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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳漢忠(Han-Chung Wu) | |
| dc.contributor.author | Chiung-Yi Chiu | en |
| dc.contributor.author | 邱瓊儀 | zh_TW |
| dc.date.accessioned | 2021-06-07T23:46:14Z | - |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-06-19 | |
| dc.identifier.citation | Adamcic, U., Skowronski, K., Peters, C., Morrison, J., and Coomber, B.L. (2012). The effect of bevacizumab on human malignant melanoma cells with functional VEGF/VEGFR2 autocrine and intracrine signaling loops. Neoplasia 14, 612-623.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16795 | - |
| dc.description.abstract | 腫瘤血管新生 (angiogenesis) 是癌症的主要特徵之一。根據以往研究顯示，血管內皮生長因子A（VEGF-A）及其受體（VEGFR-2）在腫瘤生長過程中扮演調節血管生成的重要因子，血管內皮細胞藉由 VEGF/VEGFR-2訊息傳遞路徑促進細胞之增生、存活力、遷移及轉移。因此抗血管新生策略在癌症治療中是具有前景的治療方式。為了開發抗體標靶治療，實驗室先前透過噬菌體顯現法 (phage display) 和親和力成熟技術 (affinity maturation)，篩選出專一性結合VEGFR-2的人類抗體 (anti-VEGFR2-AF antibody)。本篇研究中，我們想測試anti-VEGFR2-AF抗體對於腫瘤血管新生及抑制腫瘤生長的能力，首先，我們透過即時聚合酶鏈鎖反應(real time-PCR) 觀察到在人臍靜脈內皮細胞（HUVEC）、前列腺癌細胞株（PC-3）和白血病細胞株 (HL-60）有VEGFR-2的表現，進一步利用流式細胞儀，確認anti-VEGFR2-AF antibody專一性結合到內皮細胞表面VEGFR-2比IMC- 1121B (ramucirumab) 結合力更強，IMC- 1121B是對抗VEGFR-2單株抗體，於2014年4月經由FDA通過用於胃癌晚期治療。隨後，我們發現anti-VEGFR2-AF 抗體可與VEGF-A競爭結合到內皮細胞的VEGFR-2，進而抑制VEGFR-2磷酸化和VEGFR-2 下游訊號因子Akt / MAPK / FAK 的活化。此外，anti-VEGFR2-AF抗體不只能夠引發補體依賴性細胞毒性（complement dependent cytotoxicity）和抗體依賴性細胞毒性作用（antibody-dependent cell-mediated cytotoxicity），我們發現，IMC- 1121B及 anti-VEGFR2-AF 抗體同時處理內皮細胞會導致內皮細胞中VEGFR-2蛋白降解。進一步表明，anti-VEGFR2-AF抗體明顯抑制攝護腺癌細胞 (PC-3) 的遷移，侵襲，集落形成和增生能力。在人類前列腺癌細胞異種移植的免疫缺陷型小鼠中，我們發現anti-VEGFR2-AF抗體不論單一治療或者結合化療藥物 (Docetaxel)，治療後明顯抑制腫瘤的生長和腫瘤血管新生，其抑制能力更甚於IMC-1121B。另一方面，在人類急性前骨髓性白血病癌細胞異種移植的免疫缺陷型小鼠中，anti-VEGFR2-AF抗體比IMC- 1121B有更顯著性的治療效果，不僅延長存活率，甚至降低癌細胞浸潤卵巢及淋巴。綜合以上之結果， anti-VEGFR2-AF抗體透過直接標靶VEGFR-2表達的腫瘤細胞進而抑制腫瘤血管新生進及延遲腫瘤生長，未來，anti-VEGFR2-AF抗體在腫瘤治療中是具有極大的潛力。 | zh_TW |
| dc.description.abstract | Angiogenesis is one of the key hallmarks of cancer. Vascular endothelial growth factor A (VEGF-A) and its receptor (VEGFR-2) play the major roles to modulate angiogenesis, which is essential for solid tumor progression. Therefore, anti-angiogenesis treatment has been a promising new form of cancer therapy. To develop antibody-based targeted therapy for cancer, we have previously performed phage display and affinity maturation techniques to generate a fully human antibody against VEGFR-2, anti-VEGFR2-AF antibody. In this study, we have investigated the potential of anti-VEGFR2-AF antibody in anti-angiogenesis and tumor suppression in vitro and in vivo. First, we observed that VEGFR-2 is expressed not only in human umbilical vein endothelial cells (HUVECs), but it is also found in prostate cancer cell lines (PC-3) and leukemia cell lines (HL-60), as shown by quantitative RT-PCR. Using flow cytometry, anti-VEGFR2-AF antibody bound to HUVECs was stronger than IMC-1121B (ramucirumab), which is an anti-VEGFR2 antibody. On April 21, 2014, the U. S. Food and Drug Administration approved ramucirumab for use as a single agent for the treatment of patients with advanced or metastatic gastric cancer. Subsequently, we showed that anti-VEGFR2-AF antibody inhibited VEGF-A-induced phosphorylation of VEGFR-2 and suppressed activation of Akt/MAPK/FAK signal transduction cascades in HUVECs. We also demonstrated that anti-VEGFR2-AF antibody was able to trigger complement dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In addition, we found that treatment of HUVECs with IMC-1121B and anti-VEGFR2-AF simultaneously would cause VEGFR-2 protein degradation in HUVECs. Compared to IMC-1121B, anti-VEGFR2-AF exhibited superior ability to inhibit VEGF-A-induced migration, invasion, colony formation and viability of PC-3 cells. In prostate cancer (PC-3) xenograft mouse models, treatment with anti-VEGFR2-AF antibody both monotherapy and combination with docetaxel resulted in significantly higher reduction in tumor growth and tumor angiogenesis than treatment with IMC-1121B. Moreover, anti-VEGFR2-AF antibody possessed more significant efficacy than IMC-1121B in prolonging survival and decreasing myeloma cells infiltration of ovaries and lymph nodes in the treatment of NSG mice bearing human leukemia (HL-60). Taken together, our findings strongly suggest that anti-VEGFR2-AF human antibody may have clinical potential for cancer therapy by exerting anti-angiogenesis or by directly targeting VEGFR-2-expressing tumor cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T23:46:14Z (GMT). No. of bitstreams: 1 ntu-103-R01444004-1.pdf: 14094156 bytes, checksum: e06a0228f829e40adeabc60361ae6484 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 iii Abstract v Contents vii Content of figures and tables x List of abbreviations xii Introduction 1 1.1 Epidemiology, pathogenesis and hallmark of cancer 1 1.2 Cancer therapy and the obstacle of cancer treatment 2 1.3 Vasculogenesis, angiogenesis and tumor angiogenesis 4 1.4 VEGF/VEGFR-2 pathway in tumor angiogenesis 6 1.5 Tumor vascular targeting therapy 9 1.6 VEGF/VEGFR-2 pathway as a target for cancer therapy 11 1.6-1 Clinical trials for anti-angiogenesis 11 1.6-2 Resistance to anti-angiogenic therapies 12 1.7 Anti-VEGFR2 drug in clinical trial 13 Specific aim 18 Material and method 19 2.1 Cell lines and culture condition 19 2.2 Establishment of stable clone 19 2.3 Characterization of full-length human IgG by Western blot analysis 20 2.4 Antibody production and purification 21 2.5 Cell viability assay 22 2.6 Cell invasion assay 23 2.7 Scratch wound healing assay 24 2.8 Colony formation assay 24 2.9 Tube formation assay for angiogenesis 25 2.10 Flow cytometry analysis 26 2.11 Lentivirus-mediated short hairpin RNA (shRNA) knockdown 26 2.12 Protein extraction and Western blot analysis 27 2.13 RNA extraction, cDNA synthesis, polymerase chain reaction (PCR), and quantitative reverse transcription polymerase chain reaction (qRT-PCR) 29 2.14 Isolation of human peripheral blood mononuclear cells (PBMCs) from whole blood…………………………………………………………………………………30 2.15 Antibody-dependent cell mediated cytotoxicity (ADCC) assay 30 2.16 Complement-dependent cytotoxicity (CDC) assay 32 2.17 Study of VEGFR-2-targeted therapy in mice models 33 2.18 Immunofluorescence assay of frozen tissue section 35 2.19 Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) 36 2.20 Hematoxylin and Eosin (H&E) staining 36 2.21 Statistical analysis 37 Result 38 3.1 Elevation of VEGFR-2 expression in human cell lines 38 3.2 VEGFR-2 plays an important role for prostate cancer (PC-3) cells 39 3.3 The binding specificity of anti-VEGFR2-AF antibody 40 3.4 Anti-VEGFR2-AF antibody inhibited VEGFR-2 and downstream signal cascade activation in HUVECs 42 3.5 Dual antibody combinations that decrease surface receptor expression and signaling 43 3.6 Anti-VEGFR2-AF abrogates VEGF-A-induced HUVEC capillary-like structure formation and viability in vitro 45 3.7 Anti-VEGFR2-AF antibody mediates antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) 46 3.8 Anti-VEGFR2-AF suppresses VEGF-A-induced function potential of prostate cancer cells (PC-3) in vitro 47 3.9 Therapeutic efficacy of anti-VEGFR2-AF antibody in human prostate cancer xenografts 48 3.10 Reduction of tumor microvessel density and increased apoptotic cells in PC-3 xenograft mice treated with anti-VEGFR2-AF human antibody 49 3.11 Combination of anti-VEGFR2-AF plus docetaxel inhibited the growth of PC-3 prostate cancer xenograft mice 50 3.12 Inhibition of VEGFR-2 prolongs survival of HL-60 leukemia xenograft mice with Anti-VEGFR2 antibody 52 Discussion 56 Reference 98 Appendix 109 | |
| dc.language.iso | en | |
| dc.subject | 腫瘤血管新生 | zh_TW |
| dc.subject | 標靶治療 | zh_TW |
| dc.subject | 治療性抗體 | zh_TW |
| dc.subject | VEGFR-2 (KDR) | zh_TW |
| dc.subject | therapeutic antibody | en |
| dc.subject | targeted therapy | en |
| dc.subject | angiogenesis | en |
| dc.subject | VEGFR-2 (KDR) | en |
| dc.title | 以小鼠模式研發對抗VEGFR2之人類抗體於癌症治療之研究 | zh_TW |
| dc.title | Development of Anti-VEGFR2 Human Antibody for Cancer Therapy in Mouse Models | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 呂仁(Joyce Jean Lu),李文山(Wen-Shan Li),蕭培文(Pei-Wen Hsiao) | |
| dc.subject.keyword | 腫瘤血管新生,VEGFR-2 (KDR),治療性抗體,標靶治療, | zh_TW |
| dc.subject.keyword | angiogenesis,VEGFR-2 (KDR),therapeutic antibody,targeted therapy, | en |
| dc.relation.page | 109 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2014-06-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 病理學研究所 | zh_TW |
| 顯示於系所單位： | 病理學科所 | |
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