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研究生:吳佩純
研究生(外文):Pei-Chun Wu
論文名稱:以非線性光學顯微術量化活體黑色素細胞癌微環境之膠原蛋白變化與新生血管滲漏
論文名稱(外文):In vivo quantification of the structural changes of collagens and tumor angiogenesis permeability in the melanoma microenvironment with nonlinear optical microscopy
指導教授:劉子銘劉子銘引用關係
指導教授(外文):Tzu-Ming Liu
口試委員:朱家瑜高甫仁周必泰陳惠文
口試委員(外文):Chia-Yu ChuFu-Jen KaoPi-Tai ChouHuei-Wen Chen
口試日期:2015-07-27
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:醫學工程學研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:129
中文關鍵詞:非線性光學顯微術黑色素細胞癌微環境黑色素細胞癌幹細胞膠原 蛋白變化新生血管血管滲漏
外文關鍵詞:nonlinear optical microscopymelanoma microenvironmentmelanoma stem cellscollagen remodelingangiogenesisvessel permeability.
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惡性腫瘤連續 30 年蟬聯國人十大死因首位。目前癌症的主要治療方式為手術、化學治療與放射治療,但這些療法不只是治療腫瘤細胞亦會傷害許多正常細胞。為了能較專一性地治療腫瘤細胞,近年來發展出了標靶治療。近期許多學者把腫瘤微環境做為發展新的抗癌標靶治療的可能標的,因此本研究的目標為探討黑色素細胞癌微環境中膠原蛋白重組、新生血管、血管滲漏及腫瘤幹細胞的交互關係。腫瘤微環境中的膠原蛋白纖維,在正常組織下扮演調節細胞間溝通的角色,也被發現與腫瘤轉移有關,因此也能成為判斷腫瘤預後的指標之一。為了在活體內能依時序追蹤黑色素細胞癌長大過程中微環境之膠原蛋白變化,我們採用二倍頻及三倍頻顯微術來做觀察。並且在沒有染色情況下,發展方向指數、灰階共生矩陣、及二三倍頻訊號比等指標來量化膠原蛋白變化。我們發現黑色素細胞癌附近之膠原蛋白在早期的方向指數及二倍頻訊號較高;而在晚期則較呈多方向性且分布不均勻。此外,為了能在活體中觀察血管滲漏與黑色素細胞癌幹細胞之間的關係,我們將表現mCherry紅色螢光及以ALDH1A1啟動子調控表現綠色螢光蛋白的細胞株種入C57BL/6-c2J小鼠耳朵且透過非線性光學系統來進行觀察。我們透過小鼠尾靜脈打入150 kD (8.9 nm)葡聚醣,以葡聚醣所散發的螢光訊號來觀察及分析腫瘤新生血管的滲漏情形,結果顯示,腫瘤組織中黑色素細胞癌腫瘤幹細胞集中區域具有較高的血管滲透率。此外,我們也發現這些高滲漏之血管大多為動脈血管,且新生血管密度會隨著腫瘤生長而增加。

Malignant neoplasm is the leading cause of death for 30 years in a row in Taiwan. The major approaches for cancer treatment are surgery, chemotherapy, and radiation therapy, but these approaches not only can hurt all kinds of cancers but also do harm to the normal cells. In order to kill cancer cells specifically, targeted therapy is developed. Many researchers focused on the tumor microenvironment as a target for cancer treatment recently and they found it would be an effective and potential target. The goal of this thesis is to investigate the relationship between collagen remodeling, angiogenesis, vessel permeability and cancer stem cells (CSC) in the microenvironment of melanoma. In tumor microenvironment, the collagen fibers in normal tissues play a role in the regulation of cell communication. Recent studies found collagen fibers surrounding cancer cells may regulate cancer metastasis, indicating collagen fibers might be used as indicators for cancer prognosis. We tracked the collagen remodeling in melanoma microenvironment by using in vivo second harmonic generation (SHG) and third harmonic generation (THG) microscopy. The corresponding structural and morphological changes of collagen were quantitatively analyzed without labeling using an orientation index (OI), the gray level co-occurrence matrix (GLCM) method, and the intensity ratio of THG to SHG (RTHG/SHG). We found that collagen fibers surrounding melanoma cells had higher OI values and SHG intensities initially after implantation of melanoma cells, and these collagen networks had lower OI values and less homogeneity following the growth of tumors. To investigate the roles of melanoma CSC and the vessel permeability, we implanted the mCherry and ALDH1A1 regulatory element–driven EGFP melanoma cells into C57BL/6-c2J mice ears. The 150-kDa (the radius is about 8.9 nm) dextran labeled with fluorescein were injected via tail veins of mice with different tumor sizes. We found that the tumor region enriched with melanoma CSC correlates with higher vessel permeability. Besides, we observed that vessels with increased permeability were mainly arterioles and the density of neoangiogenesis was related to tumor growth.

Contents
CHAPTER 1 INTRODUCTION 1

1.1 Current trends in the cancer treatment 1
1.2 Tumor microenvironment 3
1.3 Targeted therapy and drug delivery system 10
1.4 Cancer stem cell 15
1.5 Cross-link between endothelial cells, cancer stem cells, and angiogenesis 17
1.6 Motivation 19
1.6.1 Collagen remodeling 20
1.6.2 Angiogenesis, vessel permeability and cancer stem cells 21

CHAPTER 2 BASIC PRINCIPLES 23

2.1 Confocal Microscopy 23
2.2 Two-photon fluorescence microscopy (2PFM) 25
2.3 Nonlinear optical and harmonic generation microscopy 29
2.4 Pharmacodynamics 37

CHAPTER 3 MATERIALS AND METHODS 41

3.1 Cell culture and stable cell line 41
3.1.1 Cell culture 41
3.1.2 The mCherry and ALDH1A1 regulatory element–driven GFP melanoma 41
stable cell line
3.2 Plasmids 42
3.3 Animal models and tumor growth 57
3.3.1 Animal and anesthesia 57
3.3.2 Melanoma and LPS implantation 58
3.4 Fluorescence dyes for in vivo angiography 60
3.5 Laser source and nonlinear optical microscope 61
3.5.1 Femtosecond Cr:forsterite laser system 61
3.5.2 Leica TCS SP5 62
3.6 Zones of observation and reference marks of orientation on the mice ear
pinnae 64
3.7 Images analysis 65
3.7.1 Quantitative analysis on the images of collagen networks 65
3.7.2 Quantitative analysis on the images of angiogenesis permeability 68
3.7.3 Statistical analyses 72
3.8 Identification of vessels types by two-photon microscopy 72
3.9 Immunohistochemistry (IHC) labeling 74

CHAPTER 4 RESULTS AND DISCUSSIONS 75

4.1 Quantification of the Structural Changes of Collagens in melanoma microenvironment 75
4.1.1 In vivo imaging collagen structures in normal mice ears 77
4.1.2 Observation of collagen remodeling within the same ear region 79
4.1.3 Quantitative analyses on the baseline variations of collagens in normal
mice ears 81
4.1.4 Characteristic features of collagen remodeling after melanoma
implantation 86
4.2 Quantification of tumor angiogenesis permeability in melanoma microenvironment 90
4.2.1 The 2002 bp (-1963/+27) murine ALDH1A1 promoter region can
be used as screens for melanoma B16F1 stem cells 91
4.2.2 The mCherry B16F1 stable cell line 92
4.2.3 The pLNC 2.0Aldh1a1GFP plasmid has been constructed and the
ALDH1A1 regulatory element–driven GFP melanoma stable cell lines 92
4.2.4 The mouse tumor models which labeled tumor and tumor stem-like cells 94
4.2.5 The dyes in different sizes for the evaluation of vessel permeability
around tumor 95
4.2.6 The permeability rate in different tumor sizes of enrich melanoma
stem-like cells 97
4.2.7 The permeability rate in different tumor sizes of non-enrich melanoma stem-like cells 105
4.2.8 Comparison of the permeability rate with enriched and non-enriched melanoma stem-like cells 107
4.2.9 Dependence of permeability rate on vessel types 109
4.2.10 Immunohistochemistry (IHC) labeling results 111

CHAPTER 5 SUMMARY 113

REFERENCE 116


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