仿肝腫瘤實驗室晶片應用於纖維母細胞與內皮細胞對酪氨酸激酶抑制劑產生之耐藥性研究

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研究生：	馬杜思 Poddar, Madhu Shree
論文名稱：	仿肝腫瘤實驗室晶片應用於纖維母細胞與內皮細胞對酪氨酸激酶抑制劑產生之耐藥性研究 Liver-on-a-Chip Insights: Fibroblast and Endothelial-Induced Resistance to Tyrosine Kinase Inhibitors
指導教授：	劉承賢 Liu, Cheng-Hsien
口試委員:	陳致真 Chen, Chih-Chen 葉昭廷 Yeh, Chau-Ting 朱育德 Chu, Yu-De 涂夏爾 Punde, Tushar
學位類別：	博士 Doctor
系所名稱：	工學院 - 奈米工程與微系統研究所 Institute of NanoEngineering and MicroSystems
論文出版年：	2024
畢業學年度：	113
語文別：	英文
論文頁數：	109
中文關鍵詞：	肝细胞癌、肝癌、酪氨酸激酶抑制剂、微流控生物芯片、肿瘤内皮细胞
外文關鍵詞：	Microfluidic bio-chip, GelMA Cancer-Associated Fibroblast, Tumor-Endothelial Cells, AHSG, CLEC3B, CD105
相關次數：	點閱：3 下載：0
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肝癌是全球癌症相關死亡的主要原因之一，在標靶治療中，尤其是索拉非尼和樂伐替尼等酪胺酸激酶抑制劑 (TKI) 的抗藥性仍然是主要挑戰。本論文全面研究了肝癌細胞對TKIs的抗藥性機制，重點分析了腫瘤微環境（TME）中的兩個關鍵成分：癌症相關成纖維細胞（CAFs）和腫瘤內皮細胞（TECs）。通過使用肝臟晶片模型，本研究探討了這些基質細胞如何驅動TKIs的抗藥性，並提出了可能克服該抗藥性的治療策略。

第一項研究探討了CAFs在促進肝癌細胞對TKIs抗藥性中的作用。研究者設計了一個模擬肝臟結構的3D微流控晶片，以類比肝癌細胞與成纖維細胞之間的複雜相互作用，並再現肝小葉的六邊形結構。該模型進行了細胞活性、藥物反應及蛋白表達的詳細分析，涵蓋了2D和3D共培養環境的研究。結果顯示，當肝癌細胞與成纖維細胞共培養時，對索拉非尼和侖伐替尼表現出更強的抗藥性。通過死活細胞分析和分子檢測，確定了兩個關鍵的抗藥介質——AHSG和CLEC3B，它們在共培養介質中的表達顯著增加。功能實驗進一步證實，重組的AHSG和CLEC3B 在 2D 和 3D 培養中增強了抗藥性，突顯了它們在 CAFs 誘導的抗藥性中的關鍵作用。

第二項研究聚焦於TECs在促進TKIs抗藥性中的作用，特別是腫瘤血管生成及CD105的表達。CD105是一種參與內皮細胞增殖和血管生成的糖蛋白。本研究在包含肝細胞癌（HCC）細胞與內皮細胞的3D微流控共培養系統中，探討了CD105在肝腫瘤微環境中的作用及其對化療抗藥性的影響。研究結果顯示，CD105在肝臟腫瘤微環境中的TECs中高度表達，並與增強的血管生成活性及降低對TKIs的敏感性相關。通過靶向CD105的抗體治療，顯示出破壞腫瘤血管結構、提高TKIs療效的潛力，為抑制腫瘤進展和克服抗藥性提供了一種新的治療策略。
綜上所述，這些研究顯示腫瘤微環境中的CAFs和TECs如何通過不同但相互關聯的機制，共同增強肝癌細胞對TKIs的抗藥性。通過在微流控晶片中再現肝臟的微環境，本論文提供了對TKIs抗藥性分子機制的關鍵見解，並提出了改善肝癌治療效果的潛在策略。這些發現強調了標靶 TME 克服抗藥性的重要性，並為未來開發更有效的肝癌治療方法奠定了基礎。

Liver cancer is a leading cause of cancer-related deaths worldwide, with resistance to targeted therapies, particularly tyrosine kinase inhibitors (TKIs) such as Sorafenib and Lenvatinib, remaining a major therapeutic challenge. This thesis presents a comprehensive investigation of the mechanisms underlying hepatoma cell resistance to TKIs, focusing on two critical components of the tumor microenvironment (TME): cancer-associated fibroblasts (CAFs) and tumor endothelial cells (TECs). Utilizing a liver-on-a-chip model, this work examines how these stromal elements drive resistance to TKIs and explores potential therapeutic strategies to overcome this resistance.
The first study explores the role of CAFs in promoting resistance to TKIs in hepatoma cells. A 3D microfluidic chip imitating the liver architecture was designed to simulate the complex interactions between liver cancer cells and fibroblasts, replicating the hexagonal structure of liver lobules. This model enabled detailed analysis of cell viability, drug response, and protein expression in both 2D and 3D co-culture environments. The results demonstrated that co-cultured liver cancer cells exhibited increased resistance to Sorafenib and Lenvatinib when in the presence of fibroblasts. Through live/dead assays and molecular profiling, the study identified two key mediators of resistance, Fetuin-A (AHSG) and C-Type Lectin Domain Family 3 Member B (CLEC3B), which were significantly upregulated in the co-culture medium. Functional assays confirmed that recombinant AHSG and CLEC3B enhanced drug resistance in both 2D and 3D cultures, highlighting their critical role in CAF-induced resistance.
The second study investigates the role of TECs in fostering resistance to TKIs, with a particular focus on tumor angiogenesis and the expression of CD105, a glycoprotein involved in endothelial cell proliferation and vessel formation. Through a 3D microfluidic co-culture system incorporating hepatocellular carcinoma (HCC) cells and endothelial cells, this research examined the impact of CD105 on tumor angiogenesis and its contribution to chemoresistance. CD105 was found to be highly expressed in TECs within the liver TME, correlating with increased angiogenic activity and reduced sensitivity to TKIs. Targeting CD105 with antibodies showed potential in disrupting tumor vasculature and enhancing the efficacy of TKIs, offering a novel approach to inhibiting tumor progression and resistance mechanisms.
Together, these studies demonstrate how key stromal components of the TME—CAFs and TECs—collaborate to enhance hepatoma cell resistance to TKIs through distinct yet interconnected mechanisms. By replicating the liver's microenvironment in a microfluidic chip, this thesis provides crucial insights into the molecular drivers of TKI resistance and proposes potential strategies for improving the therapeutic outcomes of liver cancer treatment. The findings emphasize the importance of targeting the TME to overcome drug resistance and pave the way for future research aimed at developing more effective treatments for liver cancer.

Abstract    3
摘要    5
TABLE OF CONTENTS    7
LIST OF FIGURES AND TABLES    10
ACKNOWLEDGEMENT    14
ABBREVIATIONS    16
CHAPTER 1: INTRODUCTION    17
1Background and significance    17
2Motivation and Objective     18
3Thesis outline    19
CHAPTER 2: LITERATURE SURVEY    21
1    Liver cancer    21
2    Lab on a chip    23
3    Recent Advances in Cell Culture Techniques within Microfluidic Systems    24
4 Tyrosine Kinase Inhibitors in Liver Cancer    26
5 Tumor Microenvironment (TME) in Liver Cancer     27
6 Drug Resistance in cancer     29
6.1 Role of Cancer-Associated Fibroblasts (CAFs) in liver cancer drug resistance    30
6.2 Role of Endothelial cells in liver cancer drug resistance     32
CHAPTER 3: MATERIALS AND METHODS    34
1    Preparation of microfluidic chip    34
1.1 Fabrication Process     34
1.2 PDMS molding     36
2 Experimental methods     38
2.1 Biocompatible material Gelatin methacryloyl (pre-GelMA)     38
2.2 Cell culture and preparation     40
2.2.1 Cell types    40
2.2.1.1 NIH-3T3 fibroblast     40
2.2.1.2 HepG2 liver cancer cells     41
2.2.1.3 HUVEC cells    42
2.2.2 Cell culture    43
2.2.2.1 Culture Conditions for NIH-3T3 and HepG2 Cells     43
2.2.2.2 Sub-Culturing Protocol for NIH-3T3 and HepG2 Cells    43
2.2.2.3 Culture Conditions for HUVEC Cells    44
2.2.2.4 Sub-Culturing Protocol for HUVEC Cells     44
2.3 Drug testing    45
2.3.1 Types of drugs    45
a.) Sorafenib    45
b.) Lenvatinib    45
2.3.2 IC50    46
2.3.2.1 Key Steps in the CCK-8 Assay    47
2.4 Live and dead cell viability    47
2.5 Fluorescence staining in bio-engineered chip analysis    48
2.5.1 Biomarkers    48
a.) Fibroblast Activation Protein (FAP)     48
b.) Fetuin-A (AHSG)    49
c.) C-Type Lectin Domain Family 3 Member B (CLEC3B)    49
d.) CD105    50
e.) CD31    50
f.) Albumin    51
2.5.2 Immunofluorescence    51
2.6 Protein Gel Staining, LC-MS/MS Analysis, and Western Blotting    52
a.) Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS) Analysis52
b.) Western Blotting    54
3 Preparation of cells for loading in the chip    55
3.1 Preparation of photoinitiator    55
3.2 Preparation of GelMA solution    56
3.3 Preparation of cell    56
4 Experimental setup    56
CHAPTER 4: TUMOR-STROMA STUDY    58
1 Motivation     58
2 Device design    58
3 Device operation    60
4 Tumor-Stroma Study    62
5 Results and discussion    63
5.1 Liver Lobule    63
5.2 Performance and suitability of a Liver Lobule-Inspired bio-Chip     65
5.3 Expression of Fibroblast Activation Protein within Co-Culture Systems    66
5.4 Determining the IC50 values    67
5.5 Induction of Sorafenib and Lenvatinib Resistance in Liver Cancer Cells Following Co-culture with Fibroblasts.     68
5.6 Key Regulators of Fibroblast-Driven Drug Resistance in Hepatoma Cells    71
5.7 Investigating the role of regulators in Fibroblast-Mediated Resistance to Sorafenib and Lenvatinib in Hepatocellular Carcinoma    73
CHAPTER 5: TUMOR-ENDOTHELIAL STUDY    77
1 Motivation     77
2 Device design    77
3 Device operation    78
4 Tumor-Endothelial Study    80
5 Results and discussion    81
5.1 Chip design    81
5.2 Evaluating the liver bio-chip’s suitability and biocompatibility for modeling interactions between liver cancer and endothelial cells    83
5.3 Determining the IC50 values     84
5.4 Analysis of CD105, CD31, and Albumin Expression in Liver Cancer-Endothelial Cell Co-culture     85
5.5. Emergence of Drug Resistance in Liver Cancer Cells Co-cultured with Endothelial Cells     87
5.6 Exploring CD105's Role in Endothelial-Mediated Drug Resistance in Liver Cancer Cells     89
CHAPTER 6: Conclusion and future scope    93
1 Conclusion    92
2 Future scope    94
List of Publications    98
Bibliography    99

                                

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