay……………………………………………….…24 2.8 Cell invasion assay…………………………………………………….25 2.9 Immunoblotting………………………………………………….…….26 2.10 Statistical methods…………………………………………………....27 3 Results 3.1 Constrcuction and characterization of VEGF121-VEGF165 fusion protein …………………………………………………………………….…...…28 3.2 VEGF121-VEGF165 chimeric protein inhibits cell proliferation induced by VEGF165………………………………….………………………..….....29 3.3 VEGF121-VEGF165 chimeric protein inhibits tube formation induced by VEGF165………………………………………………………………...30 3.4 VEGF121-VEGF165 chimeric protein inhibits cell migration……………31 3.5 VEGF121-VEGF165 chimeric protein impairs tumor invasion………......31 3.6 VEGF121-VEGF165 chimeric protein attenuated autocrine VEGFR2-HIF-1α -VEGF165/ Lon signaling through PI3K-AKT-mTOR pathway…..…....32 4 Discussion 4.1 Anti-angiogenic therapy and hypoxic tumor microenvironment….…..34 4.2 VEGF121 and VEGF165 functions in endothelial cells…….……….…..34 4.3 Attenuated functions of VEGF121-VEGF165: enhancing the value and effectiveness……………………………………………………...…....36 4.4 Inhibition of both paracrine and autocrine VEGF/VEGFR2 signaling pathways…………………………………………………….….…......37 5 Conclusion………………………………….………………………...….…...40 Figures and Tables…………………………………………………….....…..…41 References…………………………………………………………….......….... 66 | |
| dc.language.iso | en | |
| dc.title | 新穎蛋白嵌合體VEGF121-VEGF165調控腫瘤血管新生及缺氧誘導因子訊號路徑之機制研究 | zh_TW |
| dc.title | The novel VEGF121-VEGF165 fusion attenuates angiogenesis and drug resistance via targeting VEGFR2-HIF-1α-VEGF165/Lon signaling through PI3K-AKT-mTOR pathway | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 李岳倫(Alan Yueh-Luen Lee) | |
| dc.contributor.oralexamcommittee | 鄭添祿(Tian-Lu Cheng),廖光文(Kuang-Wen Liao),李玉梅(Yu-May Lee) | |
| dc.subject.keyword | 抗血管新生,抗藥性,缺氧,Lon,融合嵌合體,二聚體 VEGF121-VEGF165, | zh_TW |
| dc.subject.keyword | Anti-angiogenesis,drug resistance,hypoxia,Lon,the chimeric fusion,VEGF121-VEGF165, | en |
| dc.relation.page | 74 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-12-23 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生命科學系 | zh_TW |
| 顯示於系所單位： | 生命科學系 | |
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