請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72816
標題: | 肺癌起始機制之監測及組織學和生物標誌表達的預後相關性 Surveillance for the mechanism of lung cancer initiation and prognostic relevance of histologic and biomarkers expression |
作者: | Ching-Fu Weng 翁菁甫 |
指導教授: | 林泰元(Thai-Yen Ling) |
關鍵字: | 肺癌,致癌病毒,流感病毒,新生抗原,生物標誌,溶瘤病毒,組織亞型, Lung cancer,adenocarcinoma,oncovirus,influenza virus,biomarker,neoantigen,histology subtype, |
出版年 : | 2021 |
學位: | 博士 |
摘要: | 肺癌目前為全球最常被診斷且死亡率最高的癌症。癌症的起因牽涉相當複雜的機轉。過去研究顯示,致癌病毒(Oncovirus)可導致發炎反應相關的訊息傳導路徑及細胞激素分泌產生,因此被認為與腫瘤發生(Tumorigenesis)有關。此外腫瘤的異質性(heterogeneity)於細胞增生(hyperplasia)前即已被偵測到,至於完整的腫瘤發生病生理機轉至今仍尚待釐清。臨床上目前僅能知道,早期診斷合併早期介入治療,為最有效且可降低肺癌死亡率的最好方法。因此肺癌的早期偵測且與預後相關之因子是值得發展的。近半個世紀前的動物實驗研究顯示,特定呼吸道致癌病毒可導致肺腫瘤產生,例如流感病毒感染。然而直到現今,仍未有足夠臨床證據可支持這項假說。為了探討流感病毒感染與日後得到肺癌診斷風險的關聯性,本研究之一,使用台灣癌登資料庫(Taiwan Cancer Registry Database, TCRD)及全民健康保險資料庫(Taiwan’s National Health Insurance Research Database, NHIRD)進行了回溯性分析。收錄的病患皆為年齡大於40 歲。結果顯示,流感病毒感染相較於未感染者,增加了1.09 倍風險得到肺癌,並且與暴露次數呈正相關。近年來關於腫瘤治療的另一重要概念為新生抗原(Neoantigen)。本研究在早期肺腺癌細胞表面上,試圖尋找可能的新生抗原。我們發現, 與腺病毒有關之特定細胞膜載體 (adenovirus-based vectors),除了可能與腫瘤發生有關外,也可作為肺腺癌存活預後之預測因子。這兩個生物標誌(biomarkers) 分別為Coxsackievirus/ adenovirusreceptors (CARs) 及desmoglein-2 (DSG2) 。使用基因功能分類(Gene ontology enrichment analysis)及癌症基因體圖譜(Cancer Genome Atlas)分析後,再將臨床肺癌組織晶片(Tissue microarray, TMA)與免疫組織染色(Immunohistochemical assay,IHC)結果進行大數據分析比對發現,CAR 及 DSG2 基因在早期肺腺癌即共同高度表現,且高表現者預後較差。而肺癌組織晶片進行免疫組織染色後也顯示,CAR及DSG2 在肺腺癌組織中表現量明顯與正常組織不同。CAR 及DSG2,或兩者同時染色強度表現量高者預後較差。除了生物標誌外,組織學亞型過去也被研究與肺癌預後有關,但大多數研究皆為早期肺腺癌患者。本研究根據新分類系統(New International Association for the Study of Lung Cancer Pathology Committee Grading System)針對晚期肺癌病患分析,結果顯示分化不良(poorly differentiated)組別病患無疾病存活期(Progression free survival)預後較差,同樣的結果在顯示在EGFR野生 型接受化學治療的病患。有EGFR 突變之病患並無顯示存活預後統計上差異。因此分化不良相較於中等分化(moderately differentiated) 甚至良好分化(well differentiated)組別,預後是最差的。最後我們強調,於本研究中所有得到的結果,未來在細胞實驗(in vitro)或動物實驗(in vivo)皆須再被驗證。首先要建立流感病毒感染與肺腫瘤產生之明確病生理機轉。另外CAR/DSG2 共同高度表現與臨床存活預後不良有關,未來是否可作為溶瘤病毒(Oncolytic virus)之載體提供基因治療之標的,抑或可當新生抗原運用於免疫治療,也需更多研究釐清。最後則是關於腫瘤的高度異質性在疾病早期即已表現,疾病晚期往往因腫瘤異質性過於複雜,造成臨床治療困難度大幅增加。我們在本研究中建議,晚期肺腺癌病患若被歸類為分化不良EGFR 野生型且接受化學治療者,可考慮合併多種藥物治療,或選擇其他治療方法,以達到更好治療效果,延長病患存活時間。期待未來各項新的研究成果可陸續被驗證,除有助於肺癌早期偵測及診斷外,也可提供更多治療策略並降低死亡率。 Lung cancer is a leading cause of life-threatening malignancy worldwide. Cancer initiation involved multiple complex mechanisms. Oncovirus activating associated inflammatory signaling pathway and cytokine had been proposed as one of link to tumorigenesis. In addition, tumor heterogeneity could be detected in the premalignant stage although the pathogenesis remained unclear. Nevertheless, early diagnosis with prompt intervention is crucial to decrease lung-cancer-associated mortality, which would make a tool that could detect, early on, prognostic predictions very valuable. Previous animal studies have shown that certain respiratory oncoviruses can lead to tumorigenesis, especially influenza virus. However, no clinical studies other than animal studies have been conducted to test this hypothesis. To investigate the association between influenza and the risk of lung cancer using the Taiwan Cancer Registry Database (TCRD) and Taiwan’s National Health Insurance Research Database (NHIRD), we conducted a cohort study cohort consisting of patients aged 40 years or above. Influenza was associated with a 1.09- fold increased risk of lung cancer. Exposure to influenza was associated with an increased risk of lung cancer and the risk increased with cumulative exposure to influenza. In addition, cancer neoantigens presenting on the surface of individual cancer cells are fully cancer-specific and important targets for checkpoint blockade therapy. We thus attempt to discover novel neoantigens. There are two adenovirus-based vectors in the cell membrane in our study were proposed as in association with lung epithelial cell tumorigenesis and exert markers in predicting survival outcome in lung adenocarcinoma (LUAD). The two biomarkers were Coxsackievirus/adenovirus receptors (CARs) and desmoglein-2 (DSG2). After gene ontology enrichment analysis and survival analysis extracted from The Cancer Genome Atlas (TCGA), we then investigate a tissue microarray (TMA) and staining by immunohistochemical (IHC) assay then calculating by computer counting software to determine the H-score of the immune intensity. CAR and DSG2 genes are highly co-expressed in early stage LUAD and associated with significantly poorer survival. TMA also showed that CAR/DSG2 expressions were altered in lung cancer tissue. CAR, DSG2, or a co-expression of CAR/DSG2 was associated with poorer overall survival. The co-expression biomarkers predicted a worse overall survival in LUAD. Other than biomarkers, histologic subtypes also participate in prognostic relevance in lung cancer and were in our study interest. Despite important role of histologic classification in prediction outcome in early stage LUAD. We apply new International Association for the Study of Lung Cancer (IASLC) Pathology Committee Grading System among advanced stage (stages IIIA, IIIB and IV) LUAD patients, which indicate that the poorly differentiated group had a poorer prognosis in progression free survival (PFS), as did patients with wild-type EGFR who were treated with chemotherapy. There was no survival difference found among EGFR mutation patients. Patients with poorly differentiated LUAD likewise had worse survival, especially compared to those with moderately differentiated LUAD. Our findings highlight that more in vitro and in vivo investigations are warranted to validate and to better understand the mechanisms of potential association between influenza virus infection and lung cancer. Further researches are also necessary to confirm the clinical usage concept of tumor gene delivery therapy based on the concept that CAR/DSG2 co-expression in predicting prognosis and postulated to be efficiency of gene therapy using oncolytic adenoviruses for treating lung cancer, or as a neoantigen for immunotherapy. Finally, regardless of tumor heterogeneity in any stage, we emphasize that the therapeutic regimen should be adjusted for wild-type EGFR patients with poorly differentiated LUAD treated with chemotherapy for better outcomes according to new grading system classification. We look forward upcoming verified investigation results both facilitate earlier diagnosis of lung cancer and new treatment strategies for decreasing cancer related mortality. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72816 |
DOI: | 10.6342/NTU202100015 |
全文授權: | 有償授權 |
顯示於系所單位: | 藥理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
U0001-0501202111430200.pdf 目前未授權公開取用 | 4.84 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。