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系統識別號 U0026-3001201812403600
論文名稱(中文) 探討腦惡性神經膠質瘤發生及疾病進展之危險因子
論文名稱(英文) Identification of potential risk factors in the incidence and progression of malignant gliomas
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 106
學期 1
出版年 106
研究生(中文) 陳志偉
研究生(英文) Chih-Wei Chen
電子信箱 awei921@gmail.com
學號 S98001054
學位類別 博士
語文別 英文
論文頁數 90頁
口試委員 指導教授-沈延盛
指導教授-張文粲
召集委員-黃步敏
口試委員-鄭宏祺
口試委員-林志隆
口試委員-李孫榮
中文關鍵字 腦中風  惡性神經膠質細胞瘤  多形性神經膠質母細胞瘤  缺氧誘導因子  健保資料庫  多形性神經膠質母細胞瘤復發  纖維連接蛋白  上皮間質轉化  轉化生長因子  波形纖維蛋白 
英文關鍵字 Stroke  Malignant Glioma, Glioblastoma Multiforme (GBM)  Hypoxia-Inducible Factor 1α (HIF-1α)  Nationwide Population-Based Cohort  GBM Progression, Fibronectin (FN)  Vimentin (VIM)  Transforming Growth Factor-β (TGF-β)  Epithelial-Mesenchymal Transition (EMT) 
學科別分類
中文摘要 腦中風是國內疾病發生率高而且導致殘障風險高的疾病。惡性腦瘤也是一種快速導致殘疾且影響存活的重大疾病。腦中風和惡性腦瘤是兩項獨立事件,沒有什麼關聯性。之前研究認為惡性腦瘤壓迫血管循環可能導致腦中風的產生,但是腦中風會導致惡性腦瘤的生成嗎?在2015年美國腦中風醫學會有專家提出報告顯示腦中風的存活者中有較高比率惡性腫瘤的發生。回顧奇美醫院的資料,兩年內有33位惡性腦瘤病患接受手術治療,其中第四級有21位、第三級有8位、第二級有1位、第一級3位。在惡性腦瘤診斷之前就有腦中風病史的有2位都是第四級惡性腦瘤。由此資料顯示腦中風患者導致第四級惡性腦瘤比率偏高。本研究假設腦中風與惡性腦瘤的發生有相關性,為了證明此論點,本研究利用台灣健保資料庫作為探討腦中風與惡性腦瘤發生之相關性。此外腦中風會導致缺氧誘導因子hypoxia-inducible factor的產生,而此因子也會與惡性腦瘤的生成有相關。本研究也針對這些病患手術後的病理檢體進行缺氧誘導因子免疫組織化學染色去探討可能造成惡性腦瘤的病理機轉。本研究發現腦中風病人發生惡性腦瘤是未有腦中風病人的3.09倍,而且腦中風後產生缺氧誘導因子可能與導致惡性腦瘤的生成有相關性。
此外,腦部多形性神經膠質母細胞瘤患者接受開顱手術切除腦瘤合併術後化學治療及放射線治療後復發是無法避免的命運,很多病患一旦復發就很快惡化至死亡。最近研究顯示有一種纖維連接蛋白fibronectin與腫瘤惡性程度及復發有相關性。本研究假設惡性神經膠質細胞瘤復發與纖維連接蛋白有相關性,為了證明此論點,本研究使用醫學大數據資料庫分析纖維連接蛋白與惡性神經膠質細胞瘤之相關性。此外本研究也針對惡性神經膠質細胞瘤病患手術後的病理檢體進行免疫組織化學染色去探討可能造成的病理機轉。本研究在奇美醫院八年內追蹤了151位惡性神經膠質細胞瘤接受開顱切除腫瘤合併術後化學治療及放射線治療病人。有11位病人因為腦瘤復發至少接受二次以上手術切除腫瘤。本研究採取這些腫瘤檢體來做多種免疫組織化學染色包括纖維連接蛋白,控制上皮間質轉化epithelial-mesenchymal transition的轉化生長因子transforming growth factor-β及波形纖維蛋白vimentin與惡性神經膠質細胞瘤不同類型復發的關係。本研究發現纖維連接蛋白與腫瘤的復發有高度相關性,而且可能是經由轉化生長因子誘發上皮間質轉化的路徑。因此纖維連接蛋白可視為惡性神經膠質細胞瘤復發的指標。
英文摘要 Stroke and brain cancer are two distinct diseases. However, the relationship between both diseases has rarely been examined. This study investigated the longitudinal risk for developing brain cancer in ischemic stroke patients. To study this, the study first reviewed the malignant gliomas previously with or without stroke using brain magnetic resonance imaging (MRI) images and the past histories. Two glioblastoma multiforme (GBM) patients had the previous ischemic stroke history. Particularly, both GBM specimens displayed strong hypoxia-inducible factor 1α (HIF-1α) expression in immunohistochemical (IHC) staining. To elucidate the significance of this relationship, the study used a nationwide population-based cohort in Taiwan to investigate the risk for the incidence of brain cancer in patients previously with or without ischemic stroke. The incidence of all tumors in the stroke group was lower than that in the control group with an adjusted hazard ratio (HR) of 0.79 (95% confidence interval [CI]: 0.74-0.84) in both gender and age older than 60 years. But the ischemic stroke patients had higher risk of developing only brain cancer with an adjusted HR of 3.09 (95% CI: 1.80-5.30), and otherwise had lower risk of developing head and neck, digestive, respiratory, bone and skin, as well as other tumors, all with p<0.05. After stratification by gender and age, the female and aged 40-60 year old ischemic stroke patients had higher risk of developing brain cancer with an adjusted HR of 7.41 (95% CI: 3.30-16.64) and 16.34 (95% CI: 4.45-62.13), respectively, both with p<0.05. Patients with ischemic stroke, in particular female and age 40-60 years old, have an increased risk for developing brain cancer. Another focus is about GBM progression. Despite current standard therapy including microsurgical tumor resection and adjuvant radio- and chemotherapy, it has a poor prognosis mainly due to its high propensity for tumor recurrence. This study aimed to identify a protein biomarker that may discriminate GBM progressions. In an attempt to screen proteins that display low or no expression in low-grade astrocytoma but elevated level in GBM, a glycoprotein fibronectin (FN) was especially examined according to the analyses of the Human Protein Atlas database mining. Web-based open megadata minings revealed that FN was mainly mutated in the cBio Cancer Genomic Portal database but dominantly overexpressed in the ONCOMINE database in distinct tumor types. In addition, numerous different cancer patients with high FN expression were correlated with poor prognosis in the PrognoScan database, indicating that FN may involve in tumor malignancy. To investigate the correlation between FN level and cancer progression, tumor specimens from 11 malignant glioma cases with recurrences that received at least two times surgeries were enrolled and examined. The IHC staining of FN showed that the FN expression was indeed correlated with the distinct progressions of malignant gliomas. In addition, the expression of vimentin (VIM), a mesenchymal protein that is strongly expressed in malignant cancers, was similar to the pattern of FN. Moreover, the level of epithelial-mesenchymal transition (EMT) inducer transforming growth factor-β (TGF-β) was recapitulated with the expression pattern of both FN and VIM. Together, this study identifies a protein biomarker FN that can be used to distinguish GBM from low-grade astrocytoma; in addition, its expression may have functional relevance to malignant glioma progressions via TGF-β induced EMT pathway.
論文目次 Contents:
中文摘要:-------------------------------------------------------------------------------I
英文摘要:------------------------------------------------------------------------------III
Acknowledgement:-------------------------------------------------------------------V
Abbreviations:----------------------------------------------------------------------XII
表目錄 Legends of Tables:------------------------------------------------------XIV
圖目錄 Legends of Figures:------------------------------------------------------XV
Chapter 1: Background--------------------------------------------------------------1
1.1 The risk factors of malignant gliomas-----------------------------------------1
1.2 The risk of stroke is higher in patients with malignant gliomas------------2
1.3 Stroke induces hypoxia inducible factor-1α (HIF-1α) activation----------2
1.4 HIF-1α induces malignant glioma development-----------------------------3
1.5 Introduction of glioblastoma multiforme (GBM) progression after standard treatment----------------------------------------------------------------4
1.6 The relationship between epithelial-mesenchymal transition (EMT) and GBM progression-----------------------------------------------------------------6

Chapter 2: Aims and design of the study-----------------------------------------8
Topic A: Is ischemic stroke in relation with malignant glioma development?
Topic B: Is glycoprotein fibronectin involved in GBM progression?-----------8

Chapter 3: Increased risk of brain cancer incidence in ischemic stroke patients: A clinical case series, population-based and longitudinal follow-up study-----------------------------------------------------------------------10
3.1 Introduction:-----------------------------------------------------------------------10
3.1.1 Introduction of brain cancer-------------------------------------------------10
3.1.2 The risk factors of brain cancer---------------------------------------------10
3.1.3 Introduction of ischemic stroke---------------------------------------------10
3.1.4 The relationship between brain cancer and ischemic stroke------------11
3.1.5 Specific aims and study designs--------------------------------------------12
3.2 Materials and methods:----------------------------------------------------------12
3.2.1 Patients and specimens inclusion and exclusion criteria----------------12
3.2.2 Immunohistochemical (IHC) staining of HIF-1α------------------------13
3.2.3 Data sources from National Health Insurance Research Database (NHIRD) of Taiwan---------------------------------------------------------14
3.2.4 The inclusion and exclusion criteria in NHIRD study-------------------14
3.2.5 Statistical analyses------------------------------------------------------------15
3.3 Results:-----------------------------------------------------------------------------16
3.3.1 The higher possibility of ischemic stroke developing malignant glioma in clinical cases---------------------------------------------------------------16
3.3.2 HIF-1α plays an important role in ischemic stroke inducing the development of GBM-------------------------------------------------------17
3.3.3 Increased the incidence of brain cancer is associated with ischemic stroke in NHIRD study------------------------------------------------------17
3.4 Discussion:------------------------------------------------------------------------19
3.4.1 The limitation of the epidemiologic study about the risk factors of brain cancer-------------------------------------------------------------------19
3.4.2 The first nationwide population-based cohort study to investigate the brain cancer formation among the ischemic stroke patients-----------19
3.4.3 The ischemic stroke patients had higher risk of developing brain cancer compared with other cancers-----------------------------------------------20
3.4.4 The age 40-60 years old ischemic stroke patients have highest risk of developing brain cancers----------------------------------------------------20
3.4.5 The female ischemic stroke patients have higher risk of developing brain cancers------------------------------------------------------------------21
3.4.6 Reactive astrocytes may play a role in the migration of malignant glioma cells-------------------------------------------------------------------22
3.4.7 The mechanisms for developing brain cancer in ischemic stroke patients may arise from the overproduction of HIF-1α by ischemic brain tissue--------------------------------------------------------------------22
3.4.8 The limitations of the study-------------------------------------------------24
3.4.9 Conclusions and perspectives-----------------------------------------------24

Chapter 4: The fibronectin expression is correlated with distinct progressions of malignant gliomas via transforming growth factor-β pathway--------------------------------------------------------------------------------26
4.1 Introduction:-----------------------------------------------------------------------26
4.1.1 Introduction of GBM with current standard treatment------------------26
4.1.2 Introduction of GBM recurrence/progression----------------------------26
4.1.3 The mechanism of fibronectin (FN) in tumor invasion and metastasis27
4.1.4 The mechanism of EMT marker, vimentin (VIM) in tumor recurrence
4.1.5 Transforming growth factor-β (TGF-β) is a key effector of EMT in tumor progression and metastasis-----------------------------------------28
4.1.6 FN enhances the effect of TGF-β to facilitate tumorigenesis via EMT pathway-----------------------------------------------------------------------29
4.1.7 Specific aims and study designs--------------------------------------------30
4.2 Materials and methods:----------------------------------------------------------31
4.2.1 Identification the tumorigenesis of FN by using web-based open megadata minings------------------------------------------------------------31
4.2.2 Patients and specimens inclusion and exclusion criteria----------------31
4.2.3 IHC staining of FN, VIM, TGF-β, GFAP and Ki-67---------------------32
4.3 Results:-----------------------------------------------------------------------------32
4.3.1 FN may play a role in the progression of cancers according to the web-based open megadata minings----------------------------------------32
4.3.2 Clinical recruitment of malignant glioma specimens: five progression subtypes-----------------------------------------------------------------------34
4.3.3 FN, VIM, and TGF-β expression levels are increased in a case of low-grade astrocytoma with GBM transformation----------------------35
4.3.4 FN, VIM, and TGF-β expression levels are increased in a case of GBM with local recurrence--------------------------------------------------------36
4.3.5 FN, VIM, and TGF-β expression levels are increased in a case of GBM with local recurrence and remote brain metastasis-------------------- 37
4.3.6 FN, VIM, and TGF-β expression levels are increased in a case of GBM with spinal metastasis------------------------------------------------------39
4.3.7 FN, VIM, and TGF-β expression levels are initially increased in a case of GBM with local recurrence and then decreased with low-grade astrocytoma progression----------------------------------------------------40
4.4 Discussion:------------------------------------------------------------------------42
4.4.1 The prevalence of clinical GBM progression patterns in the study is consistent with the published reports--------------------------------------42
4.4.2 The study demonstrates the expression of FN is activated during GBM progression via TGF-β inducing EMT pathway-------------------------43
4.4.3 The previous report revealing FN, VIM and TGF-β unchanged in 17 matched of primary and recurrent human glioblastomas---------------45
4.4.4 The previous report revealing FN and VIM elevated in the recurrent malignant glioma samples--------------------------------------------------46
4.4.5 Conclusions and perspectives-----------------------------------------------46

References:----------------------------------------------------------------------------48
Tables:----------------------------------------------------------------------------------64
Figures:--------------------------------------------------------------------------------71
Curriculum Vitae:-------------------------------------------------------------------88
Published Papers (During Ph.D Program):------------------------------------89
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