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系統識別號 U0026-2506201510352200
論文名稱(中文) 腫瘤相關巨噬細胞經由免疫調控胃癌細胞增生的分子機制
論文名稱(英文) The molecular mechanism of gastric cancer cells proliferation through immune response by tumor-associated macrophages (TAMs)
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 林長霓
研究生(英文) Chang-Ni Lin
學號 S58994055
學位類別 博士
語文別 英文
論文頁數 107頁
口試委員 召集委員-林以行
指導教授-沈延盛
口試委員-賴明德
口試委員-張志鵬
口試委員-許博翔
口試委員-葉大森
口試委員-劉柯俊
口試委員-洪文俊
中文關鍵字 胃癌  慢性發炎  骨橋蛋白  腫瘤相關巨噬細胞 
英文關鍵字 Gastric cancer  chronic inflammation  Osteopontin (OPN)  Tumor-associated macrophages (TAMs) 
學科別分類
中文摘要 胃癌是世界第四大癌症成因且為癌症死亡率第二順位,以亞洲地區發生率最高。其成因與飲食習慣、抽菸、幽門螺旋桿菌的感染與慢性發炎有關。許多臨床研究顯示胃癌常伴隨著明顯的發炎現象,其中浸潤的發炎細胞即是所謂的腫瘤相關巨噬細胞 (Tumor-associated macrophages, TAMs),或稱之為第二型巨噬細胞 (M2-TAMs)。在腫瘤微環境中,癌細胞與M2-TAMs相互調控並影響癌症的進展。研究證實循環的單核細胞 (Monocyte) 會經由腫瘤細胞所分泌的招募分子被吸引至腫瘤周圍,並被教育成具有抑制正常免疫功能的M2-TAMs,這些浸潤的M2-TAMs則透過旁分泌訊號刺促進腫瘤進展。但癌細胞如何促進M2-TAMs分化的分子調控機制仍不清楚。
骨橋蛋白 (Osteopontin, OPN) 是一種分泌型的細胞外基質蛋白,具有招募巨噬細胞的能力,且會與細胞表面受體(例如:CD44或Integrin αvβ3)結合而活化下游訊號。近年來,研究發現OPN的過表現與腫瘤生長、血管新生及癌症轉移的過程有關。我們在170例胃癌檢體中發現胃癌細胞表現大量的OPN並與M2-TAMs浸潤及病患存活率相關,並證實OPN與M2-TAMs之間是透過旁分泌調節。因此,我們利用trans-well隔開AGS/AZ521胃癌細胞及U937/THP-1單核細胞進行共培養72小時,以模擬腫瘤微環境。我們發現AGS 胃癌細胞能夠分泌OPN並作用於U937表面受體︰ ITGAL,促進M2-TAMs形成。且活化其ERK/NFκB訊號進而降低其吞噬能力,並分泌大量TNF-α。而此TAM衍生的TNF-α則會透過TNFR訊號活化促進胃癌進展。
此外,我們在動物模型也發現,將共培養後的AGS細胞與M2-TAMs一同注射到免疫缺失鼠上可成功誘發腫瘤生長,其誘發率約為60%。一旦減少OPN或ITGAL的表現,或抑制TNF/TNFR訊息途徑活化則能減少腫瘤生長。然而,相較於正常胃上皮細胞,胃癌組織大量表現TNFR,因此,OPN/M2-TAMs/TNFR這迴路將是未來胃癌治療的重點。我們亦透過小鼠模型預測抑制TNFR訊號途徑合併5-Fu療法在胃癌治療的可行性。發現合併療法抑制腫瘤生長的能力較單獨使用5-Fu及adalimumab (TNF中和單株抗體)好。總而言之,此研究證實胃癌細胞衍生的OPN能夠作用於U937上的ITGAL進而活化ERK/NFκB訊號途徑促進M2-TAMs的形成並分泌大量TNF-α;而TAM衍生的TNF-α能活化TNFR訊號影響胃癌的進展。除了減少胃癌細胞衍生的OPN表現而降低M2-TAMs的形成之外,抑制TNFR訊號活化皆能夠有效控制胃癌的進展。合併使用5-Fu及TNF抑制劑亦是有效的輔助療法,因此,減少胃癌細胞衍生的OPN表現或抑制TNFR訊號活化是胃癌治療上一個重要的標的。
英文摘要 Gastric cancer is the fourth most commonly diagnosed cancer and is also the second leading cause of cancer related deaths worldwide. Asia is the highest incidence region. Some risk factors contribute to gastric carcinogenesis, such as diet, tobacco, Helicobacter pylori infection, and chronic inflammation. Clinical evidence indicates inflammation frequently manifested in gastric cancer. The infiltrating inflammatory cells of tumor area are called the tumor-associated macrophages (TAMs) or called type II macrophages (M2-TAMs). The interplay of gastric cancer cells and TAMs in the tumor microenvironment is crucial for cancer progression. Many studies have confirmed tumor cells can secrete recruitment molecules to recruit and educate circulating monocyte skew it toward M2-TAMs, and these M2-TAMs can promote tumor progression. But the molecular mechanism of cancer cell promotes M2-TAMs formation is still unclear.
Osteopontin (OPN) is a secreted type of extracellular matrix protein, and it possesses an ability of macrophage recruitment. OPN can activate downstream signals via binding with surface receptor, like CD44 or Integrin αvβ3. Recently, some studies found OPN contribution in tumor growth, angiogenesis, and metastasis. We also noticed OPN expression in gastric cancer specimens were associated with the quantity of infiltrating M2-TAMs. The coexpression of OPN and CD204 were also associated with poor outcome. We demonstrated paracrine regulation is existed between gastric cancer cell and M2-TAMs. Hence, we used the trans-well chamber to separate human gastric cancer cells (AGS, AZ521) and human monocytic cells (U937, THP-1) to mimic a inflammatory microenvironment. The gastric cancer cell-secreted OPN can interact with the U937 surface receptor, ITGAL, to promote the M2-TAMs formation. The OPN-ITGAL axis promotes the ERK/NFκB signal activation to produce TNF-α. And then the TAM-derived TNF-α acting on TNFR of gastric cancer cell to promote tumor progression.
In animal experiments, we successfully induced proximity 60% Xenografts grew through AGS and M2-TAMs co-injected into nude mice. But inhibition of OPN, ITGAL or TNF/TNFR signal activation can reduce the tumor development. In clinical specimens, the expression of TNFR in gastric tumor is more than normal epithelium. Thus, the loop of gastric cancer cell-secreted OPN, M2-TAMs, and TNFR signal may be the important target in future therapy. We also assess the feasibility of TNF inhibitor and 5-Fu combined therapy in mice, and found the tumor inhibition efficiency for combined therapy is better than 5-Fu or adalimumab (TNF monoclonal antibody) alone. Consequently, this study demonstrated gastric cancer cell-secreted OPN promote the M2-TAMs formation through interacting with the functional receptor, ITGAL, to activate ERK/NFκB signal and produce TNF-α. And then the TAM-derived TNF-α promotes gastric cancer progression through TNFR signal activation. The tumor progression can be reduced through inhibit the M2-TAMs formation and block the TNFR activation. 5-Fu combined with and TNF-α inhibition is also an effective adjuvant therapy. Thus, blocking the gastric cancer cell-derived OPN-ITGAL axis or inhibiting TNFR signal activation is the potential target in future therapy.
論文目次 Contents Page
1. 中文摘要 1
2. Abstract 3
3. Acknowledgement 5
4. List of tables 9
5. List of figures 10
6. Abbreviations 12
7. Introduction 15
I. Gastric cancer and chronic inflammation 15
II. Tumor-associated macrophages (TAMs) 16
III. Osteopontin (OPN) 18
IV. Integrin αL (ITGAL) 19
8. Objective of this study 21
9. Materials and methods 22
I. Cell culture and transfection 22
II. Isolation of TAMcli (CD204+ TAMs) from clinical 23
specimens
III. Isolation of CD14+ cells from human blood 23
IV. Immunostaining assay 24
V. Chemotaxis 25
VI. Western blot 26
VII. RNA isolation and RT-PCR 27
VIII. ELISA 27
IX. Phagocytosis effect detection 28
X. BrdU incorporation assay 28
XI. Flow cytometry 28
XII. Invasion assay 29
XIII. Cell adhesion assay 29
XIV. Xenograft study in mice 29
XV. Statistical analysis 30
10. Rseults 31
I. Highly co-expression of OPN and CD204 in gastric 31
tumor is correlated with disease progression.
II. Co-expression of OPN and CD204 is significantly 31
associated with overall survival and is a marker
of poor prognosis.
III. A paracrine regulation exists between OPN and 34
M2-TAMs in gastric cancer.
IV. M2-TAMs promote gastric tumor progression. 35
V. Gastric cancer cell-secreted OPN induce macrophage 36
activation and M2-TAMs formation.
VI. OPN maintain M2-TAMs dominant to promote cell 39
proliferation, invasion and xenograft growth.
VII. ITGAL is the functional receptor of OPN to skew 40
M2-TAMs.
VIII. M2-TAMs produce TNF-α through ERK signal 42
activation.
IX. TAM-derived TNF-α mediated gastric cancer 43
progression.
X. Inhibition of the loop of OPN secretion, CD204+ 45
M2-TAMs formation, and TNFR signal activation is
a potent adjuvant therapy of gastric cancer.
11. Discussion 46
12. Reference 51
13. Tables 65
14. Figures 73
15. Publication list 106
16. Appendix I. The domain structure of human 107
Osteopontin (OPN) and Integrands.
17. Curriculum vitae 108
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