臺灣博碩士論文加值系統

腫瘤血管新生對於癌症發展而言是一個重要的步驟，藉由此過程可使腫瘤細胞獲取足夠的養分得以生長並產生轉移；因此，如何有效抑制腫瘤新生血管的產生便成了癌症研究中一項重要的課題。近年來許多的科學家發現，除了藉由血管新生因子誘發癌細胞周邊的血管內皮細胞形成新生血管外，癌細胞本身也會有類血管構造的排列產生，稱之為血管擬態(Vasculogenic Mimicry, VM)。許多的研究指出此種血管擬態的發生可能與上皮-間質細胞轉換 (Epithelial-Mesenchymal Transition, EMT)或是癌症幹性(Cancer Stemness)等過程有所關聯。先前，實驗室發現一種名為Long form Collapsin Response Mediator Protein-1 (LCRMP-1)的CRMP-1蛋白異構型，其表現除了可促進癌細胞的侵襲與轉移之外，也和肺腺癌病患的不良預後有明顯的正相關性。近期，利用免疫組織染色的結果也發現LCRMP-1蛋白質的表現和腫瘤組織中血管密度有高度的正相關性；不僅如此，LCRMP-1穩定表現的細胞株(stable cells)，在基質膠 (Matrigel) 上亦可自行排列成類似血管內皮細胞所形成的管狀的構造；這些現象讓我們提出是否癌細胞可藉由LCRMP-1蛋白質的表現引發血管擬態的產生的假說。本研究中，我們除利用細胞實驗檢測LCRMP-1蛋白質的表現是否與VM 的形成有關外，我們也同時運用細胞生物學與分子生物學等體外的研究模式，探討LCRMP-1蛋白質如何參與VM的調控。實驗結果顯示， LCRMP-1可使得人類肺癌細胞株CL1-0在基質膠上排列成管狀的結構，且其與該蛋白質的表現量有明顯的正相關性; 反之，若抑制LCRMP-1蛋白質在CL1-5細胞中的表現，則將獲得相反的結果。體外研究的結果也顯示， LCRMP-1所促進之腫瘤細胞血管擬態的產生可能與細胞類型轉換有關而與癌症幹性較無直接的關聯影響。本實驗雖然只是一個現象的型態研究，但卻提供我們在未來要進一步釐清LCRMP-1如何參與肺癌血管新生擬態機制研究一項重要的脈絡依據。

Tumor-neovascularization is a physiological process in cancer progression, which contributes in controlling tumor growth and cancer metastasis. Recently, scientists found that except angiogenesis, cancer cell could form tubule-like structure by itself called vascular mimicry (VM), which is one of the major types of tumor-neovascularization. Until now, the molecular mechanism of VM remains unclear; but some literatures indicated that this phenomenum may relate to the process of epithelial-mesenchymal transition (EMT) and cancer stemness. In the past, we identified that Long Form Collapsin Response Mediator Protein-1 (LCRMP-1), an isoform of CRMP-1, is a metastasis enhancer and its expression was positively correlated with poor clinical outcome in non-small cell lung cancer (NSCLC). Recently, we found that the expressions of LCRMP-1 were positively correlated with the blood vessel density in lung cancer tissues; in addition, LCRMP-1 stable cells could form tube structures on matrigel by theirselves. The above findings let us hypothesize whether LCRMP-1 is involved in tumor vascular mimicry. In this study, we tried to explore the role of LCRMP-1 participated in VM through several cellular and molecular assays. Our data showed that overexpression of LCRMP-1 could let CL1-0 cells form tubular structures on Matrigel with a dose-dependent manner; whereas silencing the expression of LCRMP-1 in CL1-5 had the counter effect. Moreover, we found that the LCRMP-1 induced VM might through regulation of mesenchymal-endothelial like transition but less correlated with cancer stemness. Although this is a phenomenon study, the identification of the potential role of LCRMP-1 in VM may provide hints for further exploring the detail mechanism in the near future.

CONTENTS
中文摘要 I
ABSTRACT III
LIST OF FIGURES VII
LIST OF TABLES VIII
ABBREVIATIONS IX
Chapter 1 Introduction 1
1.1 Lung cancer 1
1.1.1 Histological classification of lung cancer 1
1.1.2 Genomic alterations 2
1.2 Epithelial-mesenchymal transition (EMT) in cancer 4
1.3 Mesenchymal- endothelial transition (MEndoT) 6
1.4 Tumor neovascularization 6
1.4.1 Tumor angiogenesis 7
1.4.2 Vasculogenic mimicry 8
1.5 CRMP family 10
1.5.1 Long form collapsing response mediator protein-1 (LCRMP-1) 12
Research Motivation 13
Flow Chart of Our Studies 15
Chapter 2 Materials and methods 16
2.1 Cell lines and culture conditions 16
2.2 Plasmid constructs 16
2.3 Primer design 16
2.4 Antibodies 17
2.5 Transfection and stable cells selection 17
2.6 Reverse-transcriptase polymerase chain reaction (RT-PCR) 18
2.7 Quantitative real-time polymerase chain reaction (qPCR) 18
2.8 Side population analysis 19
2.9 ALDH assay 20
2.10 Sphere formation assay 21
2.11 Endothelial differentiation system in lung cancer cells 21
2.12 Immunoblotting analysis 22
2.13 Tube formation assay 23
2.14 Statistical Analysis 23
Chapter 3 Result 24
Part I: LCRMP-1 promotes vasculogenic mimicry in lung cancer via regulation of tissue factor expression 24
3.1.1 LCRMP-1 might promote vasculogenic mimicry 24
3.1.2 LCRMP-1 dose-dependently increases tube formation in lung cancer cells 24
3.1.3 LCRMP-1 affects the expression of mesenchymal and endothelial marker 25
3.1.4 LCRMP-1 regulates the expression of vasculogenic mimicry markers TF in both transcription and translation levels 26
Part II: LCRMP-1 could increase sehphere forming but existed few CSC population 27
3.2.1 The sphere formation capacity of LCRMP-1 overexpressing stable cells 27
3.2.2 LCRMP-1 slightly enhances side population but does not have positive correlation in ALDH activity 28
Chapter 4 Summary 30
Chapter 5 Discussion 31
References 54

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