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研究生:吳佩芳
研究生(外文):Pei-Fang Wu
論文名稱:腦轉移腫瘤之研究─探尋潛在之生物標記與治療標的
論文名稱(外文):Study of brain metastasis—Exploration of potential biomarkers and therapeutic targets
指導教授:鄭安理鄭安理引用關係吳瑞美
指導教授(外文):Ann-Lii Cheng
口試委員:楊志新蘇五洲莊雙恩
口試日期:2014-05-06
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:111
中文關鍵詞:腦轉移腫瘤生物標記預後
外文關鍵詞:brain metastasisbiomarkersprognosis
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腦轉移腫瘤是一個重要但尚未充分研究的領域。隨著診斷技術和治療方式的進步,患者的存活時間延長,腦部轉移的發生率亦有逐年增加之趨勢。全腦放射線治療是目前最主要的治療方式,但是累積輻射暴露所可能造成的神經毒性是其主要限制。隨著中樞神經系統以外的癌症獲得有效控制,全腦放射線治療已不敷需求,腦部轉移已成為當前癌症治療與研究亟待突破的領域。
目前的主流觀念認為血腦屏障限制了抗癌藥物穿透到中樞神經系統,是腦轉移對藥物治療成效不彰的唯一阻礙,並且是在全身性疾病獲得有效控制的狀況下發生腦轉移的最重要原因。然而,破壞血腦屏障的治療方式並無法改善病人的預後。越來越多的證據也顯示,原發腫瘤的分子特徵並無法完全反映轉移腫瘤的情況,只根據原發腫瘤之分子標記所做的治療決定是不夠的。因此,我們提出的假說是:能夠定殖(colonize)、並在大腦中茁壯成長的轉移腫瘤具有獨特的分子特徵,透過與周遭微環境的相互作用篩選出適合生長於此處之腫瘤細胞。原發腫瘤和不同器官部位的轉移腫瘤之間對於治療反應的差異是由於腫瘤與基質細胞(stromal cell)之間交互反應、導致分子特徵的差異。深入了解腦轉移的分子特徵及其對於預後之影響,有助於此一致命性疾病發展新的治療標的。
在這篇論文中,我們的研究將從比較一個已知與化療敏感性相關的生物標記在原發腫瘤與腦轉移腫瘤的表現開始進行。O6-Methylguanine-DNA methyltransferase(MGMT)是修復致突變DNA鹼基的關鍵,並與腫瘤對Alkylating agent的反應有相關性。Temozolomide是一個已知能穿透BBB的Alkylating agent,許多研究對於此一藥物是否能用於治療腦轉移腫瘤有極大興趣,因此我們利用86例肺癌腦部轉移的檢體,研究MGMT免疫組織染色的表現(immunohistochemistry, IHC)與啟動子的甲基化狀態(promoter methylation)以及其預後關聯性。我們發現MGMT啟動子甲基化與MGMT蛋白質表現量降低呈高度相關。我們的結論是:與原發肺癌相比,MGMT的表現量在腦轉移較高(83% vs 50%,P=0.004)。MGMT在腦轉移腫瘤的表現量與存活時間呈顯著正相關(16.5個月 vs 3.5個月,P<0.001)。
為了進一步探索未知的腦轉移分子特徵,我們建立了腦轉移的動物模式。透過反覆進行將腫瘤細胞從心臟注射至小鼠體內和體外細胞原代培養的篩選過程,分離出具高度能力轉移至腦部的腫瘤細胞(brain-tropic cancer cells, PC9-Br),並利用bioluminescence影像檢查證實。我們藉由比較它們與原始腫瘤細胞(parental lung cancer cells, PC9)基因表現的差異和Ingenuity Pathway Analysis的分析結果,首先選擇IGF pathway進行進一步研究,並利用Western blot和RT–PCR驗證IGF2和activated IGF1R(pIGF1R)在PC9-Br的表現較強。
依據以上實驗的結果,我們接著探討activated IGF1R (pIGF1R)在肺腺癌腦轉移的表現與臨床意義。利用1998年1月至2009年12月間於台大醫院可以取得的86例檢體,進行pIGF1R的免疫組織染色與表皮生長因子受體酪氨酸激&;#37238;(EGFR tyrosine kinase domain)的基因型分析。研究結果發現,腦轉移瘤的細胞膜/細胞質表現較強的pIGF1R者之預後較差(存活時間中位數:10.8 vs 27.8個月,P=0.003),在EGFR突變的個案,這種相關性更為顯著。在多變項分析,調整其他潛在的預後因素,包括Graded Prognostic Assessment Score、腦轉移腫瘤的數目、是否有顱外轉移、EGFR的基因型和使用EGFR tyrosine kinase inhibitor (TKI)治療等因素之影響,pIGF1R依然是統計上有意義之預後不佳因子。
此外,我們研究26例原發肺癌-腦轉移配對檢體之IGF路徑的狀態,發現腦轉移之pIGF1R表現較強。為了進一步探討IGF pathway在腦轉移治療的角色,我們進行體外藥物敏感試驗,發現PC9-Br對於EGFR TKI治療比PC9更具抗藥性。抑制IGF2表現逆轉抗藥性,增加IGF2表現則增強抗藥性。同時,我們也發現,腫瘤細胞接觸中樞神經系統的基質細胞(以星狀細胞為代表)時將過度表達IGF2。我們也觀察到,腫瘤細胞和星狀細胞之間的相互作用會增強細胞生長能力和抗藥性,因此,我們將進一步確認IGF信號是否媒介它們之間的相互作用,並可能做為潛在的治療標的。
綜言之,我們透過深入研究腦轉移的分子特徵及其對於預後之影響,期望進一步探尋潛在的生物標記以及新穎的治療標的。

口試委員會審定書……………………………………………………i
誌謝……………………………………………………………………ii
中文摘要………………………………………………………………iii
英文摘要………………………………………………………………vi
圖目錄…………………………………………………………………xi
表目錄…………………………………………………………………xiii
博士論文內容
第一章 緒論 1
第二章 研究方法與材料 22
第三章 結果 27
第四章 討論 31
第五章 展望 36
第六章 論文英文簡述 38
第七章 參考文獻 43
第八章 圖表 76
第九章 附錄:修業期間發表之論文 110

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