利用具有奈米片段的生醫材料進行純化及去除癌症幹細胞

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黃聰閔(Tsung-Min Huang) 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

利用具有奈米片段的生醫材料進行純化及去除癌症幹細胞
(PURIFICATION AND DEPLETION OF CANCER INITIATING CELLS CULTURED ON BIOMATERIALS HAVING NANOSEGMENTS)

相關論文

★ 人類幹細胞培養於熱敏感奈米片段材料之研究	★ 抗癌藥物的鑑定性用於分析大腸癌中癌幹細胞之研究
★ 羊水間葉幹細胞培養於細胞外間質及材料硬度/彈性表面,其分化能力及多能性之研究	★ 人類脂肪幹細胞的膜純化法與分化能力研究
★ 人類羊水間葉幹細胞培養於具有奈米片段與最佳表面硬度的生醫材料，其增殖與成骨分化能力	★ 多能幹細胞在無異種條件下分化為間充質幹細胞的生物材料比較研究

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摘要(中)

腫瘤是由一般癌細胞和小比例的癌症幹細胞所組成,其中這小部分的癌症幹細胞具有自我更新且是腫瘤形成的主要原因。如果我們可以發展出個材料並且可以去除掉癌症幹細胞,這樣對未來臨床上的治療會有一定程度的幫助.舉例來說,如果我們可以發展出材料,並且可以去除掉癌症幹細胞,這樣我們可以避免使用具有副作用的抗癌藥物.除此之外,此種材料還具有純化兼業幹細胞的功能。這樣一來,在臨床上的應用會更寬廣。
癌症幹細胞的表面標記物目前還是未知的,雖然CD34+, CD44+, CD133+, CD166+,Sca-1, Lgr5,和 Muc2,等等標記物在某些文獻中認為可能是癌症幹細胞的表面標記物,但還是有些文件證明出癌症幹細胞的表面標記物是不存在的。總而言之,最直接的方法就是使用動物實驗去探討致瘤性與表面標記物的關係。
在這個實驗,我們使用了兩種癌細胞株 (LoVo, Colo205),和Primary cell.培養在TCPS盤,ECM塗佈盤,和Pluronic-grafting盤。其中Pluronic是由PEO-PPO-PEO所組成的共聚物,此種材料在某些文獻已經發表過此種材料可以促進造血幹細胞的培養。在我們的研究中,我們發現培養在這種材料的捱細胞,其致瘤性會比較差,而培養在ECM塗佈盤和decellularized盤上的癌細胞其致瘤性將會有顯著的提升。此實驗告訴我們,此種材料可以抑制腫瘤的生成,我們猜測它可以去除掉CSC(即cancer-initiating cell),而ECM塗佈盤,和decellularized盤則可以促進CSC的生長。

摘要(英)

Tumors contain a small subpopulation of cells, i.e., cancer stem cells (CSCs, cancer-initiating cells), which exhibit a self renewing capacity and are responsible for tumor generation. The cancer stem cells and not normal cancer cells persist in tumors as a distinct population, and cause relapse and metastasis by giving rise to new tumors. It is necessary to eliminate only a tiny subset of cells (0.0001-0.1%, cancer stem cells) that have the ability to generate a new tumour in cancer patients. If we succeed to develop biomaterials where CSCs are depleted or purified from tumor cells, it should be useful in clinical application. The purified CSCs can be used for the development of the specific anti-cancer drugs targeting only the cancer stem cells. We can save tumor patients with low side effects of medicine and avoid relapse and metastasis. On the other hand, the depletion of CSCs from tissue should be useful for the isolation of mesenchymal stem cells or bone marrow cells (hematopoietic stem cells) from patient tissue or blood. The mesenchymal stem cells or bone marrow depleting CSCs can be used for the stem cell therapy for the patients.
Currently, surface markers and/or gene expression of CSCs are unknown, although CD34+, CD44+, CD133+, CD166+,Sca-1, Lgr5,and Muc2, etc are suggested. There are several contrary data suggesting those surface markers and/or genes are not specific to CSCs. The most promising method to quantify and identify CSCs is in vivo experiments where the sample cells are injected into mice subcutaneously, and to evaluate the tumor generation speed by the injection of the sample cells.
In this study, several colon cancer cell lines (LoVo, Colo205, etc) and primary colon cancer cells from patients are cultured on tissue culture dishes (TCPS), extracellular matrix (ECM, collagen type I, fibronectin, vitronectin, orlaminin) coated dishes, and pluronic-grafted dishes. The pluronic is polyethylene oxide (PEO)-polypropylene oxide (PPO)-PEO triblock copolymers where it is reported that hematopoietic stem cells efficiently preserved on pluronic-grafted dishes. It is found that tumor generation of colon cancer cells was enhanced after the colon cancer cells were cultured on ECM-coated dishes and decellularized-dishes, which indicates CSCs are enriched. On the other hand, tumor generation of colon cancer cells decreased after culture of colon cancer cells on pluronic-grafted dishes. Remarkably, tumor generation did not observed when primary colon cancer cells were cultured on pluronic-grafted dishes, which indicates CSCs in primary colon cancer cells are depleted after culture on pluronic-grafted dishes. It is concluded that the pluronic-grafted surface deplete cancer-initiating cells (CSCs) from colon cancer cell lines and primary cancer cells, while CSCs in colon cancer cells are enhanced by culture on conventional TCPS, decellularized and ECM-grafted dishes promote CSCs.

關鍵字(中)

★ 去除
★ 癌症幹細胞
★ 材料

關鍵字(英)

★ deplete
★ cancer stem cell
★ material

論文目次

Chapter 1 Introduction IX
1-1The relationship between stem cells and cancer stem cells 1
1-1-1 Stem cell 1
1-1-2 Cancers and Cancer stem cells 2
1-1-3 Identity of cancer stem cells 5
1-1-4 Relationship between cancer cells and microenviroment 8
1-1-4-1 ECM 9
1-1-4-2 Purification of stem on biomaterials having nano-segment 13
1-1-4-3 Decellularized ECM from ADSCs and AFSCs 14
1-2 Analysis of CSCs by flow cytometry 16
1-3 Isolation of CSCs by magnetic-activated cell sorting (MACs) 17
1-4 Immunofluorescent staining (IF) 19
1-5 Quantitative real-time Polymerase chain reaction (QRT-PCR) 20
1-6 in vivo tumorigenic assay 22
1-7 Immunohistological staining (IHC) 22
Chapter 2 Materials and Methods 24
2-1 Cell lines and patient specimens 24
2-1-1 Cancer cell lines 24
2-1-2 Patient specimen 24
2-2 Cell culture condition 25
2-2-1 LoVo cells 25
2-2-2 Colo205 cells 25
2-2-3 Primary-colon cancer cells and adipose stem cells (ADSCs) 26
2-2-4 Amniotic fluid stem cells (AFSCs) 26
2-3 Preparation of buffer solution 27
2-4 Preparation of ECM-coated dish 27
2-5 Preparation of CDI activated pluronic Poly-L-lysine plate 28
2-6 Preparation of decellularized-dish 29
2-7 X-ray photoelectron spectra (XPS) 29
2-8 Water contact angle 29
2-9 Flow cytometry 30
2-10 MACs sorting method 31
2-11 Isolation of RNA and QRT-PCR 32
2-11-1 Isolation of RNA 32
Chapter 1 Introduction IX
1-1The relationship between stem cells and cancer stem cells 1
1-1-1 Stem cell 1
1-1-2 Cancers and Cancer stem cells 2
1-1-3 Identity of cancer stem cells 5
1-1-4 Relationship between cancer cells and microenviroment 8
1-1-4-1 ECM 9
1-1-4-2 Purification of stem on biomaterials having nano-segment 13
1-1-4-3 Decellularized ECM from ADSCs and AFSCs 14
1-2 Analysis of CSCs by flow cytometry 16
1-3 Isolation of CSCs by magnetic-activated cell sorting (MACs) 17
1-4 Immunofluorescent staining (IF) 19
1-5 Quantitative real-time Polymerase chain reaction (QRT-PCR) 20
1-6 in vivo tumorigenic assay 22
1-7 Immunohistological staining (IHC) 22
Chapter 2 Materials and Methods 24
2-1 Cell lines and patient specimens 24
2-1-1 Cancer cell lines 24
2-1-2 Patient specimen 24
2-2 Cell culture condition 25
2-2-1 LoVo cells 25
2-2-2 Colo205 cells 25
2-2-3 Primary-colon cancer cells and adipose stem cells (ADSCs) 26
2-2-4 Amniotic fluid stem cells (AFSCs) 26
2-3 Preparation of buffer solution 27
2-4 Preparation of ECM-coated dish 27
2-5 Preparation of CDI activated pluronic Poly-L-lysine plate 28
2-6 Preparation of decellularized-dish 29
2-7 X-ray photoelectron spectra (XPS) 29
2-8 Water contact angle 29
2-9 Flow cytometry 30
2-10 MACs sorting method 31
2-11 Isolation of RNA and QRT-PCR 32
2-11-1 Isolation of RNA 32
2-11-2 Single-strand cDNA synthesis 32
2-11-3 Q-PCR (Polymerase Chain Reaction) steps 34
2-12 In vivo tumor generation 35
2-13 Immunofluorescence 37
2-14 Immunohistochemistry 38
Chapter 3 Result and Discussion 40
3-1 Physical characteristics of ECM coating plates and CDI activated Pluronic poly-L-lysine plates 40
3-2 The effect of the microenviroment on the cell morphology 50
3-2-1 The cell morphology on ECM-coating dishes 50
3-2-2 The cell morphology on pluronic-grafting dishes 50
3-2-3 The cell morphology on decellularized-dishes 51
3-3 Characterization of purified cancer stem cells (CSC) 57
3-3-1 Putative cancer stem cell markers analyzed by Q-PCR (Quantitative-Polymerase Chain Reaction) 57
3-3-2 Putative cancer stem cell markers analyzed by flow cytometry and immunofluorescence 60
3-3-3 In vivo tumorigenic bioassay 71
3-3-3-1 The tumorigenic potential of putative cancer stem cells sorted by MACS 71
3-3-3-2 The tumorigenic potential of colon cancer cells cultivated on surface modified plates 71
3-3-4 The relationship between the expression of surface markers and tumor volume 85
3-3-4-1 The relationship between gene expression and tumor volume for Colo205 cells 85
3-3-4-2 The relationship between LGR5 and CD133 expression in protein level and tumor volume for Colo205 cells 87
3-3-4-3 The relationship between expression of LGR5 and CD133 in gene level and tumor generation for primary-colon-cancer cells 89
Chapter 4 Conclusions 91
Supplementary data 95
Reference 113

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指導教授

樋口亞绀(Akon Higuchi)

審核日期

2012-7-13

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