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系統識別號 U0026-0602201719362300
論文名稱(中文) 脾臟間質幹細胞促進胰臟癌的進展
論文名稱(英文) Spleen-derived mesenchymal stem cells promote progression of pancreatic cancer
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 105
學期 1
出版年 106
研究生(中文) 吳予
研究生(英文) Yu Wu
學號 S96034069
學位類別 碩士
語文別 英文
論文頁數 79頁
口試委員 指導教授-沈延盛
召集委員-陳立宗
口試委員-江伯敏
中文關鍵字 胰臟癌  間質幹細胞  腫瘤相關纖維母細胞  CXCL15 
英文關鍵字 Pancreatic cancer  Mesenchymal stem cells  tumor-associated fibroblasts  CXCL15 
學科別分類
中文摘要 根據美國2016年的統計,胰臟癌是癌症相關致死率第三名,五年存活率大概只有8%,這代表著對於胰臟癌的治療策略仍顯不足。為了增加局部晚期胰臟癌病人的治癒率,手術時應該擴增切除的區域,包含周圍的血管及脾臟,研究統計顯示手術時保留脾臟對病人的預後較差,因此本篇我們想用小鼠動物模型去探討脾臟間質幹細胞與胰臟癌惡化兩者之間的關係。先前文獻指出,腫瘤以及它的微環境之中會分泌一些炎性細胞因子、趨化因子、生長因子等等…,造成正常組織來的間質幹細胞(NMSCs)移動到腫瘤微環境中,進而被教育成腫瘤相關的間質幹細胞(TMSCs),有趣的是這兩種型態的間質幹細胞有著不同的功能,NMSCs是抗癌的角色,而TMSCs卻會促進癌症發展。所以在細胞實驗上,我們先將mspMSCs (mouse spleen-derived MSCs)誘導成mspNMSCs和mspTMSCs,再利用共同培養的系統來看不同型態的間質幹細胞對KrasG12D; Trp53R172H; Pdx1-Cre (KPC)胰臟癌細胞功能的影響,結果發現胰臟癌細胞和mspMSCs、mspTMSCs共培養後,發現它們會使胰臟癌細胞遷移能力提升,但是將mspNMSCs和胰臟癌細胞共培養後促遷移的效果較不明顯。在動物實驗上,我們將KPC cells植入C57B/L6小鼠的胰臟,建立原位胰臟癌小鼠模型,並將誘導後不同型態的間質幹細胞以腹腔注射的方式打入小鼠,觀察其對胰臟癌發展的影響,結果發現,在原位胰臟癌小鼠模型中,不同型態的mspMSCs皆會促進腫瘤的生長,只是mspNMSCs比起mspMSCs對促進胰臟癌腫瘤生長較不顯著,而mspTMSCs不只會更加劇胰臟癌腫瘤的生長也會讓小鼠生存率大幅下降。此外,我們也發現mspNMSCs並不像先前文獻所述會抑制腫瘤生長,因此,希望透過了解間質幹細胞在整個胰臟癌發展過程中是否有mspMSCs轉變成mspTMSCs的現象並了解它的機制,進而發展出新的胰臟癌治療方法與策略。然而,目前沒有特定的標記可以區分MSCs和TMSCs,有文獻指出,間質幹細胞會轉變成腫瘤相關纖維母細胞並促進癌症發展,在這裡我們發現將胰臟癌細胞與間質幹細胞共培養後,胰臟癌細胞的CXCL15表現量會增加,造成間質幹細胞表現出腫瘤相關纖維母細胞的標記,而且它的分化是與ERK pathway有關的。此外,我們將CXCL15的受器CXCR2基因剃除或是抑制ERK pathway皆可減少間質幹細胞表現出腫瘤相關纖維母細胞的標記並且抑制胰臟癌細胞增生及移動能力。從結果看來,我們發現KPC胰臟癌細胞會釋放CXCL15導致mspMSC活化ERK訊息傳遞路徑並轉變成mspTMSCs,進而加劇胰臟癌發展的能力。因此,本篇透過動物模型證實了mspMSCs會促進胰臟癌的發展,所以在臨床上執行遠端胰臟切除手術時,一併將脾臟切除對胰臟癌病人術後預後較佳。
英文摘要 In 2016, pancreatic cancer has the third highest incidence rate of cancer related fatality in the Unites States, with the 5 year overall survival rate of about 8%, exhibiting the lack of treatment strategies. To increase the chance of cure for locally advanced pancreatic cancer, extended resections such as vascular resections or the removal of spleen should be performed in patients. It has been suggested that preservation of spleen may contribute to increasing mortality rates in pancreatic cancer patients. Therefore, we planned to prove this phenomenon in mice model and sought to know the role of spleen-derived mesenchymal stem cells (spMSCs) in pancreatic cancer progression in this study. A number of inflammatory cytokines, chemokines, growth factors, and other factors in the tumors and their microenvironments can induce MSCs homing. After homing to tumor tissue, normal tissue-derived MSCs (NMSCs) are educated by tumor microenvironment and transform to tumor-derived MSCs (TMSCs). Interestingly, the function of NMSCs and TMSCs is quite different. NMSCs express a pro-inflammatory phenotype that is against tumor growth. On the contrary, TMSCs have an immunosuppressive capability that promotes tumor progression. We used an in vitro co-culture system and several functional assays to examine the characteristics of mouse spleen-derived NMSCs (mspNMSCs) and mouse spleen-derived TMSCs (mspTMSCs) on KrasG12D; Trp53R172H; Pdx1-Cre (KPC) pancreatic cancer cells. We observed that co-culture with mspMSCs (mouse spleen-derived MSCs) or mspTMSCs could enhance the migration and proliferation ability of KPC cells; however, co-culture with mspNMSCs could decrease this effect as compared to mspMSCs. In in vivo experiments, KPC cells were inoculated into the pancreas of C57B/L6 mice to form tumors, and then mspMSCs were intraperitoneally injected into mice to investigate the effect of mspNMSCs and mspTMSCs on pancreatic cancer progression. We found that tumor growth was enhanced by mspTMSCs and, to a lesser extent, mspNMSCs in the orthotopic pancreatic cancer mouse model. Previous studies have shown that NMSC can suppress tumor growth, but this effect was not observed in our results. Therefore, understanding the mechanism of mspMSC─mspTMSC transformation in the tumor progression may benefit in development of novel cancer treatment ideas and therapeutic strategies. Furthermore, tumor-associated fibroblasts (TAFs) have been reportedly shown to play an important role in tumor formation, growth and metastasis. We found that CXCL15 expression in KPC cells is increased after co-culture with mspMSCs. In addition, mspMSCs are observed to express TAF marker through the ERK signaling pathway after co-culture with KPC cells or treatment with CXCL15. Finally, we found that knockdown of CXCR2 in mspMSC could decrease TAF marker expression and repressed the migration and proliferation ability of KPC cells after co-culture. Taken together, these results revealed that KPC cells may secrete CXCL15 to induced mspMSCs transformation towards mspTMSCs which exhibit tumor-promoting ability by activating the ERK pathway. In this study, we have proved that spleen-derived mesenchymal stem cells are capable of promoting progression of pancreatic cancer in the orthotopc mouse model. Therefore, removal of spleen in the operation may benefit patients whose tumor cells grow in the tail of the pancreas or the tail and a part of the body of the pancreas.
論文目次 摘要 I
Abstract IV
Acknowledgement VI
Contents VIII
Abbreviation XI
I. Introduction 1
1. Pancreatic cancer 1
1.1 The statistics of pancreatic cancer 1
1.2 The surgical therapy of pancreatic cancer 1
2. Tumor stroma 2
2.1 The role of tumor stroma in cancer progression 2
2.2 Tumor/Cancer associated fibroblasts (TAFs/CAFs) 3
3. Mesenchymal stem cells (MSCs) 4
3.1 The discovery of mesenchymal stem cells 4
3.2 Current clinical applications of MSCs 5
3.3 Mesenchymal stem cells in the tumor microenvironment 6
4. Research motive 8
4.1 Significance 8
4.2 Specific Aims 9
II. Material and methods 10
Cell preparation 10
Cell culture 11
Flow cytometric and cell sorting 11
Cell differentiation 12
Oil Red O stain 12
Alizarin Red S stain 13
Alcian blue stain 13
RNA extraction 13
cDNA synthesis 14
Real-time quantitative PCR (qPCR) 15
Total Protein Extraction 15
Western Blotting (WB) 16
Migration assay 16
Co-culture system 17
MTT cell proliferation assay 17
Tumor Formation in C57BL/6 Mice and MSC injected 17
Non Invasion In Vivo Imaging System (IVIS) 18
Immunohistochemistry (IHC) 18
Immunofluorescence (IF) 19
Statistical analysis 20
III. Results 21
Characterizing cell surface markers and differentiation capacity of mouse spleen-derived mesenchymal stem cells (mspMSCs) 21
Activation of TLR3 and TLR4 on mspMSCs leads to different phenotypes 21
Alterations in the migration and proliferation ability of KPC cells after indirect co-culture with different phenotypes of mspMSCs 22
mspTMSCs promote tumor cell growth and reduce survival rate of pancreatic cancer mouse models 23
mspMSCs express tumor-associated fibroblast markers after co-culture with KPC cells 24
TSP-1High expression-mspMSCs have differentiation ability but the efficiency was reduced 25
ERK signaling pathway in TSP-1-expressing mspMSCs was activated by KPC cells 25
ERK signaling pathway was activated in TSP-1-expressing mspMSCs via CXCL15/CXCR2 axis 26
Targeting mspMSCs towards mspTMSCs represses tumor progression 27
IV. Discussion & Conclusion 28
V. References 33
VI. Figure 46
VII. Supplementary information 68
VIII. Applendix 75
I. List of primary antibodys 75
II. List of secondary antibodys 77
III. List of primers 78
IV. Curriculum vitae 79
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