利用具有特定奈米片段及彈性的生醫材料去除癌症幹細胞

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周育瑄(Yu-Hsuan Chou) 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

利用具有特定奈米片段及彈性的生醫材料去除癌症幹細胞
(Depletion of Colon Cancer-Initiating Cells on Biomaterials Having Specific Nanosegments and Elasticity)

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★ 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	★ 用於人類胚胎幹細胞生長之生醫材料其奈米片段分子之設計

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摘要(中)

癌症起始細胞或癌症幹細胞（癌幹細胞）表現自我更新的能力，並負責腫瘤生成。癌幹細胞是一種幹細胞會生成腫瘤，並表現出幹細胞特性，例如自我更新和分化為多種細胞類型的能力的幹細胞。癌幹細胞在腫瘤中作為一個獨特的群體，並導致腫瘤生成從而形成復發和轉移。針對癌幹細胞的特殊療法的發展可能提高生存率和癌症患者的生活品質，特別是那些深受腫瘤轉移疾病之苦的患者。研究者提出了許多標記抗體來辨識癌幹細胞，例如：CD29，CD133，Lgr5，Msi-1，ALDH-1等。然而，專一且可信任的標記抗體來辨識大腸癌細胞尚未確定。唯一可靠的方法來識別和量化癌幹細胞是透過觀察動物體內實驗腫瘤的產生。本研究將大腸癌細胞培養在具有不同軟硬度的細胞外間質衍生之寡?的水凝膠上，評估癌幹細胞是否增加（純化）或減少（耗竭）。癌幹細胞能透過培養在Pluronic接枝的基底上被耗盡，且於動物體內實驗沒有腫瘤生成，相反地，癌幹細胞會存活在具有不同軟硬度的細胞外間質衍生之寡?的水凝膠上，且於動物體內實驗生成腫瘤。此外，本研究亦利用服樂癌注射劑來辨識癌幹細胞，從研究成果發現體外培養與動物體內實驗呈現相同的趨勢。本研究提出一種特殊的生醫材料Pluronic，當大腸癌細胞培養在Pluronic接枝的盤子上可以耗盡癌幹細胞，而癌幹細胞卻可以在具有不同軟硬度的細胞外間質衍生之寡?的水凝膠上存活或增加。

摘要(英)

Cancer-initiating cells or cancer stem cells (CSCs) exhibit a self-renewing capacity and are responsible for tumor generation. CSCs are stem cells that form tumors and exhibit stem cell properties, such as self-renewal and the ability to differentiate into multiple cell types. It was suggested that CSCs persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. The development of specific therapies targeted at CSCs may improve the survival rates and the quality of life of cancer patients, particularly those suffering from metastatic disease. Several markers for colon CSCs have been proposed: CD24, CD29, CD44, CD133, CD166, Lgr5, Muc2, ESA, Msi-1, and ALDH-1. However, specific and reliable surface markers of colon CSCs have not been identified. The only reliable method to identify and quantify CSCs is the observation of tumor generation in the serial xenotransplantation model. In this study, the Colo205 and LoVo colon cancer cell lines and colon cancer cells established from the cells of colon cancer patients (Primary-colon cancer cells 0317) were cultured on ECM (nanosegment)-grafted, oligopeptide (nanosegment)-grafted, and Pluronic (nanosegment)-grafted dishes having different elasticity (100 kPa to 16 MPa elasticity) as well as tissue culture dishes (TCPS, 10GPa elasticity). The oligopeptide-grafted dishes were prepared from polyvinylalcohol-co-itaconic acid (PVA-IA) coating dishes grafted with several nanosegments (KGGPQVTRGDVFTMP [cell-binding domain derived from vitronectin, oligoVN], GGNGEPRGDTYRAY [cell-binding domain from bone sialoprotein, oligoBSP], and GKKQRFRHRNRKG [heparin-binding domain, oligoHBD]). We evaluated whether the CSCs were enhanced (purified) or decreased (depleted) among the colon cancer cells after the colon cancer cells were cultured on ECM-grafted, oligopeptide-grafted, TCPS, or Pluronic-grafted dishes. The ratio of the CSCs was evaluated from the tumor generation of cancer cells in mice that were subcutaneously xenotransplanted into mice. CSCs in colon cancer cells could be selectively depleted from colon cancer cells (Colo205, LoVo, and Primary-colon cancer cells) when they were cultured on Pluronic-grafted dishes having optimal elasticity, whereas CSCs were maintained on TCPS and extracellular matrix (ECM)-immobilized dishes as well as oligopeptide-immobilized dishes. Furthermore, there is no tumor generation of colon cancer cells cultured on pluronic-grafted dishes while there is tumor generation of colon cancer cells cultured on oligopeptide-immobilized dishes. On the other hand, anticancer drug (5-Fluorouracil) was used as well to identify CSCs in colon cancer cells. The results show the same tendency in in vitro cultivation and in vivo experiment. It was concluded that the pluronic-grafted dishes deplete cancer-initiating cells (CSCs) from colon cancer cells while CSCs in colon cancer cells remain or enhance on TCPS and oligopeptide-immobilized dishes, which was explained by specific biomedical characteristics of Pluronic.

關鍵字(中)

★ 癌症幹細胞

關鍵字(英)

★ Colon Cancer-Initiating Cells

論文目次

Index of Contents

Chapter 1 Introduction VIII
1-1 The relationship between stem cells and cancer stem cells 1
1-1-1 Stem cells 1
1-1-2 Cancers and cancer stem cells 3
1-1-3 Identity of cancer stem cells 6
1-1-4 Relationship between cancer cells and microenvironment 10
1-1-4-1 ECM 11
1-1-4-2 Purification of cancer stem cells on biomaterials having nano-segment 15
1-2 Sphere-forming assay 17
1-3 Immunofluorescent staining (IF) 18
1-4 In vivo tumorigenic assay 20
Chapter 2 Materials and Methods 21
2-1 Cell lines and patient specimens 21
2-1-1 Cancer cell lines 21
2-1-2 Patient specimen 21
2-2 Cell culture condition 22
2-2-1 LoVo cells 22
2-2-2 Colo205 cells 22
2-2-3 Primary-colon cancer cells 23
2-3 Preparation of chemotherapeutic agents 23
2-4 Preparation of buffer solution 24
2-5 Preparation of CDI activated pluronic Poly-L-lysine plates 24
2-6 Preparation of ECM-grafted Poly(VA-IA) plates 25
2-6-1 Material for PVA-IA film preparation 25
2-6-2 PVA-IA film preparation 25
2-6-3 Preparation of PVA-IA coating plates grafted with ECM and oligopeptide 26
2-7 Sphere-forming assay 27
2-8 In vivo tumor generation 28
2-9 Immunofluorescence 29
Chapter 3 Results and Discussion 32
3-1 The effect of drug treatment on the cell morphology 32
3-1-1 The cell morphology of LoVo colon cancer cells cultivated under drug treatment 32
3-2 The effect of the microenvironment on the cell morphology 33
3-2-1 The cell morphology on Pluronic-immobilized plates 33
3-2-2 The cell morphology on Poly(VA-IA) and ECM-grafted Poly(VA-IA) plates 34
3-3 Characterization of purified cancer stem cells (CSCs) 43
3-3-1 Putative cancer stem cell markers analyzed by immunofluorescence staining 44
3-3-2 The tumorigenic potential of putative cancer stem cells analyzed by sphere-forming assay 45
3-4 In vivo tumorigenic bioassay 60
3-4-1 The tumorigenic potential of putative cancer stem cells sorted by chemotherapy 61
3-4-2 The tumorigenic potential of colon cancer cells cultivated on surface modified plates 61
Chapter 4 Conclusion 64
Supplementary data 66
Reference 67

Index of Figures
FIGURE 1 HSC SYSTEM IS THE FIRST- AND BEST-CHARACTERIZED INTERNS OF HIERARCHICAL ORGANIZATION AND CONSECUTIVE DIFFERENTIATION OF CELLULAR POPULATIONS [9]. 3
FIGURE 2 PARALLELS BETWEEN NORMAL STEM CELLS AND CANCER STEM CELLS [10]. 5
FIGURE 3 SPECIFIC THERAPY TARGETING THE CANCER STEM CELLS. 10
FIGURE 4 ECM CAN TRIGGER TUMOR CELLS, WHICH SECRETE SEVERAL FACTORS INCLUDING PROTEASES OF MMPS AND PLASMIN THAT DEGRADE ECM FACILITATING THEIR MIGRATION AND INVASION [46]. 12
FIGURE 5 REACTION SCHEME FOR THE SYNTHESIS OF CDI-ACTIVATED PLURONIC F68 AND F127 AND IMMOBILIZATION OF CDI-ACTIVATED PLURONIC F68 AND F127 ON POLY-L-LYSINE COATED PLATE [69]. 17
FIGURE 6 TWO MAJOR TYPES OF IMMUNOFLUORESCENCE STAINING. 19
(A) DIRECT IMMUNOFLUORESCENCE STAINING, (B) INDIRECT IMMUNOFLUORESCENCE STAINING 19
FIGURE 7 CANCER STEM-LIKE CELLS WERE PURIFIED OR CULTURED ON SEVERAL CONDITIONS. 29
FIGURE 8 THE MORPHOLOGY OF LOVO CELLS TREATED WITH 0.01MM AND 0.001MM 5-FU UNDER 2H, 12H, 24H, 48H, AND 7DAYS OF CULTIVATION. 35
FIGURE 9 THE MORPHOLOGY OF 0317-PRIMARY COLON CANCER CELLS CULTIVATED ON THE PLURONIC-IMMOBILIZED PLATES (PLL-F68-50 AND PLL-F127-50), TCPS PLATES AND PLL0 PLATES DURING 7 DAYS OF CULTIVATION. 36
FIGURE 10 THE MORPHOLOGY OF COLO205 CELLS CULTIVATED ON THE PLURONIC-IMMOBILIZED PLATES (PLL-F68-50 AND PLL-F127-50), TCPS PLATES AND PLL0 PLATES DURING 7 DAYS OF CULTIVATION. 37
FIGURE 11 THE MORPHOLOGY OF LOVO CELLS CULTIVATED ON THE PLURONIC-IMMOBILIZED PLATES (PLL-F68-50 AND PLL-F127-50), TCPS PLATES AND PLL0 PLATES DURING 7 DAYS OF CULTIVATION. 38
FIGURE 12 THE GROWTH CURVE OF 0317-PRIMARY-COLON CANCER CELLS CULTIVATED ON THE PLURONIC-IMMOBILIZED PLATES (PLL-F68-50 AND PLL-F127-50), TCPS AND PLL0 PLATES DURING 7 DAYS OF CULTIVATION. 39
FIGURE 13 THE GROWTH CURVE OF COLO205 CELLS CULTIVATED ON THE PLURONIC-IMMOBILIZED PLATES (PLL-F68-50 AND PLL-F127-50), TCPS AND PLL0 PLATES DURING 7 DAYS OF CULTIVATION. 39
FIGURE 14 THE GROWTH CURVE OF LOVO CELLS CULTIVATED ON THE PLURONIC-IMMOBILIZED PLATES (PLL-F68-50 AND PLL-F127-50), TCPS AND PLL0 PLATES DURING 7 DAYS OF CULTIVATION. 40
FIGURE 15 THE MORPHOLOGY OF 0317-PRIMARY-COLON CANCER CELLS, COLO205 CELLS, AND LOVO CELLS CULTIVATED ON POLY(VA-IA) PLATES AFTER 5 DAYS OF CULTIVATION. 41
FIGURE 16 THE MORPHOLOGY OF 0317-PRIMARY-COLON CANCER CELLS, COLO205 CELLS, AND LOVO CELLS CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES AFTER 5 DAYS OF CULTIVATION. 42
FIGURE 17 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH MASASHI-1 (MSI-1) CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 47
FIGURE 18 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH MASASHI-1 (MSI-1) CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 48
FIGURE 19 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH ALDEHYDE DEHYDROGENASE-1 (ALDH-1) CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 49
FIGURE 20 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH ALDEHYDE DEHYDROGENASE-1 (ALDH-1) CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 50
FIGURE 21 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 51
FIGURE 22 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH CD133 CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 52
FIGURE 23 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH CD29 CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 53
FIGURE 24 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH CD29 CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 54
FIGURE 25 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH LGR5 CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 55
FIGURE 26 THE IMMUNOFLUORESCENCE ANALYSIS OF LOVO CELLS STAINED WITH LGR5 CULTIVATED ON ECM-GRAFTED POLY(VA-IA) PLATES. 56
FIGURE 27 SPHERE FORMATION OF LOVO CELLS CULTURED ON ECM-GRAFTED POLY(VA-IA) PLATES THEN SHIFTED TO ULTRA-LOW ATTACHMENT PLATES UNTIL DAY 14. 57
FIGURE 28 SPHERE FORMATION OF LOVO CELLS CULTURED ON ECM-GRAFTED POLY(VA-IA) PLATES THEN SHIFTED TO ULTRA-LOW ATTACHMENT PLATES UNTIL DAY 14. 58
FIGURE 29 SPHERE FORMATION OF LOVO CELLS CULTURED ON PLURONIC-IMMOBILIZED PLATES THEN SHIFTED TO ULTRA-LOW ATTACHMENT PLATES UNTIL DAY 9. 59
FIGURE 30 THE NUMBERS OF SPHERE FORMATION OF LOVO CELLS CULTURED ON SEVERAL CONDITIONS. 59
FIGURE 31 EVALUATION OF TUMORIGENIC POTENTIAL OF LOVO CELLS CULTURED WITH 5-FLUOROURACIL (5-FU) TREATMENT. 63
FIGURE 32 EVALUATION OF TUMORIGENIC POTENTIAL OF LOVO CELLS CULTURED ON SEVERAL CONDITIONS. 63

Index of Tables
TABLE 1 CANCER STEM CELLS IDENTIFIED AND THEIR SURFACE MARKERS [40]. 9
TABLE 2 THE SURFACE MARKER OF COLON CANCER-INITIATING CELLS [28]. 9
TABLE 3 TYPES OF COLLAGEN[64]. 14
TABLE 4. PRIMARY ANTIBODIES 30
TABLE 5. SECONDARY ANTIBODIES 30
TABLE 6 THE TUMOR VOLUME AFTER INJECTION OF LOVO CELLS UNDER CHEMOTHERAPEUTIC REAGENT TREATMENT INTO BALB/C NUDE FEMALE MICE SUBCUTANEOUSLY. 62
TABLE 7 THE TUMOR VOLUME AFTER INJECTION OF LOVO CELLS UNDER SEVERAL CONDITIONS INTO BALB/C NUDE FEMALE MICE SUBCUTANEOUSLY. 62

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指導教授

?口亞紺(Akon Higuchi)

審核日期

2014-6-17

推文