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研究生：	許文乾 Hsu, Wen-Chien
論文名稱：	建構三維腫瘤與巨噬細胞微環境系統並評估氧化鐵奈米粒子對調控微環境的影響 Developing Three-Dimensional Tumor and Macrophage Microenvironmental Systems and Evaluating the Effects of Iron Oxide Nanoparticles on the Regulation of Microenvironment
指導教授：	吳炳慶 Wu, Ping-Ching
共同指導教授:	涂庭源 Tu, Ting-Yuan
學位類別：	碩士 Master
系所名稱：	工學院 - 生物醫學工程學系 Department of BioMedical Engineering
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	129
中文關鍵詞：	腫瘤微環境、腫瘤相關巨噬細胞、體外腫瘤模擬、3D細胞培養、膠原蛋白、細胞侵襲、氧化鐵奈米粒子、ROS 、巨噬細胞M1/M2比率
外文關鍵詞：	Tumor microenvironment, tumor-associated macrophage, in vitro tumor mimicking, 3D cell culture, collagen, cell invasion, iron oxide nanoparticle, ROS, M1/M2 ratio
相關次數：	點閱：73 下載：0
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截至今日，癌症的死亡率居高不下，許多學者開始研究如何治療癌症。然而，臨床上較常用於治療癌症患者的方法包含手術切除，傳統化學療法和放射療法。這些治療方法都是針對癌細胞，但總是忽略癌細胞周圍的環境可能通過其他途徑促進癌細胞生長。本研究建立了一個簡易的體外3D腫瘤微環境模型，並在該模型中，藉由調節巨噬細胞的表型來抑制腫瘤細胞的侵襲或遷移。
我們使用低貼附的圓底96孔盤培養乳腺癌細胞腫瘤球體，並以相同方式將巨噬細胞和乳腺癌細胞共培養成球體。而後將球體嵌入膠原蛋白膠中來創建簡易的3D腫瘤微環境模型。我們將pEGFP-N1轉染到4T1細胞中使得細胞帶有綠色螢光，另外透過活細胞追蹤染劑讓巨噬細胞RAW264.7帶有紅色螢光，如此一來便可以在微環境模型中觀察到兩種細胞的分布以及癌細胞的侵襲。在腫瘤微環境中，巨噬細胞會受到癌細胞影響而轉變成M2表型。而我們利用氧化鐵奈米粒子，使腫瘤微環境中的巨噬細胞轉變為M1表型。
我們的研究結果顯示4T1腫瘤球體的直徑會因為接種細胞數量的增加而增加；但是在與RAW264.7共培養的條件下腫瘤球體的型態會隨著巨噬細胞的數量增加而分散，也會因為基質膠(Matrigel)濃度的增加而有所不同。巨噬細胞在與條件培養基(培養4T1細胞達八分滿時，將培養液抽出，並用0.22 μm過濾細胞碎片等，再依所需比例與新鮮培養液混合)培養的情況下，RAW264.7細胞傾向M2表型。此外，M2巨噬細胞在經過氧化鐵奈米粒子處理24小時之後，能轉變為M1表型的巨噬細胞。細胞毒性測試顯示出氧化鐵奈米粒子對兩種細胞皆不具毒性。但在活/死細胞分析中，腫瘤微環境模型會因氧化鐵奈米粒子濃度的提高而導致死細胞的比率提高。在ROS與細胞凋亡的分析中，氧化鐵奈米粒子濃度提高也使得ROS以及凋亡細胞的比率提高。在M1/M2比率的實驗中，50 nM氧化鐵奈米粒子在共培養微環境中培養24小時有最高的M1/M2比率，但是4T1的死細胞比率卻不高。然而，當我們把共培養為環境加入氧化鐵奈米粒子24小時之後移除氧化鐵奈米粒子，並給予新的培養液測量24小時後的4T1死細胞比率，得知死細胞比率從原先的8%提高到17%。由此可知，氧化鐵奈米粒子提升共培養微環境中的M1巨噬細胞比例，且M1巨噬細胞可以對4T1細胞產生免疫反應。
3D腫瘤微環境體外模型在腫瘤學以及藥物發展的研究是極具潛力的，它更能反應出藥物在體內的情形。未來，可以運用在不同細胞以及其他抗癌藥物的研究中。

Today, the fatality rate of cancer is growing continuously. The methods commonly used to treat cancer patients include surgical resection, traditional chemotherapy, and radiation therapy. These treatments are directed at cancer cells, but always ignore the tumor microenvironment that may be promoting the growth of cancer cells through other pathways. In this study, a 3D tumor microenvironment model was established in vitro. In this model, cancer cell invasion or migration is inhibited by modulating the phenotype of macrophages.
Breast cancer cell spheroids were cultured using a low-attached round-bottom 96-well plate, and co-cultured macrophages and breast cancer cells were cultured into spheroids in the same manner. Then, the spheroids were embedded into collagen to create a simple 3D tumor microenvironment model. By transfecting pEGFP-N1 into 4T1 cells and allowing breast cancer cells to develop green fluorescence, cancer cell invasion can be observed in a microenvironment model. In addition, the macrophage RAW264.7 can be made red-fluorescent using a live cell tracking dye to observe the distribution of the two cells in the microenvironment model. In the tumor microenvironment, macrophages were converted into the M2 phenotype by the cancer cells. We induced macrophage polarization to the M1 phenotype using iron oxide nanoparticles.
Our results show that the diameter of the 4T1 tumor sphere increased as the number of cells seeded increased. In the co-cultured spheroids, the morphology of the tumor spheroids dispersed as the number of macrophages increased and were also affected by the Matrigel concentration. The cytotoxicity analysis showed that iron oxide nanoparticles were not toxic to the 4T1 and RAW264.7 cells. However, in the live/dead cell analysis, the ratio of dead cells in the co-cultured spheroids increased as the concentration of iron oxide nanoparticles increased. In the ROS and apoptosis analysis, the ratio of ROS generation and dead cells in the co-cultured spheroids increased as the concentration of iron oxide nanoparticles increased. The co-cultured spheroids have the highest M1/M2 ratio in 50 nM iron oxide nanoparticles for 24 hours. In addition, the co-cultured spheroids and iron oxide nanoparticles were incubated for 24 hours and then aspirated, the 4T1 dead cell ratio of co-culture spheroids increased from 8% to 15%.
The development of three-dimensional spheroids has potential. In the future, we plan to simulate the effects of different drugs in different cell environments using a simple micro-environment model.

摘要 ........................... ..................... I
Abstract ......................... .. ............ III
誌謝 ............................................. V
Contents ............................... ........... VII
List of Table ............................... XII
List of Figures ................................. XIV
Chapter 1. Introduction ...................1
1 Background ......................................... 1
2 Tumor Microenvironment (TME) ................................ ................ 2
2.1 Tumor-associated Macrophages (TAMs) ............................... 4
2.2 Tumor Cell Migration ................................ ............................ 7
2.3 The Function of Extracellular Matrix (ECM) in the Tumor Microenvironment ................................ ................................ ............... 9
3 The advantages of a Three-dimensional Culture ........................ 10
4 Definitions of Different Three-dimensional Tumor Models ........ 11
5 Methods for Preparing 3D Multicellular Spheroids ................... 12
6 Mimicking the Tumor Microenvironment ................................ .. 14
7 Application of Nanotechnology in a TME ................................ .. 15
7.1 Introduction of Nanotechnology and Nanomedicine ............ 15
7.2 Nanoparticles Induce Macrophage Polarization .................. 16
7.3 Effect of Iron Oxide Nanoparticles on Macrophages ........... 17
8 Motivation and Aims of the Research ................................ ......... 18
Chapter 2. Materials and Methods ................................ ............................... 20
1 Experimental Process ................................ ................................ . 20
2 Materials ................................ ................................ .................... 22
3 Experimental Instruments ................................ .......................... 23
4 Cell Culture ................................ ................................ ................ 24
4.1 Cell Culture of 4T1 Cells ................................ ...................... 24
4.2 Cell Culture of RAW 264.7 Cells ................................ .......... 24
4.3 Cell Counts ................................ ................................ ........... 25
5 Tumor Spheroid Culture ................................ ............................ 26
5.1 4T1 Cell Spheroid Formation ................................ .............. 26
5.2 Heterospheroid Formation (Cell Co-culture Model) ............ 26
6 The Tumor Microenvironment Model ................................ ........ 27
7 Immunofluorescence for Identifying the RAW 264.7 Phenotype 28
8 Cell Transfection ................................ ................................ ........ 29
8.1 4T1 Cells Transfected with pEGFP-N1 ................................ 29
8.2 G-418 Eliminate Non-transfected cells ................................ . 29
8.3 Cell Sorting of Stably Transfected Cells ............................... 30
9 Live Cell Tracking Imaging ................................ ........................ 31
10 Imaging ................................ ................................ ....................... 31
11 Image Quantization ................................ ................................ .... 32
11.1 Tumor Spheroids Diameter and Invasion Distance .............. 32
11.2 Fluorescence Image Quantization ................................ ........ 32
12 Iron Oxide Nanoparticles for the Tumor Microenvironment ..... 33
12.1 Iron Oxide Nanoparticles ................................ ..................... 33
12.2 Cytotoxicity Analysis of Iron Oxide NPs .............................. 33
12.3 Spheroids Dissociation ................................ ......................... 34
12.4 Live/dead Cytotoxicity Analysis of Iron Oxide NPs Added to Tumor Spheroids ................................ ................................ ........................... 35
12.5 Relationship Between ROS and the Dead Cell Ratio of Iron Oxide Nanoparticles Added to Tumor Spheroids ................................ ......... 36
13 Statistical Analysis ................................ ................................ ...... 37
Chapter 3. Results ................................ ................................ ......................... 38
1 Characterization of Tumor Spheroids ................................ ........ 38
1.1 Morphology and Diameter of Tumor Spheroids .................. 38
1.2 Morphology and Invasion Distance of Tumor Spheroids Embedded in Collagen ................................ ................................ ........................ 39
2 Characterization of Heterospheroids ................................ ......... 39
3 Cell Distribution in the Heterospheroids ................................ .... 40
4 Confirmation of Macrophage Phenotype ................................ ... 42
4.1 The Phenotype of M1 and M2 Macrophages ....................... 42
4.2 Phenotypes of Macrophages Stimulated with Conditioned Medium (CM) and Iron Oxide NPs ................................ ................................ . 43
5 Cytotoxicity Analysis of Iron Oxide NPs ................................ .... 44
6 Live/dead Cytotoxicity Analysis of Iron Oxide NPs .................... 45
7 The Relationship Between ROS Production and the Dead Cell Ratio of Iron Oxide NPs Added to Spheroids ................................ .................. 46
8 Exploration of the Types of Dead Iron Oxide Nanoparticle Cells in Spheroids ................................ ................................ ........................... 48
9 Exploration of the M1/M2 Ratio of Iron Oxide Nanoparticles in the Spheroids ................................ ................................ ........................... 49
Chapter 4. Discussion ................................ ................................ .................... 50
1 Establishment of Tumor Microenvironment .............................. 50
1.1 Formation of the Tumor Spheroids ................................ ...... 50
1.2 Tumor Spheroids Embedded in Collagen and Invasion ....... 51
2 Formation of Heterospheroids ................................ .................... 52
2.1 Cell Number Determining Factor ................................ ........ 52
2.2 Effect of Matrigel Concentration ................................ ......... 53
2.3 Cell Tracking of Heterospheroids ................................ ........ 54
3 Macrophage Phenotype ................................ .............................. 55
3.1 Macrophage Cultured in Conditioned Medium ................... 56
3.2 M2 Macrophage Cultured in Iron Oxide NPs ...................... 57
4 Cytotoxicity Analysis of Iron Oxide NPs in 4T1 Spheroids, RAW264.7 and Co-cultured Spheroids ................................ ................................ 58
5 The Relationship Between ROS Production and Apoptosis of Iron Oxide NPs Added to the 4T1 Spheroids, RAW264.7 and Co-cultured Spheroids ................................ ................................ ........................... 59
6 The Relationship Between M1/M2 Ratio and Dead Cell Ratio of Iron Oxide NPs Added to Co-cultured Spheroids ................................ ..... 60
Chapter 5. Conclusion ........................63
References ..............................  ...... 117
                                    

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