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系統識別號 U0026-1308202012305000
論文名稱(中文) 早期前列腺癌誘發下尿路症狀病態生理機轉之動物模式研究
論文名稱(英文) Study on the pathophysiological mechanism responsible for lower urinary tract symptoms associated with early prostate cancer using an animal model
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所碩士在職專班
系所名稱(英) Institute of Clinical Medicine(on the job class)
學年度 108
學期 2
出版年 109
研究生(中文) 許齡內
研究生(英文) Lin-Nei Hsu
電子信箱 nei0217@gmail.com
學號 S97071048
學位類別 碩士
語文別 英文
論文頁數 45頁
口試委員 指導教授-蔡育賢
指導教授-蘇文彬
指導教授-唐一清
召集委員-莊燿吉
中文關鍵字 前列腺癌  下尿路症狀  膀胱  神經傳導物質  組織標記物 
英文關鍵字 Prostate cancer  lower urinary tract symptoms  urinary bladder  neurotransmitter  biomarker 
學科別分類
中文摘要 下尿路症狀(LUTS)是一種排尿症狀,包括頻尿、急尿、尿失禁和排尿困難。男性中,下尿路症狀通常與良性前列腺增生(BPH)相關。然而,前列腺癌(PCa)亦為引起下尿路症狀的原因之一。近年來,由於臨床前列腺篩檢之普及,百分之六十六的男性因下尿路症狀所擾而就醫時便會接受前列腺特異性抗原(PSA)篩查,其中一部分因而意外發現罹患前列腺癌。根據文獻回顧,超過三分之一的家庭醫學科醫師也已發現下尿路症狀與早期前列腺癌之間的關聯性。前列腺癌可能導致組織突變或神經傳遞物質之釋放而造成下尿路系統,如膀胱或尿道微環境之變異。迄今,前列腺癌誘發下尿路症狀的機轉目前仍不明確。此外,良性和惡性前列腺疾患之間的下尿路症狀表現是否存有差異仍然是臨床診治上一個重要的課題。若然,我們便可藉下尿路症狀特徵來提供臨床局限性前列腺癌檢測之參考。此次,我們藉由動物實驗模型來研究局限性前列腺癌與下尿路症狀間之病理生理機轉。
體內實驗部分,我們建立了人類前列腺癌(PCa)的小鼠原位模型。我們將人類前列腺癌細胞株 (DU145) 以前列腺原位注射的方式注射在NOD-SCID小鼠的前列腺旁葉。前列腺癌細胞原位注射後,以非侵入式3D全光譜活體分子影像系統 (IVIS) 依照每隔7天之射頻率來量化癌症的生長與檢測前列腺腫瘤生長反應。
此外,為比較尿路動力學參數、膀胱組織學和生物學指標,我們將分析三組實驗動物:1. 假手術但無前列腺原位注射組 (sham operation,偽對照組)、2.生理食鹽水前列腺原位注射組 (對照組) 及3. 前列腺癌細胞原位注射組 (實驗組),且實驗為期六週。六週的實驗期間,每週以膀胱壓力檢查來測量尿路動力學參數與評估其膀胱功能,藉由測量膀胱壁的厚度與量化膀胱的纖維化程度來評估膀胱壁的結構變化,更以免疫組織化學染色和免疫熒光共聚焦激光掃描顯微鏡來偵測膀胱組織中組織標記物 (包括毒蕈鹼M2受體、TRPV4、Bax與Caspase3) 在各組實驗動物間之變化。
研究結果證實,通過基於熒光素酶的IVIS可成功監測DU145細胞在小鼠前列腺中的生長,並量化前列腺癌原位注射後的腫瘤生長反應。此外,在前列腺原位注射後六週內,我們並未發現腫瘤所造成肉眼所見明顯的膀胱出口和尿道之解剖阻塞。另一方面,此實驗結果發現:前列腺癌的存在會引起膀胱組織學、生物標記物及膀胱功能參數的改變。膀胱壓力檢查顯示從第四週開始小鼠排尿頻率增加並出現排尿期之膀胱內壓上升,意即逼尿肌過度活動的特徵。前列腺癌原位注射後四週,膀胱組織學分析顯示逼尿肌增厚和膀胱壁纖維化增加之情況。免疫組織化學染色和免疫熒光共聚焦激光掃描顯微鏡檢查顯示在前列腺癌原位注射後之最初第一週或第二週,前列腺癌小鼠膀胱中之引發神經傳遞物質(如TRPV4與M2)上升與細胞凋亡因子(如caspase3與Bax)的表達量增加。
綜合本研究發現,早期前列腺癌在不造成明顯的膀胱出口阻塞之情況下,可導致膀胱組織病變或釋放神經傳遞物質與生物介質以干擾膀胱微環境,而造成膀胱組織學和功能的改變,以及下尿路症狀之表現。
英文摘要 Lower urinary tract symptoms (LUTS) are a constellation of urination symptoms including urine frequency, urgency, incontinence and voiding difficulty. In the male, LUTS are often associated with benign prostatic hyperplasia (BPH). However, LUTS are also caused by prostate cancer. Reports showed that more than one-third of general practitioners perceived a link between LUTS and early prostate cancer; 66% would carry out prostate specific antigen (PSA) screening in men with bothersome LUTS. Prostate cancer (PCa) can induce tissue changes and release of neurotransmitters or inflammatory mediators in the microenvironment of the lower urinary tract including the bladder and urethra. However, the biological mechanism of how a malignant process in the prostate leads to LUTS is still undefined. In addition, an important clinical question remains whether there is a difference in LUTS presentation between benign and malignant prostate disorders. If so, can we detect early PCa based on its LUTS characteristics? We postulate that the presence of PCa can induce tissue changes and release of biological mediators in the microenvironment of the urinary bladder thus leading to the development of LUTS. This study aimed to elucidate the functional, structural and biochemical alteration of the urinary bladder in a mouse model of localized PCa.
For in vivo experiments, we developed an orthotopic model of human PCa. An orthotopic PCa model in mice was established by injection of human DU145 cells into the prostate gland lateral lobe of NOD-SCID mice. Cancer growth was quantified by luciferase-based in vivo imaging system (IVIS) serially every seven days. Mice were divided into three experimental groups: 1. mice with sham operation but no injection; 2. mice with injection of sterile saline in the prostate; and 3. mice with injection of DU145 cell suspension in the prostate. Comparisons were made for urodynamic parameters, bladder histology and biological markers until the sixth week. Bladder wall structural changes were assessed by the bladder wall thickness and degree of fibrosis. Biomarker expressions in bladder tissue including muscarinic M2 receptor, TRPV4, Bax and caspase3 were evaluated by immunohistochemical staining and immunofluorescence confocal laser scanning microscopy.
DU145 cell growth in the prostate were successfully monitored by luciferase-based IVIS. after orthotopic injection. Using our injection technique, no anatomical obstruction of the bladder outlet and urethra were noted up to six weeks after injection. On the other hand, the presence of PCa induced changes in urinary bladder histology, biomarkers and urodyanmic parameters. Cystometry showed features of detrusor overactivity with increased voiding frequency and high amplitude voiding contractions from the fourth week onward. Histological analyses four weeks after DU145 injection demonstrated detrusor thickening and bladder wall fibrosis. Immunohistochemistry showed increased expressions of bladder M2, TRPV4, Bax and caspase3 in the PCa mice as early as in the first or second week.
In conclusion, our study has demonstrated that early PCa can induce bladder microenvironment changes involving neural receptors and biological mediators leading to histological and functional alterations even in the absence of overt anatomical obstruction.
論文目次 中文摘要 (Chinese abstract)…………………..……………………….i
Abstract……………………..……………………………………….....iii
Acknowledgement……………………………………………………....v
Contents………………………………………………………………...vi
List of figures…………………………………………………………...ix
Supplementary data.………………………………………………......xi
Abbreviation…………………………………………………………..xii
Main body……………………………………………………………….1
1. Introduction……………………………………………………………………….1
1.1 Early prostate cancer……………..………………………………………….1
1.2 Lower urinary tract symptoms……………………………………………….1
1.3 The relationship between lower urinary tract symptoms and early prostate cancer…………………………………………………………………………… 2
2.1 Rodent model for prostate cancer…………………………………………….3
2.2 In vivo bioluminescent imaging of prostate cancer using IVIS spectrum……4
3.1 Rodent model for urodynamic investigation…………………………………4
3.2 Cystometric parameters……………………………………………………...4
3.2.1 Pressure parameters……………………………………………….… 4
3.2.2 Volume parameters………………………………………………...…5
3.2.3 Bladder capacity (BC)………………………………………………. 5
3.2.4 Micturition frequency (MF)………………………………………… 5
2. Specific aim………………………………………………………………………..6
3. Material and Methods…………………………………………………………….7
3.1 Materials..……………………………………………………………………7
3.1.1 Animals………….……………………………………………………7
3.1.2 Human PCa cell line……..……………………………………………7
3.1.3 IVIS system…………………………………………………………..7
3.1.4 Cystometry…………………………………………………………...7
3.1.5 Chemicals and antibodies…………………………………………….8
3.1.6 Immunofluorescence confocal laser scanning microscope…………..8
3.2 Methods…………………………………….………………………………..8
3.2.1 Tumor xenograft animal model………………………………………8
3.2.2 IVIS system and quantification of the prostate cancer growth……….9
3.2.3 Scheme of cystometry study………………………………………….9
3.2.4 Scheme of bladder histology and biomarkers study………………….9
3.2.5 Bladder catheterization for cystometry study…………………….…10
3.2.6 Awake cystometry…………………………………………………...10
3.2.7 Histology and Immunohistochemistry study………………………..10
3.2.8 Immunofluorescence confocal laser scanning microscope………….11
3.2.9 Statistical analysis………………………………………….………..11
4. Results…………………………………………………………………………….12
4.1 Tumor growth in PCa mice…………………………………………………12
4.2 Urodynamic changes in PCa mice………………………………………….12
4.3.1 Bladder histology changes in PCa mice…………………………………..12
4.3.2 Bladder biomarker changes in PCa mice from immunohistochemistry study……………………………………………………………………………12
4.3.3 Bladder biomarker changes in PCa mice from immunofluorescence confocal laser scanning study…………………………………………………..13
5. Discussion………………………………………………………………………...14
5.1 The relationship between lower urinary tract symptoms and early prostate cancer………………………………………………………………………….. 14
5.2 Prostate cancer cell lines.…………….……………………………………..14
5.3 Rodent model for prostate cancer…………………………………………..14
5.4 The biological process of how prostate cancer induces LUTS -- the morphological changes of urinary bladder and changes of cystometric parameters in rodent model with prostate cancer…….……………………………………..15
5.5 The biological process of how prostate cancer induces LUTS -- the biomarkers of urinary bladder in rodent model with prostate cancer……….…..17
6. Conclusion………………………………………………………………………..19
7. References………………………………………………………………………..20
Figures…………………………………………………………………29
Supplementary data…………………………………………………..45

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