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研究生:何思儀
研究生(外文):HO, SZU-YI
論文名稱:表皮生長因子作為骨微環境影響胰臟癌細胞的三維生長
論文名稱(外文):Epidermal Growth Factor as a Bone Microenvironment Effects on Three-Dimensional Growth of Pancreatic Cancer Cells
指導教授:董國忠董國忠引用關係許志雄許志雄引用關係
指導教授(外文):DONG, GUO-CHUNGHSI, CHI-SHIUNG
口試委員:胡威文李亦淇董國忠許志雄
口試委員(外文):HU, WEI-WENLee, I-CHIDONG, GUO-CHUNGHSI, CHI-SHIUNG
口試日期:2022-07-11
學位類別:碩士
校院名稱:國立聯合大學
系所名稱:工程科技轉譯醫學學程
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:中文
論文頁數:76
中文關鍵詞:表皮生長因子細胞外基質加速分泌三維培養胰臟癌細胞
外文關鍵詞:Epidermal Growth Factor(EGF)Extracellular Matrix(ECM)Accelerate secretion3D culturingPancreatic Cancer Cell
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胰臟癌是各國癌症死亡的主要原因之一,也是全球致死率最高的惡性腫瘤,具有局部侵襲性以及遠處轉移的傾向,而早期的胰臟癌腫瘤是由KRAS突變所產生,其中啟動KRAS基因的關鍵受體是胰臟癌細胞表面過表達的EGFR,若EGFR不斷受刺激,會促使胰臟癌腫瘤生長,可能也是造成胰臟癌在治療上更具挑戰性的原因之一。因此許多用於胰臟癌腫瘤EGFR的抑制劑正在被開發,並以二維細胞培養及動物實驗作為藥物測試的大宗,結果發現在二維環境下有效的EGFR抑制劑對動物體內的腫瘤卻絲毫不傷,由於二維與動物實驗間最大的差距在於細胞的生長型態以及受體分佈上,因此提出可能與胰臟癌的腫瘤結構以及EGFR分佈有關聯的假設,實驗透過體外三維培養模型模仿出與動物體內相仿的腫瘤組織,藉以縮短二維與動物實驗間的距離,其中以EGF作為刺激胰臟癌細胞在三維環境下生長成腫瘤的重要因子。
結果表明,EGF在三維培養環境下,除了加快胰臟癌細胞中整合素-α3的生成並使大量細胞外基質分泌促進細胞團簇的產生,還加速了胰臟癌細胞的生長,同時也對胰臟癌細胞的遷移造成了影響。
綜合以上所述,我們利用EGF作為刺激,建立了一個適合胰臟癌腫瘤生長的三維體外培養環境,若後續有胰臟癌相關腫瘤模型的開發,我們認為EGF確實可以作為促進胰臟癌腫瘤生長的因子之一。雖然最初選用EGF作為對胰臟癌細胞外源性刺激,是想了解EGF會影響哪方面的細胞行為進行測試,沒想到意外發現了EGF可能有加速胰臟癌細胞ECM分泌的效果,而提供外源性生長因子刺激癌細胞ECM分泌的相關機制探討更是近年來炙手可熱的議題之一,後續經確認這樣的現象穩定發生後,我們在未來將規劃相關實驗並對機制進行進一步的探討。
Pancreatic cancer is the main cancer causing death in developed countries, and it is also one of the malignant tumors with the highest mortality rate in the world. The death rate of pancreatic cancer ranks among the top ten in the world. In the past few decades, regardless of gender or country, the death rate of pancreatic cancer has continued to rise, and within five years of being diagnosed, the survival rate is less than 6% and more literatures pointed out that pancreatic cancer has the potential to exceed breast, prostate and colorectal cancers as one of the top three causes of cancer by 2030.
Most pancreatic cancers originate from the microscopic non-invasive epithelial proliferation of pancreatic ducts in vivo, referred to as pancreatic intraepithelial neoplasia, early local invasiveness of the tumor and the tendency of distant metastasis. In addition, early pancreatic tumors are caused by KRAS mutations and alterations. EGFR, which is overexpressed on the surface of pancreatic cancer cells, is a key receptor that activates the KRAS gene. If it is continuously stimulated, it will promote the growth of pancreatic cancer tumors, which may be the one of reason why pancreatic cancer is more challenging to treat.
Due to the high resistance of pancreatic cancer tumors to drugs, and the late stage tumors cannot be surgically removed, there had no more effective treatment strategy, the survival rate after the disease is extremely low. Little progress has been made in terms of poor prognosis. Pancreatic cancer tumors are extremely resistant to drugs. There have been literatures discussing the related mechanisms of tumorigenesis, mainly due to the combination of KRAS, CDKN2A, TP53 and SMAD4-related tumorigenic genes plus the surface of pancreatic cancer cells. The phenomenon of overexpression of epidermal growth factor receptor (EGFR), which in turn leads to the formation of pancreatic cancer tumors, so many drugs for inhibiting EGFR in pancreatic cancer tumors are being developed many related experiments are performed in two-dimensional environment for the culture of pancreatic cancer cells due to the economical and convenient operation, and EGFR inhibitors can block the activity of EGFR on the surface of almost all pancreatic cancer cells; however, the use of inhibitors in pancreatic cancer cells in animal models of cancer, the treatment of tumors in organisms has different results, and EGFR inhibitors have no corresponding effect on tumors in animals.
It has been proposed in the literature that 2D culture has many advantages, but cells are less resistant to drugs in 2D monolayer growth, and pancreatic cancer tumors in animal models are 3D structures that not only provide protection against drug penetration influenced by the microenvironment, the distribution of EGFR differs from that of pancreatic cancer cells grown in 2D monolayers; therefore, we propose the hypothesis that the large gap in pancreatic cancer in 2D culture and animal experiments may be related to tumor structure and EGFR distribution in pancreatic cancer related.
Therefore, we imitated tumor tissues similar to those in animals through in-vitro 3D culture models, thereby shortening the distance between 2D and animal experiments. Taking advantage of the characteristic of overexpressing EGFR on the surface of pancreatic cancer cells, EGF was added to the three-dimensional culture scaffold in-vitro to stimulate the growth of cells. It is hoped that EGF can promote pancreatic cancer cells to form pancreatic cancer tumor tissue in a three-dimensional environment.
The results showed that EGF in a three-dimensional culture environment not only accelerated the production of integrin-α3 in pancreatic cancer cells and secreted a large amount of extracellular matrix to promote the production of cell clusters, but also accelerated the growth of pancreatic cancer cells. At the same times,EGF also played a role on migration of pancreatic cancer cells.
Based on the above, we used EGF as a stimulus to establish a three-dimensional in vitro culture environment suitable for the growth of pancreatic cancer tumors. If there is a subsequent development of pancreatic cancer-related tumor models, EGF can indeed be one of.used as a factor to promote the growth of pancreatic cancer tumors. Although EGF was originally selected as an exogenous stimulus for pancreatic cancer cells, I wanted to know which aspects of cell behavior EGF would affect to test. Unexpectedly, I found that EGF may have the effect of accelerating the secretion of ECM of pancreatic cancer cells. The mechanism of exogenous growth factor-stimulated ECM secretion in cancer cells is one of the hottest topics in recent years. After confirming that this phenomenon occurs stably, we will plan related experiments and further explore the mechanism in the future.

致謝 I
中文摘要 II
Abstract III
目錄 VI
圖目錄 IX
表目錄 XI
第一章 緒論 1
1.1研究背景 1
1.2研究動機 2
1.3研究目的 2
第二章 理論基礎 3
2.1 EGF在二維的現況 3
2.2二維與三維環境間的不同 5
2.3 EGF在三維的現況 8
2.4 固定EGF的體外三維支架GHG與癌細胞共培養 10
2.5 胰臟癌在三維培養的現況 11
第三章 材料與方法 14
3.1實驗藥品 14
3.2實驗儀器 16
3.3實驗流程規劃 18
3.4 體外三維支架的製備與分析以及EGF固定 19
3.4.1支架的製備 19
3.4.2固定EGF蛋白支架的製備以及蛋白固定量 23
3.4.3支架結構的分析方法 27
3.5 EGF支架與癌細胞的動態培養模式 30
3.5.1胰臟癌細胞來源 30
3.5.2胰臟癌細胞繼代 30
3.5.3 EGF支架的胰臟癌細胞種植 32
3.5.4 EGF支架與胰臟癌細胞反應器的動態培養 33
3.6 EGF對癌細胞三維胞外基質分泌表現分析 36
3.7 EGF對癌細胞的生長效果分析 39
3.8 EGF對癌細胞在三維下的遷移能力分析 41
第四章 結果與討論 42
4.1 三維體外支架的組成與環境特性 42
4.1.1支架巨觀以及微觀結構介紹 42
4.1.2三維體外支架的EGF固定 46
4.2 固定EGF的三維體外支架對細胞外基質分泌速度的影響 48
4.3 固定EGF的三維體外支架對細胞生長的影響 57
4.4 固定EGF的三維體外支架對細胞遷移的影響 59
第五章 結論與展望 64
第六章 參考文獻 66
第七章 附錄 76
7.1 研討會以及活動參與 76
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