從人類初始結腸癌組織分離結腸癌細胞和癌症幹細胞為建立病患專一癌細胞株

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陳亭曄(Ting-Yeh Chen) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

從人類初始結腸癌組織分離結腸癌細胞和癌症幹細胞為建立病患專一癌細胞株
(Isolation of colon cancer cells and cancer stem cells from primary colon cancer tissue for establishing patient-specific cancer cell lines)

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摘要(中)

癌症初始細胞或癌症幹細胞 (CSCs) ，是腫瘤內具有幹細胞特性之細胞，例如:自我更新和分化成多種細胞型態的能力，而這些特性賦予癌症初始細胞在引起腫瘤的復發及轉移中扮演重要的角色。這也意味著，在腫瘤內，癌症幹細胞是一個特殊的群落並且隨著新增生的腫瘤而造成癌症的復發與轉移。
為了發展出一套能夠鎖定癌症幹細胞方法，的我們結合物理及生化訊號，設計出能夠篩選細胞的培養皿。接枝不同的細胞外間質(ECM)及不同片段的寡?(理想生物訊號)於不同軟硬度(理想物理訊號)的篩選培養皿上。在生物訊號方面：成長因子、賀爾蒙、小化學分子和細胞外間質，可以決定幹細胞的分化路徑和多能性。因此，為了模仿幹細胞的微環境，許多研究致力於找出可溶性分化因子。在這個研究當中，不單單只有生物訊號，研究者也將開始評估物理訊號影響幹細胞之潛在的重要性，例如培養細胞基材的軟硬度。
目前尚未有關於藉由培養初始結腸癌症細胞於結合這兩個觀念的細胞篩選培養皿上的研究，去分離或消除癌症幹細胞和建立病患專一的結腸癌細胞株的研究。我們將會探討並找出最佳分離或消除癌症幹細胞的培養皿軟硬度和最佳的奈米片段。藉由注射癌症細胞於細胞篩選培養皿上，去評估和分析癌症幹細胞。
分析癌症幹細胞的方法，主要是利用偵測細胞的表面抗原來判定。已知結腸癌症幹細胞的表面具有許多抗原，例如： CD24 (HSA; 細胞貼附分子)、CD29 (β1受體; 細胞貼附分子)、CD44 (CDW44; 透明質酸受器)、CD133和CD166 (ALCAM; 細胞貼附分子)、Lgr5 (GPR49; Wnt目標基因)、Muc2和ESA (EpCAM，BerEp4; 細胞貼附分子)、Msi-1 (Musashi-1; 與RNA結合的蛋白質)、ALDH-1 (ALDC; 酵素)。對於白血病、腦腫瘤、視網膜母細胞瘤、腎腫瘤、胰腫瘤、結腸癌、前列腺癌和肝細胞癌中的癌症幹細胞而言，在這些抗原之中，CD133被認為是一個重要的表面抗原。但是CD133並不只專一表現在腸道幹細胞或癌症幹細胞中，而且CD133+的腫瘤細胞會造成更多活躍且具有形成腫瘤能力(在免疫缺陷老鼠)的CD133- 細胞。至今，專一且可靠的結腸癌症幹細胞表面抗原並未被發現。而目前確認且量化癌症幹細胞，唯一較可靠的方法是觀察在一連串異種移植模型中腫瘤的產生。
我們將會研究癌症幹細胞和固定於培養皿上的奈米片段之間特定的交互作用，以發展能夠分離或消除癌症幹細胞的細胞篩選培養皿。同樣地，我們也會發展具有純化癌症幹細胞的細胞篩選培養皿和從病人的初始結腸癌組織中建立病患專一的結腸癌細胞株。最終，我們希望試著利用純化的癌症幹細胞去分析癌症幹細胞的分子機構以及發展新穎癌幹細胞標靶藥物。

摘要(英)

Tumors contain a small subpopulation of cells, i.e., cancer-initiating cells or cancer stem cells (CSCs), which exhibit stem cell properties, possess a self-renewing capacity and are responsible for tumor generation and metastasis. Cancer stem cells persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Furthermore, it is expected to establish primary colon cancer cell lines in vitro, since patient specific colon cancer cell lines is in great advantages of developing patient specific therapy in clinical application.
We are developing a method of establishing cancer cell lines from primary patient colon cancer tissue. Colon cancer tissue is digested by collagenase to generate colon cancer tissue solution. Subsequently, primary colon cancer cell lines were established by (a) culture method on specific culture materials, and (b) the membrane migration method through Nylon mesh filter.1 We investigate which factor is more important to establish the cancer cell lines from minimum amount of colon cancer tissue and determine the optimal conditions to establish patient specific colon cancer cell lines from primary colon cancer tissues. The patient specific colon cancer cell line will be useful for the patient-specific therapy in the future.
In this study, we designed cell sorting dishes from two combined concepts, which are physical cues and biological cues. Different extracellular matrix (ECM) and cell binding domain oligopeptides (biological cues) having different elasticity (physical cues) are immobilized on the cell sorting dishes as biological cues and physical cues for capturing CSCs. Optimal ECM/ECM-derived oligopeptide and elasticity of the dishes for (a) establishment of the patient-specific cancer cell lines and (b) isolation or depletion of CSCs have been shown in this study. Moreover, CSCs identification is quantified by colony forming assay and/or tumor generation in serial xenotransplantation model.

關鍵字(中)

★ 結腸癌
★ 癌症起始細胞
★ 癌症幹細胞
★ 細胞分選
★ 細胞外間質

關鍵字(英)

★ colon cancer
★ cancer-initiating cells
★ cancer stem cells
★ cell sorting dish
★ extracellular matrix

論文目次

Abstract…………………………………………………………………….….....i
Index of contents……………………………………………………..………... iv
Index of figures……………………………………………………………….. vii
Index of tables…………………………………………………………………. xi
Chapter 1 Introduction
1-1 The relationship between stem cells and cancer stem cells
1-1-1 Stem Cells………………………………………………………………….….........1
1-1-2 Existence of cancer stem cells………………………………………………...........3
1-1-3 Cancer stem cells model……………………………………………………............4
1-1-4 Challenge of primary culture…………………………………………………….…5
1-2 The relationship between cancer stem cells and microenvironment
1-2-1 Impact of cancer niche on cancer propagation…………………………………...8
1-2-2 Extracellular Matrix (ECM) …………………………………………………....15
1-2-3 Decellularization…………………………………………………………….….19
1-3 Identification of cancer stem cells
1-3-1 CSCs surface marker analysis by flow cytometry……………………………...22
1-3-2 In vitro tumorigenicity assay…………………………………………………...23
1-3-3 Carcinoembryonic antigen (CEA) detection by ELISA………………………..24
1-3-4 Immunofluorescent staining (IF) ………………………………………………25
1-4 Goal of this study…………………………………………………………………….26
Chapter 2 Materials and Methods
2-1 Culture substrates preparation
2-1-1 Preparation of extracellular matrix-coated dishes……………………………….27
2-1-2 Preparation of tumorigenesis-mimicking matrices dishes (Decellularization)….28 2-2 Culture medium preparation
2-2-1 Preparation of serum-free DMEM medium……………………………………..29
2-2-2 Preparation of serum-containing DMEM medium………………………………29
2-2-3 Preparation of phosphate buffer saline solution (PBS) …………………………29
2-2-4 Preparation of transportation medium…………………………………………...30
2-2-5 Preparation of digestion solution………………………………………………...30
2-2-6 Preparation of ACK lysis buffer……………………………………………...….30
2-3 Cell lines
2-3-1 Colon cancer cell lines…………………………………………………………..31
2-3-2 Isolation of human primary colon cancer cells………………………………….31
2-4 Cell culture
2-4-1 Culture and passage of colon cancer cell line…………………………………...33
2-4-2 Culture and passage of human primary colon cancer cells…………………...…34
2-5 Flow cytometry of cancer stem cells surface markers analysis………………………35
2-6 In vitro Colony forming assay………………………………………………………..36
2-7 ELISA of carcinoembryonic antigen (CEA) detection……………………………….38
Chapter 3 Results and Discussions
3-1 Colo 205 culture on different ECM substrate with decreasing seeding density
3-1-1 Morphology of Colo 205 on different ECM substrate with decreasing seeding density………………………………………………………………………………………...39
3-1-2 Cell growth curve and doubling time of Colo 205 on different ECM substrate...45
3-1-3 Flow cytometry analysis of Colo 205 on different ECM substrate………….…..55
3-1-4 Evaluation of tumorigenic potential of Colo 205 under different culture conditions……………………………………………………………………………………..73
3-2 Isolation of primary human colon cancer cells
3-2-1 Improvement of isolation process of human colon cancer cells………………...81
3-2-2 Evaluation of primary human colon cancer cells………………………….…....92
3-2-3 Culture of primary human colon cancer cells………………………………..….97
Chapter 4 Conclusion………………………………………………………………..……98
Supplementary date………………………………………………………….…99
Reference…………………………………………………………………………………..104

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指導教授

?口亞紺(Akon Higuchi)

審核日期

2018-7-30

推文