探討內皮間質轉化衍生細胞刺激巨噬細胞產生非典型活化及腫瘤惡性

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研究生：	范吉炫 Fan, Chi-Shuan
論文名稱：	探討內皮間質轉化衍生細胞刺激巨噬細胞產生非典型活化及腫瘤惡性 Endothelial-Mesenchymal Transition-Derived Cells Promote Macrophage M2-Polarization and Tumor Malignancy
指導教授：	黃智興 Huang, Tze-Sing 汪宏達 Wang, Horng-Dar
口試委員:	陳雅雯 Chen, Ya-Wen 吳漢忠 Wu, Han-Chung 楊慕華 Yang, Muh-Hwa
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	145
中文關鍵詞：	內皮間質轉化衍生細胞、巨噬細胞、腫瘤惡性、腫瘤幹細胞
外文關鍵詞：	Endothelial-Mesenchymal Transition-Derived Cells, M2-Polarization, macrophahge, stemness, HSP90alpha, OPN
相關次數：	點閱：76 下載：0
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OPN是一種磷酸化的醣蛋白同時具許多生理意義，能夠刺激內皮細胞並調控血管新生，然而在血管新生的過程中，血管上的內皮細胞會透過EndoMT的方式生產新生血管的出芽以利血管分支的產生，我們好奇OPN能否影響並調控EndoMT的發生，在臨床上的確能在大腸直腸腫瘤組織的檢體上觀察到在表現OPN細胞周圍有EndoMT細胞的分佈，進一步我们將內皮細胞處理OPN重組蛋白以觀查刺激內皮細胞發生EndoMT情況及探討可能的機制。我们發現OPN能夠透過與Integrin αVβ3作用調控EndoMT的發生，而非是透過與CD44的反應，在OPN與Integrin αVβ3的作用後會活化PI3K/Akt/TSC2路逕，讓mTORC1活化的方式以增加HIF-1α蛋白質生合成，增加後的HIF-1α會使的TCF12基因活化並表現，TCF12再與EZH2直接作行成基因轉錄的負向調控複合體，作用在VE-cadherin基因上抑制其表現以利於EndoMT的發生。經過EndoMT過程內皮細胞會轉化帶有癌纖維母細胞特性，這類的細胞能夠產生並分泌重要的蛋白質正面地幫助腫瘤的生長及轉移，我们利用microwestern array去分析EndoMT細胞所分泌的上清液，並且找到HSP90α及JAG1為EndoMT細胞所分泌，並且為刺激大腸直腸癌細胞帶癌幹細胞特性的後選因子，因此未來針對OPN刺激形成的EndoMT細胞可以作為治癌症的一個方向。
在腫瘤微環境內間質細胞是很重要的存在，能去支持並幫助腫瘤的生長及惡化，其中EndoMT細胞不但是腫瘤微環境中的一個要角並幫助腫瘤的生長，然而EndoMT細胞是否能與巨噬細胞作用調控發炎反應，並影響腫瘤微環境，其中的機制依然值得進一步探討，我們實驗中發現EndoMT細胞能夠分泌HSP90α，HSP90α能活化NF-κB訊號傳路徑，並造成巨噬細胞M2類型的轉變，HSP90α刺激並分化形成的M2巨噬細胞能夠分泌IL-10及表現CD163, CD204，另外分泌性的HSP90α也能與CD91 及TLR4受器結合，活化JAK2 /YK2訊號傳遞路徑使的STAT3磷酸化，磷酸化的STAT3展現轉錄因子的特性正向調控Sec22b基因的表現，導致巨噬細胞phagocytosis的能力降低，在動物實驗中我们也觀察到EndoMT cells會吸引表現F4/80+巨嗜細胞進入腫瘤組織，並且有較多M2巨噬細胞的存在，然而在實驗的小鼠有接受HSP90α mAb的組別，可以觀察到腫瘤微環境中的HSP90α抑制能減緩腫瘤的生長，因此針對分泌性的HSP90α作為治癌症的一個方向以抑至腫瘤微環境中的M2巨噬細胞及癌幹細胞可以達到治療癌症一個可能。

Osteopontin (OPN) is a multi-functional phospho-glycoprotein that can stimulate angiogenesis through acting on endothelial cells. As angiogenic sprouting involves endothelial-to-mesenchymal transition (EndoMT), we are intrigued to know whether OPN exerts an effect on EndoMT. Clinically, we indeed detected EndoMT-derived cells next to OPN-expressing cells in colorectal cancer tissues. Furthermore, we treated OPN to primary cultures of endothelial cells to investigate the EndoMT-inducing activity and the underlying mechanisms. Integrin αVβ3 rather than CD44 is involved in OPN-induced EndoMT. OPN-integrin αVβ3 engagement induces HIF-1α expression through a PI3K/Akt/TSC2-mediated and mTORC1-dependent protein synthesis pathway, which in turn trans-activates TCF12 gene expression. TCF12 further interacts with EZH2 and histone deacetylases to transcriptionally repress VE-cadherin gene and thus facilitates EndoMT. Like cancer-associated fibroblasts, EndoMT-derived cells promote tumor growth and metastasis by secreting certain proteins. Secreted HSP90α and JAG1 are the candidates suggested by microwestern array assay, and are herein verified to induce stemness properties in colorectal cancer cells. As OPN is overexpressed in human cancers, OPN-induced EndoMT and EndoMT-derived cells can be potentially taken as cancer therapeutic targets. EndoMT-derived cells could be considered as stromal cells that have emerged as important stimulators in tumor microenvironment reprogramming to support tumor growth and malignancy. EndoMT-derived cells, as one of the units of tumor microenvironment, could interact with surrounding cells and contribute to tumor growth. However, the underlying mechanism on how EndoMT-derived cells interact with macrophages to suppress inflammation in tumor microenvironment is still unclear. In this study, we show that the HSP90α secreted from EndoMT-derived cells is essential for M2 macrophage polarization. It increases the expressions of M2-like macrophage markers like CD163, CD204, and IL-10 through NF-κB signaling cascade. Moreover, HSP90α binds with CD91 and TLR4 receptors to initiate the activation of JAK2 and TYK2, subsequently leads to phosphorylation of STAT3. Activated STAT3 then induces Sec22b transcription and suppresses the phagocytic ability of macrophages. We demonstrate that EndoMT cells induce F4/80+ macrophage infiltration into tumor tissue and increase the level of M2-like macrophages to promote tumor growth in mouse models. Nonetheless, such effect on tumor growth could be diminished through intravenous injection of HSP90α mAb. Taken together, our results suggest that EndoMT cells induce M2-like macrophages polarization through HSP90α secretion to promote tumor growth, indicating that HSP90α could be a potential therapeutic target for pancreatic cancer.

Abstract    1
中文摘要    3
誌謝    5
Figure contents    10
Chapter One: Osteopontin-integrin αvβ3 engagement induces PI3K-Akt- HIF-1α-TCF12 to mediate Endothelial-Mesenchymal Transition    13
1-1 Introduction    13
1-1-1 Tumor microenvironment    13
1-1-2 Endothelial-Mesenchymal transition    13
1-1-3 Osteopontin in cancer    15
1-1-4 HIF-1α    15
1-1-5 TCF12    16
1-2 Specific aims    18
1-3 Materials and methods    19
1-3-1 Clinical samples and clinicopathological characteristics    19
1-3-2 HUVECs collection and culture condition    19
1-3-3 Cell lines and culture condition    19
1-3-4 Protein extraction and western blot analysis    20
1-3-5 mRNA extraction,  RT-PCR and qRT-PCR    22
1-3-6 Cell migration assay    22
1-3-7 Transwell invasion assay    23
1-3-8 Calcein-transfer assay    23
1-3-9 TCF12 knockdown and overexpression in ECs    24
1-3-10 Flow cytometric analyses of cell-surface stemness markers    24
1-3-11 Proximity ligation assay    24
1-3-12 Nuclear extraction for immunoprecipitation    25
1-3-13 Chromatin immunoprecipitation (ChIP) assay    26
1-3-14 E-box pull-down and immunoblot analysis    27
1-3-15 Immunohistofluorescence    28
1-3-16 Mouse tumor transplantation models    28
1-3-17 Preparation of Endo and EndoMT conditioned media    29
1-3-18 Statistical analysis    29
1-3-19 In silico analyses of the microarray datasets of clinical specimens    29
1-4 Results    30
1-4-1 OPN induces EndoMT    30
1-4-2 TCF12 is a key factor in OPN-induced EndoMT    35
1-4-3 TCF12 functions as a transcriptional repressor of VE-cadherin gene    38
1-4-4 OPN induces TCF12 expression through integrinαvβ3-PI3K-Akt    42
signaling axis    42
1-4-5 HIF-1α is involved in OPN-induced TCF12 expression    45
1-4-6 EndoMT enhances CRC malignancy    50
1-5 Discussion    54
Chapter Two: EndoMT-derived cells induce cancer cell stemness    57
2-1 Introduction    57
2-1-1 Colon and colorectal cancer    57
2-1-2 Cancer stem cells (CSCs)    58
2-1-3 HSP90α    59
2-1-4 Notch signaling in cancer    60
2-2 Specific aims    61
2-3 Materials and methods    62
2-3-1 Clinical samples and clinicopathological characteristics    62
2-3-2 HUVECs collection and culture condition    62
2-3-3 Cell lines and culture condition    62
2-3-4 Protein extraction and western blot analysis    62
2-3-5 mRNA extraction, RT-PCR and qRT-PCR    63
2-3-6 TCF12, KLF4, Nanog or KLF4 knockdown in SW620    63
2-3-7 Flow cytometric analyses of cell-surface stemness markers    63
2-3-8 Nuclear extraction for immunoprecipitation    63
2-3-9 Chromatin immunoprecipitation (ChIP) assay    63
2-3-10 E-box pull-down and immunoblot analysis    64
2-3-11 Cell-spheroid formation assay    64
2-3-12 Measurement of secreted HSP90α and Jag1 levels    64
2-3-13 Mouse tumor transplantation models    65
2-3-14 Microwestern array assay    65
2-3-15 Preparation of Endo and EndoMT conditioned media    65
2-3-16 Statistical analysis    66
2-4 Results    67
2-4-1 EndoMT-derived cells express and secrete HSP90α    67
2-4-2 EndoMT-derived cells produce eHSP90α to induce stemness in CRC cells.    69
2-4-3 EndoMT-derived cells express and secrete JAG1    73
2-4-4 EndoMT-derived cells produce JAG1 to induce CRC stemness    76
2-4-5 Recombinant JAG1 induces CRC stemness    79
2-4-6 JAG1 induces Oct4, Nanog and KLF4 to maintain CRC stemness    82
2-4-7 TCF12 involves in CRC stemness    85
2-5 Discussion    92
Chapter Three: Endothelial-Mesenchymal Transition-Derived Cells Secrete HSP90 to Promote Macrophage M2-Polarization and Tumor Development    94
3-1 Introduction    94
3-1-1 Pancreas and Pancreatic cancer    94
3-1-2 Immunity and Cancer    96
3-1-3 Macrophage and M2 polarization    97
3-2 Specific aims    98
3-3 Materials and methods    99
3-3-2 Cell culture    99
3-3-3 Antibodies and reagent    99
3-3-4 Preparation of Endo and EndoMT conditioned media    100
3-3-5 Protein extraction and western blot analysis    100
3-3-6 mRNA extraction, RT-PCR and qRT-PCR    101
3-3-7 ELISA assay    101
3-3-8 Flow cytometry    101
3-3-9 Phagocytosis assay    101
3-3-10 Chromatin immunoprecipitation (ChIP) assay    102
3-3-11 Immunohistofluorescence    102
3-3-12 Immunohistochemistry    102
3-3-13 Mice    102
3-3-14 Sec22b knockdown in THP1    103
3-3-15 In silico analyses of the microarray datasets of clinical specimens    103
3-3-16 Proximity ligation assay    103
3-3-17 Statistical analysis    103
3-4 Results    104
3-4-1 EndoMT-derived cells promote tumor formation with high macrophage infiltration    104
3-4-2 EndoMT-derived cells stimulate macrophage infiltration and M2-polarization    107
3-4-3 EndoMT-derived cells secrete HSP90 to induce macrophage M2-polarization    110
3-4-4 Anti-HSP90 antibody exhibits therapeutic potency against EndoMT cells-promoted cancer    116
3-4-5 eHSP90 induces macrophage M2-polarization through cellular receptors CD91 and TLR4    119
3-4-6 eHSP90 induces macrophage M2 markers via the IRAK1–IKK/–NF-B/IRF3 pathway    122
3-4-7 eHSP90 represses macrophage phagocytosis via the JAK2/TYK2–STAT-3–Sec22b pathway    126
3-5 Discussion    130
Chapter Four: Final discussion    133
References    135
Appendix I    144
Appendix II    145


                                

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