神經膠質瘤 (glioma) 是人類致死率最高的腫瘤之一，其平均存活時間約為2-5年。當中，高惡性度神經膠質瘤 (high-grade glioma) 容易侵略至周邊的正常腦組織，導致術後仍有高達90 %的患者有復發的情況。隨著神經膠質瘤的發展，腫瘤巨噬細胞 (TAMs) 會大量滲入腫瘤當中，而這些非腫瘤細胞會透過釋放細胞因子 (cytokine) 幫助腫瘤的生長、轉移甚至躲避免疫攻擊。我們利用第三級膠質瘤細胞株 (ALTS1C1) 及中樞神經系統中的巨噬細胞株 (BV2) 作為細胞模型。在本研究中證明了BV2與ALTS1C1的細胞接觸會影響ALTS1C1的球體形成，其形成的原因可能來自ALTS1C1細胞間機械交互作用力的失衡及細胞遷徙 (migration) 能力的上升。腫瘤微環境硬度的增加會促使細胞-基質間機械作用力上升，同時，我們也注意到細胞間黏附似乎有下降的趨勢。此外，mRNA的相對表現量暗示隙型連結 (gap junction) 可能是膠質瘤間主要的黏附結構，而非鈣依賴型的黏連結合 (adherens junction)。根據上述結果與臨床觀察資料，我們推論，前期的柔軟組織環境及TAM的侵入促使癌細胞聚集，進而形成有利生長的腫瘤型態；惡化程度的增加及腦壓的上升，使得癌細胞傾向於入侵周邊健康組織，造成不易治療的擴散結構。本研究以細胞力學的觀點，透過細胞間的機械交互作用力解釋了腫瘤形成的可能原因，並期望藉由進一步瞭解TAM 與腫瘤微環境的關係，能對將來的臨床治療方法有一定程度的貢獻。

High-grade glioma is frequently accompanied with the increased intracranial pressure and the prognosis of the patient is about 2-5 years, and the high invasive capacity of glioma leads to 90 % recurrence after surgery. During the glioma development, tumor-associated macrophages (TAM) infiltrate into the solid tumor, and the roles of TAM in glioma formation have not been fully explored yet. In this study, from the perspective of biophysics, we utilize the grade III astrocytoma (ALTS1C1) and the CNS resident macrophage (BV2) as the cell model, to study the mechanosignal transmission in TAM-glioma structure assembly. We notice that the physical contacts between BV2 and glioma are essential for tumor spheroid formation. A tug-of-war model was established to interpret the imbalanced traction force in the 3-dimensional TAM-glioma spheroid formation. The quantitative mRNA results indicated gap junction may serve a role in tumor formation progress. Engineered hydrogels with various physiological stiffness are utilized to modulate the TAM-glioma interactions, and the results implied that the soft tissue and TAM infiltration can contribute to the formation of 3-dimensional TAM-glioma cell architecture. Our results demonstrated mechanosignals may play essential roles in brain tumor formation, and the findings are expected to contribute to our understanding about tumor progression.

摘要 I
Abstract II
致謝 III
Table of Contents IV
List of Figures VI
Chapter 1 Introduction 1
1.1 Astrocytoma 1
1.2 Tumor-Associated Macrophage 4
1.3 Cellular Mechanotransduction 6
1.4 Mechanical properties 8
1.5 Motivation and Purpose 10
Chapter 2 Materials and Methods 11
2.1 Cell Culture 11
2.2 Microglia Contact Analysis 12
2.3 Artificial Spheroid Assay 12
2.3.1 Preparation of Dots Array Spheroid Formation Device 12
2.3.2 Preparation of Artificial Spheroids 13
2.4 Preparation of Hydrogel Substrate 13
2.4.1 Traction Force Microscopy (TFM) 15
2.4.2 Traction force reconstruction 16
2.5 RNA Isolation & Quantitative Real-Time PCR (qRT-PCR) 17
Chapter 3 Experimental Results and Discussion 19
3.1 The Necessity of BV2 Contact 19
3.1.1 BV2 Contact Analysis 19
3.1.2 Artificial Spheroid Assay 21
3.2 Cellular Traction Force Quantification 26
3.2.1 Cell Adhesion Types 26
3.2.2 Stiffening Microenvironment 27
3.3 Spheroid Formation Process Analysis 28
3.4 Morphology of Spheroid Formation 34
3.4.1 Normal Condition 34
3.4.2 Contractility Inhibition 35
3.4.3 Low Calcium Condition 37
3.5 Expression of Membrane Protein 39
Chapter 4 Conclusion 41
References 42

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